MRI EVALUATION OF WHITE MATTER DISEASES

DR SINDU P GOWDAR

MODERATOR DR JEEVIKAMU

NORMAL MYELINATION

After normal myelination in utero myelination of the neonatal brain is far from complete

The first myelination is seen as early as the 16th week of gestation but only really takes off from the

24th week1

It does not reach maturity until 2 years or so It correlates very closely to developmental milestones 3

The progression of myelination is predictable and abides by a few simple general rules myelination progresses

from

1 central to peripheral

2 caudal to rostral

3 dorsal to ventral

4 sensory then motor

NORMAL MYELINATION

After normal myelination in utero myelination of the neonatal brain is far from complete

The first myelination is seen as early as the 16th week of gestation but only really takes off from the

24th week1

It does not reach maturity until 2 years or so It correlates very closely to developmental milestones 3

The progression of myelination is predictable and abides by a few simple general rules myelination progresses

from

1 central to peripheral

2 caudal to rostral

3 dorsal to ventral

4 sensory then motor

Myelination pattern on MR imagingMyelination of the brain during infancy progresses in an orderly and predictable fashion

At birth only certain structures are myelinated

dorsal brainstem

ventrolateral thalamus

lentiform nuclei

central corticospinal tracts

posterior portion of posterior limb of internal capsule

Subsequently different parts become myelinated the first change is increase in T1 signal and later decrease in T2

2 - 3 months anterior limb of internal capsule becomes T1 bright

3 months cerebellar white matter tracts becomes T1 bright

3 - 6 months splenium of corpus callosum becomes T2 dark

6 months genu of corpus callosum becomes T1 bright

8 months subcortical white matter becomes T1 bright

8 months genu of corpus callosum becomes T2 dark

11 months anterior limb of internal capsule becomes T2 dark

1 year 2 months occipital white matter becomes T2 dark

1 year 4 months frontal white matter becomes T2 dark

1 12 years majority of white matter becomes T2 dark (except terminal myelination zones adjacent to frontal

horns and periatrial regions)

2 years almost all of white matter becomes T2 dark

AXIAL T1 MR 6 MONTHS

AXIAL T1 MR 9 MONTHS

AXIAL T1 MR 12 MONTHS

AXIAL T1 MR 18 MONTHS

bull A wide number of diseases may affect brain white matter This presentation will attempt to address this wide topic by dividing brain white matter lesions into three categories

bull 1 Demyelinating Diseases

bull 2 Non-demyelinating Diseases of Adults

bull 3 Dysmyelinating Disorders of Childhood

Demyelinating Diseases

Due to loss of myelin in previously normal white matter regions

Multiple sclerosis (MS) is a relatively common acquired chronic relapsing demyelinating disease involving the central

nervous system It is by definition disseminated not only in space (ie multiple lesions) but also in time (ie lesions are of

different age)

A number of clinical variants are recognised each with specific imaging findings and clinical presentation They include

bull classic multiple scleroris (Charcot type)

bull tumefactive multiple sclerosis

bull acute malignant Marburg type

bull Schilder type (diffuse cerebral sclerosis)

bull Balo concentric sclerosis (BCS)

Epidemiology

Presentation is usually between adolescence and the sixth decade with a peak at approximately 35 years of age 12 There is a

strong well recognised female predilection with a FM ratio of 2-31

Multiple sclerosis has a fascinating geographic distribution it is rarely found in equatorial regions with incidence gradually

increasing with distance from the equator

AXIAL T1 MR 6 MONTHS

AXIAL T1 MR 9 MONTHS

AXIAL T1 MR 12 MONTHS

AXIAL T1 MR 18 MONTHS

bull A wide number of diseases may affect brain white matter This presentation will attempt to address this wide topic by dividing brain white matter lesions into three categories

bull 1 Demyelinating Diseases

bull 2 Non-demyelinating Diseases of Adults

bull 3 Dysmyelinating Disorders of Childhood

Demyelinating Diseases

Due to loss of myelin in previously normal white matter regions

Multiple sclerosis (MS) is a relatively common acquired chronic relapsing demyelinating disease involving the central

nervous system It is by definition disseminated not only in space (ie multiple lesions) but also in time (ie lesions are of

different age)

A number of clinical variants are recognised each with specific imaging findings and clinical presentation They include

bull classic multiple scleroris (Charcot type)

bull tumefactive multiple sclerosis

bull acute malignant Marburg type

bull Schilder type (diffuse cerebral sclerosis)

bull Balo concentric sclerosis (BCS)

Epidemiology

Presentation is usually between adolescence and the sixth decade with a peak at approximately 35 years of age 12 There is a

strong well recognised female predilection with a FM ratio of 2-31

Multiple sclerosis has a fascinating geographic distribution it is rarely found in equatorial regions with incidence gradually

increasing with distance from the equator

AXIAL T1 MR 12 MONTHS

AXIAL T1 MR 18 MONTHS

bull A wide number of diseases may affect brain white matter This presentation will attempt to address this wide topic by dividing brain white matter lesions into three categories

bull 1 Demyelinating Diseases

bull 2 Non-demyelinating Diseases of Adults

bull 3 Dysmyelinating Disorders of Childhood

Demyelinating Diseases

Due to loss of myelin in previously normal white matter regions

Multiple sclerosis (MS) is a relatively common acquired chronic relapsing demyelinating disease involving the central

nervous system It is by definition disseminated not only in space (ie multiple lesions) but also in time (ie lesions are of

different age)

A number of clinical variants are recognised each with specific imaging findings and clinical presentation They include

bull classic multiple scleroris (Charcot type)

bull tumefactive multiple sclerosis

bull acute malignant Marburg type

bull Schilder type (diffuse cerebral sclerosis)

bull Balo concentric sclerosis (BCS)

Epidemiology

Presentation is usually between adolescence and the sixth decade with a peak at approximately 35 years of age 12 There is a

strong well recognised female predilection with a FM ratio of 2-31

Multiple sclerosis has a fascinating geographic distribution it is rarely found in equatorial regions with incidence gradually

increasing with distance from the equator

bull A wide number of diseases may affect brain white matter This presentation will attempt to address this wide topic by dividing brain white matter lesions into three categories

bull 1 Demyelinating Diseases

bull 2 Non-demyelinating Diseases of Adults

bull 3 Dysmyelinating Disorders of Childhood

Demyelinating Diseases

Due to loss of myelin in previously normal white matter regions

Multiple sclerosis (MS) is a relatively common acquired chronic relapsing demyelinating disease involving the central

nervous system It is by definition disseminated not only in space (ie multiple lesions) but also in time (ie lesions are of

different age)

A number of clinical variants are recognised each with specific imaging findings and clinical presentation They include

bull classic multiple scleroris (Charcot type)

bull tumefactive multiple sclerosis

bull acute malignant Marburg type

bull Schilder type (diffuse cerebral sclerosis)

bull Balo concentric sclerosis (BCS)

Epidemiology

Presentation is usually between adolescence and the sixth decade with a peak at approximately 35 years of age 12 There is a

strong well recognised female predilection with a FM ratio of 2-31

Multiple sclerosis has a fascinating geographic distribution it is rarely found in equatorial regions with incidence gradually

increasing with distance from the equator

Demyelinating Diseases

Due to loss of myelin in previously normal white matter regions

Multiple sclerosis (MS) is a relatively common acquired chronic relapsing demyelinating disease involving the central

nervous system It is by definition disseminated not only in space (ie multiple lesions) but also in time (ie lesions are of

different age)

A number of clinical variants are recognised each with specific imaging findings and clinical presentation They include

bull classic multiple scleroris (Charcot type)

bull tumefactive multiple sclerosis

bull acute malignant Marburg type

bull Schilder type (diffuse cerebral sclerosis)

bull Balo concentric sclerosis (BCS)

Epidemiology

Presentation is usually between adolescence and the sixth decade with a peak at approximately 35 years of age 12 There is a

strong well recognised female predilection with a FM ratio of 2-31

Multiple sclerosis has a fascinating geographic distribution it is rarely found in equatorial regions with incidence gradually

increasing with distance from the equator

Clinical presentation is both highly variable acutely as a result of varying plaque location as well as over time with a

number of patterns of longitudinal disease being described 11-12

1relapsingndashremitting

1 most common (70 of cases)

2 patients exhibit periodic symptoms with complete recovery (early on)

2secondary progressive

1 approximately 85 of patients with relapsing-remitting MS eventually enter a secondarily progressive phase

3primary progressive

1 uncommon (10 of cases)

2 patients do not have remissions with neurological deterioration being relentless

4progressive with relapses

5benign multiple sclerosis

1 15-50 of cases

2 defined as patients who remain functionally active for over 15 years

As is evident from this list there is overlap and in some cases patients can drift from one pattern to another

Symptoms may be sensory or motor or mixed including cranial nerve involvement egtrigeminal neuralgia or optic

neuritis

Pathology

The exact aetiology is poorly known although it is believed to have both genetic and acquired contributory components

MS is believed to result from a cellular mediated autoimmune response against ones own myelin components with loss of

oligodendrocytes with little or no axonal degeneration

Demyelination occurs in discrete foci termed plaques which range in size from a few millimetres to a few centimeters and

are typically perivenular

Each lesion goes through three pathological stages

bullearly acute stage (active plaques)

bull active myelin break down

bull plaques appear pink and swollen

bullsubacute stage

bull plaques become paler in colour (chalky)

bull abundant macrophages

bullchronic stage (inactive plaquesgliosis)

bull little or no myelin breakdown

bull gliosis with associated volume loss

bull appear greytranslucent

Patients serum IgG levels tend to be elevated and CSF analysis commonly shows oligoclonal bands

Associations

bulla strong association with HLA-DR2 class II has been identified

Radiographic features

Plaques can occur anywhere in the central nervous system They are typically ovoid in

shape and perivenular in distribution

CT

CT features are usually non-specific and significant change may be seen on MRI with

an essentially normal CT scan Features that may be present include

bullplaques can be homogeneously hypo attenuating

bullbrain atrophy may be evident in with long standing chronic MS

bullsome plaques may show contrast enhancement in the active phase

MRI

bullT1

bull lesions are typically iso- to hypointense (chronic)

bull callososeptal interface may have multiple small hypointense lesions (Venus necklace) or the corpus callosum may

merely appear thinned 11

bullT2 lesions are typically hyperintense

bullFLAIR

bull lesions are typically hyperintense

bull when arranged perpendicular to lateral ventricles extending radially outward (best seen on parasagittal images)

they are termed Dawson fingers

bull FLAIR is more sensitive than T2 in detection of juxtracortical and periventricular plaques while T2 is more

sensitive in infratentorial lesions

bullT1 C+ (Gd)

bull active lesions show enhancement

bull enhancement is often incomplete around the periphery (open ring sign)

bullDWIADC active plaques may demonstrate restricted diffusion 10-11

bullMR spectroscopy may show reduced NAA peaks within plaques

bulldouble inversion recovery DIR a new sequence that suppress both CSF and white matter signal and better delineation of

the plaques

Radiographic features

Plaques can occur anywhere in the central nervous system They are typically ovoid in

shape and perivenular in distribution

CT

CT features are usually non-specific and significant change may be seen on MRI with

an essentially normal CT scan Features that may be present include

bullplaques can be homogeneously hypo attenuating

bullbrain atrophy may be evident in with long standing chronic MS

bullsome plaques may show contrast enhancement in the active phase

MRI

bullT1

bull lesions are typically iso- to hypointense (chronic)

bull callososeptal interface may have multiple small hypointense lesions (Venus necklace) or the corpus callosum may

merely appear thinned 11

bullT2 lesions are typically hyperintense

bullFLAIR

bull lesions are typically hyperintense

bull when arranged perpendicular to lateral ventricles extending radially outward (best seen on parasagittal images)

they are termed Dawson fingers

bull FLAIR is more sensitive than T2 in detection of juxtracortical and periventricular plaques while T2 is more

sensitive in infratentorial lesions

bullT1 C+ (Gd)

bull active lesions show enhancement

bull enhancement is often incomplete around the periphery (open ring sign)

bullDWIADC active plaques may demonstrate restricted diffusion 10-11

bullMR spectroscopy may show reduced NAA peaks within plaques

bulldouble inversion recovery DIR a new sequence that suppress both CSF and white matter signal and better delineation of

the plaques

MRI

bullT1

bull lesions are typically iso- to hypointense (chronic)

bull callososeptal interface may have multiple small hypointense lesions (Venus necklace) or the corpus callosum may

merely appear thinned 11

bullT2 lesions are typically hyperintense

bullFLAIR

bull lesions are typically hyperintense

bull when arranged perpendicular to lateral ventricles extending radially outward (best seen on parasagittal images)

they are termed Dawson fingers

bull FLAIR is more sensitive than T2 in detection of juxtracortical and periventricular plaques while T2 is more

sensitive in infratentorial lesions

bullT1 C+ (Gd)

bull active lesions show enhancement

bull enhancement is often incomplete around the periphery (open ring sign)

bullDWIADC active plaques may demonstrate restricted diffusion 10-11

bullMR spectroscopy may show reduced NAA peaks within plaques

bulldouble inversion recovery DIR a new sequence that suppress both CSF and white matter signal and better delineation of

the plaques

Location of the plaques can be

bull infratentorial

bull deep white matter

bull periventricular

bull juxtacortical or

bull mixed white matter-grey matter lesions

Even on a single scan some features are helpful in predicting relapsing-

remitting vs progressive disease

Features favouring progressive disease include

bull large numerous plaques

bull hypo intense T1 lesions

McDonalds criteria are MRI criteria used in the diagnosis of multiple sclerosis improves sensitivity from 46-

74

The diagnosis of multiple sclerosis requires establishing disease disseminated in both space and time

bull Dissemination in space

Dissemination in space requires ge1 T2 bright lesions in two or more of the following locations 1

bull periventricular

bull juxtacortical

bull infratentorial

bull spinal cord

if a patient has a brainstemspinal cord syndrome the symptomatic lesion(s) are excluded from the

criteria not contributing to the lesion count

bull Dissemination in time

Dissemination in time can be established in one of two ways

bull a new lesion when compared to a previous scan (irrespective of timing)

T2 bright lesion andor gadolinium enhancing

bull presence of asymptomatic enhancing lesion and a non-enhancing T2 bright lesion on any one scan

McDonalds criteria are MRI criteria used in the diagnosis of multiple sclerosis improves sensitivity from 46-

74

The diagnosis of multiple sclerosis requires establishing disease disseminated in both space and time

bull Dissemination in space

Dissemination in space requires ge1 T2 bright lesions in two or more of the following locations 1

bull periventricular

bull juxtacortical

bull infratentorial

bull spinal cord

if a patient has a brainstemspinal cord syndrome the symptomatic lesion(s) are excluded from the

criteria not contributing to the lesion count

bull Dissemination in time

Dissemination in time can be established in one of two ways

bull a new lesion when compared to a previous scan (irrespective of timing)

T2 bright lesion andor gadolinium enhancing

bull presence of asymptomatic enhancing lesion and a non-enhancing T2 bright lesion on any one scan

Primary progressive multiple sclerosis (PPMS)

In addition to the above criteria the diagnosis of primary progressive multiple sclerosis has also been

revised

The diagnosis now requires

bull ge1 year of disease progression (this can be determined either prospectively or retrospectively)

bullplus two of the following three criteria

bull brain dissemination in space ( ge1 T2 bright lesions in ge1 of juxtacortical periventricular

infratentorial areas)

bull spinal cord dissemination in space (ge2 T2 bright lesions)

bull positive CSF (oligoclonal bands andor elevated IgG index)

10 Advanced MR Imaging

bull A number of advanced MR imaging techniques including diffusion imaging MR spectroscopy

and magnetization transfer imaging have been used to better understand MS For the most part

these techniques have been used to diagnose MS but to better understand physiological changes

involved in disease progression

bull Diffusion tensor imaging (DTI) is an example of a technique that can help to better understand

whether normal-appearing white matter in MS patients is in fact normal

bull Studies using DTI have shown that normal-appearing white matter adjacent to plaques is very

abnormal in terms of diminished anisotropy values (correlating with loss of integrity of white

matter pathways) Even white matter distant from MS plaques can be seen to be similarly

altered

31-year-old man with a 10- year history of relapsing-remitting neurologic symptoms

Callosal Involvement with multiple sclerosis in 48-year-old woman with clinically definite

multiple sclerosis for 20 years

Multiple sclerosis involving upper spinal cord in 35-year-old woman with acute onset of

quadriparesis

Typical cerebral lesions of multiple

sclerosis in 64-year-old woman with

sudden onset of diplopia and ataxia

Multiple sclerosis lesion in brainstem

of 38-year-old man with bilateral

weakness and sensory symptoms in

lower extremities

Multiple sclerosis in 42-year-old woman with clinically definite

multiple sclerosis but no acute symptoms

MULTIPLE SCLEROSIS

The differential diagnosis is dependent on the location and appearance of demyelination

For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement

For intracranial disease the differential includes almost all other demyelinating disease as well as

bullCNS fungal infection (eg Cryptococcus neoformans ) patients tend to be immunocompromised

bullmucopolysaccharidosis (eg Hurler disease) congenital and occurs in a younger age group

bullSusac syndrome

bullCNS manifestations of primary antiphospholipid syndrome

For spinal involvement the following should be considered

bulltransverse myelitis

bullinfection

bullspinal cord tumours eg astrocytomas

10 Advanced MR Imaging

bull A number of advanced MR imaging techniques including diffusion imaging MR spectroscopy

and magnetization transfer imaging have been used to better understand MS For the most part

these techniques have been used to diagnose MS but to better understand physiological changes

involved in disease progression

bull Diffusion tensor imaging (DTI) is an example of a technique that can help to better understand

whether normal-appearing white matter in MS patients is in fact normal

bull Studies using DTI have shown that normal-appearing white matter adjacent to plaques is very

abnormal in terms of diminished anisotropy values (correlating with loss of integrity of white

matter pathways) Even white matter distant from MS plaques can be seen to be similarly

altered

31-year-old man with a 10- year history of relapsing-remitting neurologic symptoms

Callosal Involvement with multiple sclerosis in 48-year-old woman with clinically definite

multiple sclerosis for 20 years

Multiple sclerosis involving upper spinal cord in 35-year-old woman with acute onset of

quadriparesis

Typical cerebral lesions of multiple

sclerosis in 64-year-old woman with

sudden onset of diplopia and ataxia

Multiple sclerosis lesion in brainstem

of 38-year-old man with bilateral

weakness and sensory symptoms in

lower extremities

Multiple sclerosis in 42-year-old woman with clinically definite

multiple sclerosis but no acute symptoms

MULTIPLE SCLEROSIS

The differential diagnosis is dependent on the location and appearance of demyelination

For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement

For intracranial disease the differential includes almost all other demyelinating disease as well as

bullCNS fungal infection (eg Cryptococcus neoformans ) patients tend to be immunocompromised

bullmucopolysaccharidosis (eg Hurler disease) congenital and occurs in a younger age group

bullSusac syndrome

bullCNS manifestations of primary antiphospholipid syndrome

For spinal involvement the following should be considered

bulltransverse myelitis

bullinfection

bullspinal cord tumours eg astrocytomas

31-year-old man with a 10- year history of relapsing-remitting neurologic symptoms

Callosal Involvement with multiple sclerosis in 48-year-old woman with clinically definite

multiple sclerosis for 20 years

Multiple sclerosis involving upper spinal cord in 35-year-old woman with acute onset of

quadriparesis

Typical cerebral lesions of multiple

sclerosis in 64-year-old woman with

sudden onset of diplopia and ataxia

Multiple sclerosis lesion in brainstem

of 38-year-old man with bilateral

weakness and sensory symptoms in

lower extremities

Multiple sclerosis in 42-year-old woman with clinically definite

multiple sclerosis but no acute symptoms

MULTIPLE SCLEROSIS

The differential diagnosis is dependent on the location and appearance of demyelination

For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement

For intracranial disease the differential includes almost all other demyelinating disease as well as

bullCNS fungal infection (eg Cryptococcus neoformans ) patients tend to be immunocompromised

bullmucopolysaccharidosis (eg Hurler disease) congenital and occurs in a younger age group

bullSusac syndrome

bullCNS manifestations of primary antiphospholipid syndrome

For spinal involvement the following should be considered

bulltransverse myelitis

bullinfection

bullspinal cord tumours eg astrocytomas

Callosal Involvement with multiple sclerosis in 48-year-old woman with clinically definite

multiple sclerosis for 20 years

Multiple sclerosis involving upper spinal cord in 35-year-old woman with acute onset of

quadriparesis

Typical cerebral lesions of multiple

sclerosis in 64-year-old woman with

sudden onset of diplopia and ataxia

Multiple sclerosis lesion in brainstem

of 38-year-old man with bilateral

weakness and sensory symptoms in

lower extremities

Multiple sclerosis in 42-year-old woman with clinically definite

multiple sclerosis but no acute symptoms

MULTIPLE SCLEROSIS

The differential diagnosis is dependent on the location and appearance of demyelination

For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement

For intracranial disease the differential includes almost all other demyelinating disease as well as

bullCNS fungal infection (eg Cryptococcus neoformans ) patients tend to be immunocompromised

bullmucopolysaccharidosis (eg Hurler disease) congenital and occurs in a younger age group

bullSusac syndrome

bullCNS manifestations of primary antiphospholipid syndrome

For spinal involvement the following should be considered

bulltransverse myelitis

bullinfection

bullspinal cord tumours eg astrocytomas

Multiple sclerosis involving upper spinal cord in 35-year-old woman with acute onset of

quadriparesis

Typical cerebral lesions of multiple

sclerosis in 64-year-old woman with

sudden onset of diplopia and ataxia

Multiple sclerosis lesion in brainstem

of 38-year-old man with bilateral

weakness and sensory symptoms in

lower extremities

Multiple sclerosis in 42-year-old woman with clinically definite

multiple sclerosis but no acute symptoms

MULTIPLE SCLEROSIS

The differential diagnosis is dependent on the location and appearance of demyelination

For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement

For intracranial disease the differential includes almost all other demyelinating disease as well as

bullCNS fungal infection (eg Cryptococcus neoformans ) patients tend to be immunocompromised

bullmucopolysaccharidosis (eg Hurler disease) congenital and occurs in a younger age group

bullSusac syndrome

bullCNS manifestations of primary antiphospholipid syndrome

For spinal involvement the following should be considered

bulltransverse myelitis

bullinfection

bullspinal cord tumours eg astrocytomas

Typical cerebral lesions of multiple

sclerosis in 64-year-old woman with

sudden onset of diplopia and ataxia

Multiple sclerosis lesion in brainstem

of 38-year-old man with bilateral

weakness and sensory symptoms in

lower extremities

Multiple sclerosis in 42-year-old woman with clinically definite

multiple sclerosis but no acute symptoms

MULTIPLE SCLEROSIS

The differential diagnosis is dependent on the location and appearance of demyelination

For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement

For intracranial disease the differential includes almost all other demyelinating disease as well as

bullCNS fungal infection (eg Cryptococcus neoformans ) patients tend to be immunocompromised

bullmucopolysaccharidosis (eg Hurler disease) congenital and occurs in a younger age group

bullSusac syndrome

bullCNS manifestations of primary antiphospholipid syndrome

For spinal involvement the following should be considered

bulltransverse myelitis

bullinfection

bullspinal cord tumours eg astrocytomas

Multiple sclerosis in 42-year-old woman with clinically definite

multiple sclerosis but no acute symptoms

MULTIPLE SCLEROSIS

The differential diagnosis is dependent on the location and appearance of demyelination

For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement

For intracranial disease the differential includes almost all other demyelinating disease as well as

bullCNS fungal infection (eg Cryptococcus neoformans ) patients tend to be immunocompromised

bullmucopolysaccharidosis (eg Hurler disease) congenital and occurs in a younger age group

bullSusac syndrome

bullCNS manifestations of primary antiphospholipid syndrome

For spinal involvement the following should be considered

bulltransverse myelitis

bullinfection

bullspinal cord tumours eg astrocytomas

MULTIPLE SCLEROSIS

The differential diagnosis is dependent on the location and appearance of demyelination

For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement

For intracranial disease the differential includes almost all other demyelinating disease as well as

bullCNS fungal infection (eg Cryptococcus neoformans ) patients tend to be immunocompromised

bullmucopolysaccharidosis (eg Hurler disease) congenital and occurs in a younger age group

bullSusac syndrome

bullCNS manifestations of primary antiphospholipid syndrome

For spinal involvement the following should be considered

bulltransverse myelitis

bullinfection

bullspinal cord tumours eg astrocytomas

The differential diagnosis is dependent on the location and appearance of demyelination

For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement

For intracranial disease the differential includes almost all other demyelinating disease as well as

bullCNS fungal infection (eg Cryptococcus neoformans ) patients tend to be immunocompromised

bullmucopolysaccharidosis (eg Hurler disease) congenital and occurs in a younger age group

bullSusac syndrome

bullCNS manifestations of primary antiphospholipid syndrome

For spinal involvement the following should be considered

bulltransverse myelitis

bullinfection

bullspinal cord tumours eg astrocytomas

Acute disseminated encephalomyelitis (ADEM)

bull Can occur either on a post-infectious or post-vaccinial basis

bull The history of either of these precipitating factors is important in making the diagnosis

bull The disease can be seen in both adults and children Compared to children onset in adults is more often

seen as a more widespread CNS syndrome with impaired consciousness

bull Mean age of onset in childhood is approximately 7 years

bull In approximately 80 one of the following events in the preceding 3 weeks can be found

bull upper respiratory illness or nonspecific fever (60)

bull specific viral or bacterial illness (20) and

bull immunization (10)

bull The most common infections to precede this disorder are measles rubella and chickenpox Neurological

illness typically progresses over the course of a week

Imaging Findings

bull Typically bilateral asymmetric lesions in central white matter varying in size from

many mm to several cm

bull Solitary confluent or multiple lesions involving only one hemisphere can be seen in

a minority of cases

bull Thalamic or basal ganglia lesions in 25

bull Contrast enhancement seen in about 25 of cases

bull Lesions are seen on MR imaging of the spinal cord in only about 13 of cases of

myelopathy

bull On follow-up MR imaging weeks to months later 36 have normal studies 60

have persistent but usually smaller lesions and 5 have new lesions

MRI is far more sensitive than CT

bullT2 demonstrates regions of high signal with surrounding oedema typically situated in subcortical

locations the thalami and brainstem can also be involved

bullT1 C+ (Gd) punctate ring or arc enhancement (open ring sign) is often demonstrated along the leading

edge of inflammation absence of enhancement does not exclude the diagnosis

bullDWI there can be peripheral restricted diffusion the center of the lesion although high on T2 and low

on T1 does not have increased restriction on DWI (cfcerebral abscess) nor does it demonstrate absent

signal on DWI as one would expect from a cyst this is due to increase in extra cellular water in the region

of demyelination

Magnetization transfer may help distinguish ADEM from MS in that normal appearing brain (on T2

weighted images) has normal magnetization transfer ratio (MTR) and normal diffusivity whereas in MS

both measurements are significantly decreased 3

Imaging Findings

bull Typically bilateral asymmetric lesions in central white matter varying in size from

many mm to several cm

bull Solitary confluent or multiple lesions involving only one hemisphere can be seen in

a minority of cases

bull Thalamic or basal ganglia lesions in 25

bull Contrast enhancement seen in about 25 of cases

bull Lesions are seen on MR imaging of the spinal cord in only about 13 of cases of

myelopathy

bull On follow-up MR imaging weeks to months later 36 have normal studies 60

have persistent but usually smaller lesions and 5 have new lesions

MRI is far more sensitive than CT

bullT2 demonstrates regions of high signal with surrounding oedema typically situated in subcortical

locations the thalami and brainstem can also be involved

bullT1 C+ (Gd) punctate ring or arc enhancement (open ring sign) is often demonstrated along the leading

edge of inflammation absence of enhancement does not exclude the diagnosis

bullDWI there can be peripheral restricted diffusion the center of the lesion although high on T2 and low

on T1 does not have increased restriction on DWI (cfcerebral abscess) nor does it demonstrate absent

signal on DWI as one would expect from a cyst this is due to increase in extra cellular water in the region

of demyelination

Magnetization transfer may help distinguish ADEM from MS in that normal appearing brain (on T2

weighted images) has normal magnetization transfer ratio (MTR) and normal diffusivity whereas in MS

both measurements are significantly decreased 3

MRI is far more sensitive than CT

bullT2 demonstrates regions of high signal with surrounding oedema typically situated in subcortical

locations the thalami and brainstem can also be involved

bullT1 C+ (Gd) punctate ring or arc enhancement (open ring sign) is often demonstrated along the leading

edge of inflammation absence of enhancement does not exclude the diagnosis

bullDWI there can be peripheral restricted diffusion the center of the lesion although high on T2 and low

on T1 does not have increased restriction on DWI (cfcerebral abscess) nor does it demonstrate absent

signal on DWI as one would expect from a cyst this is due to increase in extra cellular water in the region

of demyelination

Magnetization transfer may help distinguish ADEM from MS in that normal appearing brain (on T2

weighted images) has normal magnetization transfer ratio (MTR) and normal diffusivity whereas in MS

both measurements are significantly decreased 3

Potential location of lesions in patients with acquired demyelination

MRI of patient a week before a febrile illness

ADEM

Differential diagnosis of ADEM

bull Multiple sclerosis (plus variants)

bull Cerebral lymphoma

bull Infectious encephalitis

bull Viral EBV CMV HSV1+2 JCV HIV HHV-6 FSME HTLV

bull enteroviruses measles

bull Bacterial Tropheryma whipplei Mycoplasma Listeria

bull Brucella spp

bull Fungal (eg Histoplasma spp)

bull Other autoimmune diseases

bull Vasculitis (eg Behcetrsquos disease panarteritis nodosa)

bull Sarcoidosis

bull Porphyrias

bull Leukodystrophies

bull Mitochondrial disorders (eg MELAS)

bull Myelinolysis after electrolyte imbalances (eg central pontine myelinolysis)

II Non-demyelinating White Matter Diseases of Adults

1 Posterior Reversible Encephalopathy Syndrome (PRES)-

This syndrome was formerly known as hypertensive encephalopathy but it has recently been recognized

that it can be caused by a number of entities other than simply systemic hypertension The syndrome is an

emergency condition because patients can proceed to cerebral infarction and death if not appropriately

treated

Treatment consists of reversal of hypertension (if present) or removal of causative agents in other cases

The syndrome typically occurs in the following settings

- acute rise in systemic blood pressure which may be only moderate in degree

- pre-eclampsia or eclampsia

- following treatment with a variety of immunosuppressive agents including cyclosporine A cisplatin and

tacrolimus

The pathophysiological mechanism is thought to be development of vasogenic edema due to loss of

autoregulation within cerebral blood vessels

Aetiology

bullsevere hypertension

bull post partum

bull eclampsiapreeclampsia

bull acute glomerulonephritis

bullhaemolytic uraemic syndrome (HUS)

bullthrombocytopaenic thromboic purpura (TTP)

bullsystemic lupus erythematosus (SLE)

bulldrug toxicity

bull cisplatin

bull interferon

bull erythropoietin

bull tacrolimus

bull cyclosporin

bull azathioprine

bullbone marrow or stem cell transplantation

bullsepsis

MRI of patient a week before a febrile illness

ADEM

Differential diagnosis of ADEM

bull Multiple sclerosis (plus variants)

bull Cerebral lymphoma

bull Infectious encephalitis

bull Viral EBV CMV HSV1+2 JCV HIV HHV-6 FSME HTLV

bull enteroviruses measles

bull Bacterial Tropheryma whipplei Mycoplasma Listeria

bull Brucella spp

bull Fungal (eg Histoplasma spp)

bull Other autoimmune diseases

bull Vasculitis (eg Behcetrsquos disease panarteritis nodosa)

bull Sarcoidosis

bull Porphyrias

bull Leukodystrophies

bull Mitochondrial disorders (eg MELAS)

bull Myelinolysis after electrolyte imbalances (eg central pontine myelinolysis)

II Non-demyelinating White Matter Diseases of Adults

1 Posterior Reversible Encephalopathy Syndrome (PRES)-

This syndrome was formerly known as hypertensive encephalopathy but it has recently been recognized

that it can be caused by a number of entities other than simply systemic hypertension The syndrome is an

emergency condition because patients can proceed to cerebral infarction and death if not appropriately

treated

Treatment consists of reversal of hypertension (if present) or removal of causative agents in other cases

The syndrome typically occurs in the following settings

- acute rise in systemic blood pressure which may be only moderate in degree

- pre-eclampsia or eclampsia

- following treatment with a variety of immunosuppressive agents including cyclosporine A cisplatin and

tacrolimus

The pathophysiological mechanism is thought to be development of vasogenic edema due to loss of

autoregulation within cerebral blood vessels

Aetiology

bullsevere hypertension

bull post partum

bull eclampsiapreeclampsia

bull acute glomerulonephritis

bullhaemolytic uraemic syndrome (HUS)

bullthrombocytopaenic thromboic purpura (TTP)

bullsystemic lupus erythematosus (SLE)

bulldrug toxicity

bull cisplatin

bull interferon

bull erythropoietin

bull tacrolimus

bull cyclosporin

bull azathioprine

bullbone marrow or stem cell transplantation

bullsepsis

ADEM

Differential diagnosis of ADEM

bull Multiple sclerosis (plus variants)

bull Cerebral lymphoma

bull Infectious encephalitis

bull Viral EBV CMV HSV1+2 JCV HIV HHV-6 FSME HTLV

bull enteroviruses measles

bull Bacterial Tropheryma whipplei Mycoplasma Listeria

bull Brucella spp

bull Fungal (eg Histoplasma spp)

bull Other autoimmune diseases

bull Vasculitis (eg Behcetrsquos disease panarteritis nodosa)

bull Sarcoidosis

bull Porphyrias

bull Leukodystrophies

bull Mitochondrial disorders (eg MELAS)

bull Myelinolysis after electrolyte imbalances (eg central pontine myelinolysis)

II Non-demyelinating White Matter Diseases of Adults

1 Posterior Reversible Encephalopathy Syndrome (PRES)-

This syndrome was formerly known as hypertensive encephalopathy but it has recently been recognized

that it can be caused by a number of entities other than simply systemic hypertension The syndrome is an

emergency condition because patients can proceed to cerebral infarction and death if not appropriately

treated

Treatment consists of reversal of hypertension (if present) or removal of causative agents in other cases

The syndrome typically occurs in the following settings

- acute rise in systemic blood pressure which may be only moderate in degree

- pre-eclampsia or eclampsia

- following treatment with a variety of immunosuppressive agents including cyclosporine A cisplatin and

tacrolimus

The pathophysiological mechanism is thought to be development of vasogenic edema due to loss of

autoregulation within cerebral blood vessels

Aetiology

bullsevere hypertension

bull post partum

bull eclampsiapreeclampsia

bull acute glomerulonephritis

bullhaemolytic uraemic syndrome (HUS)

bullthrombocytopaenic thromboic purpura (TTP)

bullsystemic lupus erythematosus (SLE)

bulldrug toxicity

bull cisplatin

bull interferon

bull erythropoietin

bull tacrolimus

bull cyclosporin

bull azathioprine

bullbone marrow or stem cell transplantation

bullsepsis

Differential diagnosis of ADEM

bull Multiple sclerosis (plus variants)

bull Cerebral lymphoma

bull Infectious encephalitis

bull Viral EBV CMV HSV1+2 JCV HIV HHV-6 FSME HTLV

bull enteroviruses measles

bull Bacterial Tropheryma whipplei Mycoplasma Listeria

bull Brucella spp

bull Fungal (eg Histoplasma spp)

bull Other autoimmune diseases

bull Vasculitis (eg Behcetrsquos disease panarteritis nodosa)

bull Sarcoidosis

bull Porphyrias

bull Leukodystrophies

bull Mitochondrial disorders (eg MELAS)

bull Myelinolysis after electrolyte imbalances (eg central pontine myelinolysis)

II Non-demyelinating White Matter Diseases of Adults

1 Posterior Reversible Encephalopathy Syndrome (PRES)-

This syndrome was formerly known as hypertensive encephalopathy but it has recently been recognized

that it can be caused by a number of entities other than simply systemic hypertension The syndrome is an

emergency condition because patients can proceed to cerebral infarction and death if not appropriately

treated

Treatment consists of reversal of hypertension (if present) or removal of causative agents in other cases

The syndrome typically occurs in the following settings

- acute rise in systemic blood pressure which may be only moderate in degree

- pre-eclampsia or eclampsia

- following treatment with a variety of immunosuppressive agents including cyclosporine A cisplatin and

tacrolimus

The pathophysiological mechanism is thought to be development of vasogenic edema due to loss of

autoregulation within cerebral blood vessels

Aetiology

bullsevere hypertension

bull post partum

bull eclampsiapreeclampsia

bull acute glomerulonephritis

bullhaemolytic uraemic syndrome (HUS)

bullthrombocytopaenic thromboic purpura (TTP)

bullsystemic lupus erythematosus (SLE)

bulldrug toxicity

bull cisplatin

bull interferon

bull erythropoietin

bull tacrolimus

bull cyclosporin

bull azathioprine

bullbone marrow or stem cell transplantation

bullsepsis

II Non-demyelinating White Matter Diseases of Adults

1 Posterior Reversible Encephalopathy Syndrome (PRES)-

This syndrome was formerly known as hypertensive encephalopathy but it has recently been recognized

that it can be caused by a number of entities other than simply systemic hypertension The syndrome is an

emergency condition because patients can proceed to cerebral infarction and death if not appropriately

treated

Treatment consists of reversal of hypertension (if present) or removal of causative agents in other cases

The syndrome typically occurs in the following settings

- acute rise in systemic blood pressure which may be only moderate in degree

- pre-eclampsia or eclampsia

- following treatment with a variety of immunosuppressive agents including cyclosporine A cisplatin and

tacrolimus

The pathophysiological mechanism is thought to be development of vasogenic edema due to loss of

autoregulation within cerebral blood vessels

Aetiology

bullsevere hypertension

bull post partum

bull eclampsiapreeclampsia

bull acute glomerulonephritis

bullhaemolytic uraemic syndrome (HUS)

bullthrombocytopaenic thromboic purpura (TTP)

bullsystemic lupus erythematosus (SLE)

bulldrug toxicity

bull cisplatin

bull interferon

bull erythropoietin

bull tacrolimus

bull cyclosporin

bull azathioprine

bullbone marrow or stem cell transplantation

bullsepsis

Aetiology

bullsevere hypertension

bull post partum

bull eclampsiapreeclampsia

bull acute glomerulonephritis

bullhaemolytic uraemic syndrome (HUS)

bullthrombocytopaenic thromboic purpura (TTP)

bullsystemic lupus erythematosus (SLE)

bulldrug toxicity

bull cisplatin

bull interferon

bull erythropoietin

bull tacrolimus

bull cyclosporin

bull azathioprine

bullbone marrow or stem cell transplantation

bullsepsis

On unenhanced CT regions of hypodensity predominating within the posterior half of the brain and

generally involving white matter up to the gray-white junction are seen

On MR

bull T1- hypointense and T2 hyperintense lesions

bull No contrast enhancement

bull Cortical regions can occasionally be involved

bull The predilection for involvement of the posterior white matter is thought to be due to decreased

innervation of arteries of these regions by autonomic fibers compared to the remainder of the cerebral

circulation

bull On diffusion-weighted images lesions often appear isointense rather than having the hypointense

signal expected in vasogenic edema

bull This finding is most likely due to the net effect of a combination of elevated apparent diffusion

coefficient values on diffusion weighted images (due to vasogenic edema) and increased signal intensity

due to T2 prolongation effects (so-called ldquoT2 shine-through effectrdquo)

PRES

A 50-year-old woman 6 months post liver transplant experienced a generalized seizure and unresponsiveness Blood

pressure at the time of the toxic event fluctuated markedly with a range between 106 and 200 mm Hg systolic and 54 and

80 mm Hg diastolic

A 36-year-old man with severe type 1 diabetes and recurrent septic arthritis of the shoulder requiring frequent

debridement presented with several days of headache nausea and visual changes along with hypertension Blood

pressure at toxicity was 184111 mm Hg

PROGRESSIVE MULTIFOCAL LEUKOENCEPHELOPATHY (PML)

bull It is probably the best known virally induced demyelinating disease

bull It is caused by reactivation of a latent Papova virus (the JC virus) infection

bull Though generally seen in immunocompromised patients it is found to have a strong association with

AIDS

bull The patient clinically presents with hemiparesis homonymous hemianopia and altered mentation

bull MR is more sensitive than CT and is the imaging modality of choice in PML

bull MR reveals increased signal intensity in the subcortical or periventricular white matter of parieto

occipital region

bull Multifocal distribution pattern is seen which may be unilateral or more often bilateral and

asymmetric

bull There is absence of mass effect and enhancement due to the paucity of perivenous inflammation

bull The subcortical lesions result in a scalloped appearance due to the involvement of subcortical U

fibres

bull PML is commonly seen to involve the posterior fossa also

PML

A 12-year-old boy with seizures and headache

Marked progression of PML documented by serial MR studies

HIV ENCEPHALOPATHY

bull Human retroviruses like HIV are known to cause white matter changes which may be difficult to assess

subjectively especially in the early stages of the disease

bull HIV encephalopathy is a progressive subcortical dementia that is a form of subacute encephalitis

bull The most common neurological manifestation would be subacute encephalopathy presenting as dementia and

global cognitive impairment

bull Though CT and MRI are relatively insensitive in detecting microglial nodules early in the course of the

disease they are very sensitive in the detection of secondary parenchymal changes

bull The hallmarks of the disease are cortical atrophy and diffuse white matter changes

bull The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass

effect or contrast enhancement

bull Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding

bull Lesions in white matter may extend to the basal ganglia and cortex with disease progression

bull Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the

pathogenesis of HIV dementia

bull Lesions may also be located in the brain stem cerebellum and spinal cord

bull White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

PRES

A 50-year-old woman 6 months post liver transplant experienced a generalized seizure and unresponsiveness Blood

pressure at the time of the toxic event fluctuated markedly with a range between 106 and 200 mm Hg systolic and 54 and

80 mm Hg diastolic

A 36-year-old man with severe type 1 diabetes and recurrent septic arthritis of the shoulder requiring frequent

debridement presented with several days of headache nausea and visual changes along with hypertension Blood

pressure at toxicity was 184111 mm Hg

PROGRESSIVE MULTIFOCAL LEUKOENCEPHELOPATHY (PML)

bull It is probably the best known virally induced demyelinating disease

bull It is caused by reactivation of a latent Papova virus (the JC virus) infection

bull Though generally seen in immunocompromised patients it is found to have a strong association with

AIDS

bull The patient clinically presents with hemiparesis homonymous hemianopia and altered mentation

bull MR is more sensitive than CT and is the imaging modality of choice in PML

bull MR reveals increased signal intensity in the subcortical or periventricular white matter of parieto

occipital region

bull Multifocal distribution pattern is seen which may be unilateral or more often bilateral and

asymmetric

bull There is absence of mass effect and enhancement due to the paucity of perivenous inflammation

bull The subcortical lesions result in a scalloped appearance due to the involvement of subcortical U

fibres

bull PML is commonly seen to involve the posterior fossa also

PML

A 12-year-old boy with seizures and headache

Marked progression of PML documented by serial MR studies

HIV ENCEPHALOPATHY

bull Human retroviruses like HIV are known to cause white matter changes which may be difficult to assess

subjectively especially in the early stages of the disease

bull HIV encephalopathy is a progressive subcortical dementia that is a form of subacute encephalitis

bull The most common neurological manifestation would be subacute encephalopathy presenting as dementia and

global cognitive impairment

bull Though CT and MRI are relatively insensitive in detecting microglial nodules early in the course of the

disease they are very sensitive in the detection of secondary parenchymal changes

bull The hallmarks of the disease are cortical atrophy and diffuse white matter changes

bull The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass

effect or contrast enhancement

bull Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding

bull Lesions in white matter may extend to the basal ganglia and cortex with disease progression

bull Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the

pathogenesis of HIV dementia

bull Lesions may also be located in the brain stem cerebellum and spinal cord

bull White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

A 36-year-old man with severe type 1 diabetes and recurrent septic arthritis of the shoulder requiring frequent

debridement presented with several days of headache nausea and visual changes along with hypertension Blood

pressure at toxicity was 184111 mm Hg

PROGRESSIVE MULTIFOCAL LEUKOENCEPHELOPATHY (PML)

bull It is probably the best known virally induced demyelinating disease

bull It is caused by reactivation of a latent Papova virus (the JC virus) infection

bull Though generally seen in immunocompromised patients it is found to have a strong association with

AIDS

bull The patient clinically presents with hemiparesis homonymous hemianopia and altered mentation

bull MR is more sensitive than CT and is the imaging modality of choice in PML

bull MR reveals increased signal intensity in the subcortical or periventricular white matter of parieto

occipital region

bull Multifocal distribution pattern is seen which may be unilateral or more often bilateral and

asymmetric

bull There is absence of mass effect and enhancement due to the paucity of perivenous inflammation

bull The subcortical lesions result in a scalloped appearance due to the involvement of subcortical U

fibres

bull PML is commonly seen to involve the posterior fossa also

PML

A 12-year-old boy with seizures and headache

Marked progression of PML documented by serial MR studies

HIV ENCEPHALOPATHY

bull Human retroviruses like HIV are known to cause white matter changes which may be difficult to assess

subjectively especially in the early stages of the disease

bull HIV encephalopathy is a progressive subcortical dementia that is a form of subacute encephalitis

bull The most common neurological manifestation would be subacute encephalopathy presenting as dementia and

global cognitive impairment

bull Though CT and MRI are relatively insensitive in detecting microglial nodules early in the course of the

disease they are very sensitive in the detection of secondary parenchymal changes

bull The hallmarks of the disease are cortical atrophy and diffuse white matter changes

bull The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass

effect or contrast enhancement

bull Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding

bull Lesions in white matter may extend to the basal ganglia and cortex with disease progression

bull Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the

pathogenesis of HIV dementia

bull Lesions may also be located in the brain stem cerebellum and spinal cord

bull White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

PROGRESSIVE MULTIFOCAL LEUKOENCEPHELOPATHY (PML)

bull It is probably the best known virally induced demyelinating disease

bull It is caused by reactivation of a latent Papova virus (the JC virus) infection

bull Though generally seen in immunocompromised patients it is found to have a strong association with

AIDS

bull The patient clinically presents with hemiparesis homonymous hemianopia and altered mentation

bull MR is more sensitive than CT and is the imaging modality of choice in PML

bull MR reveals increased signal intensity in the subcortical or periventricular white matter of parieto

occipital region

bull Multifocal distribution pattern is seen which may be unilateral or more often bilateral and

asymmetric

bull There is absence of mass effect and enhancement due to the paucity of perivenous inflammation

bull The subcortical lesions result in a scalloped appearance due to the involvement of subcortical U

fibres

bull PML is commonly seen to involve the posterior fossa also

PML

A 12-year-old boy with seizures and headache

Marked progression of PML documented by serial MR studies

HIV ENCEPHALOPATHY

bull Human retroviruses like HIV are known to cause white matter changes which may be difficult to assess

subjectively especially in the early stages of the disease

bull HIV encephalopathy is a progressive subcortical dementia that is a form of subacute encephalitis

bull The most common neurological manifestation would be subacute encephalopathy presenting as dementia and

global cognitive impairment

bull Though CT and MRI are relatively insensitive in detecting microglial nodules early in the course of the

disease they are very sensitive in the detection of secondary parenchymal changes

bull The hallmarks of the disease are cortical atrophy and diffuse white matter changes

bull The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass

effect or contrast enhancement

bull Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding

bull Lesions in white matter may extend to the basal ganglia and cortex with disease progression

bull Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the

pathogenesis of HIV dementia

bull Lesions may also be located in the brain stem cerebellum and spinal cord

bull White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

PML

A 12-year-old boy with seizures and headache

Marked progression of PML documented by serial MR studies

HIV ENCEPHALOPATHY

bull Human retroviruses like HIV are known to cause white matter changes which may be difficult to assess

subjectively especially in the early stages of the disease

bull HIV encephalopathy is a progressive subcortical dementia that is a form of subacute encephalitis

bull The most common neurological manifestation would be subacute encephalopathy presenting as dementia and

global cognitive impairment

bull Though CT and MRI are relatively insensitive in detecting microglial nodules early in the course of the

disease they are very sensitive in the detection of secondary parenchymal changes

bull The hallmarks of the disease are cortical atrophy and diffuse white matter changes

bull The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass

effect or contrast enhancement

bull Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding

bull Lesions in white matter may extend to the basal ganglia and cortex with disease progression

bull Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the

pathogenesis of HIV dementia

bull Lesions may also be located in the brain stem cerebellum and spinal cord

bull White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

A 12-year-old boy with seizures and headache

Marked progression of PML documented by serial MR studies

HIV ENCEPHALOPATHY

bull Human retroviruses like HIV are known to cause white matter changes which may be difficult to assess

subjectively especially in the early stages of the disease

bull HIV encephalopathy is a progressive subcortical dementia that is a form of subacute encephalitis

bull The most common neurological manifestation would be subacute encephalopathy presenting as dementia and

global cognitive impairment

bull Though CT and MRI are relatively insensitive in detecting microglial nodules early in the course of the

disease they are very sensitive in the detection of secondary parenchymal changes

bull The hallmarks of the disease are cortical atrophy and diffuse white matter changes

bull The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass

effect or contrast enhancement

bull Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding

bull Lesions in white matter may extend to the basal ganglia and cortex with disease progression

bull Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the

pathogenesis of HIV dementia

bull Lesions may also be located in the brain stem cerebellum and spinal cord

bull White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

Marked progression of PML documented by serial MR studies

HIV ENCEPHALOPATHY

bull Human retroviruses like HIV are known to cause white matter changes which may be difficult to assess

subjectively especially in the early stages of the disease

bull HIV encephalopathy is a progressive subcortical dementia that is a form of subacute encephalitis

bull The most common neurological manifestation would be subacute encephalopathy presenting as dementia and

global cognitive impairment

bull Though CT and MRI are relatively insensitive in detecting microglial nodules early in the course of the

disease they are very sensitive in the detection of secondary parenchymal changes

bull The hallmarks of the disease are cortical atrophy and diffuse white matter changes

bull The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass

effect or contrast enhancement

bull Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding

bull Lesions in white matter may extend to the basal ganglia and cortex with disease progression

bull Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the

pathogenesis of HIV dementia

bull Lesions may also be located in the brain stem cerebellum and spinal cord

bull White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

HIV ENCEPHALOPATHY

bull Human retroviruses like HIV are known to cause white matter changes which may be difficult to assess

subjectively especially in the early stages of the disease

bull HIV encephalopathy is a progressive subcortical dementia that is a form of subacute encephalitis

bull The most common neurological manifestation would be subacute encephalopathy presenting as dementia and

global cognitive impairment

bull Though CT and MRI are relatively insensitive in detecting microglial nodules early in the course of the

disease they are very sensitive in the detection of secondary parenchymal changes

bull The hallmarks of the disease are cortical atrophy and diffuse white matter changes

bull The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass

effect or contrast enhancement

bull Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding

bull Lesions in white matter may extend to the basal ganglia and cortex with disease progression

bull Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the

pathogenesis of HIV dementia

bull Lesions may also be located in the brain stem cerebellum and spinal cord

bull White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

bull The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass

effect or contrast enhancement

bull Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding

bull Lesions in white matter may extend to the basal ganglia and cortex with disease progression

bull Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the

pathogenesis of HIV dementia

bull Lesions may also be located in the brain stem cerebellum and spinal cord

bull White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

HIV ENCEPHALOPATHY

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

A 34-year-old male with loss of orientation to time

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

HERPES SIMPLEX ENCEHPALITIS (HSE)

bull HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis

bull It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the

predilection of the disease for the temporal lobes

bull Clinical symptoms include nonspecific alteration in mental status fever and focal neurological deficits

EEG shows activity localized to the temporal lobe

bull Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is

by brain biopsy

bull Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential

as antiviral therapy significantly reduces the mortality

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

MRI

Affected areas however have a similar appearance in terms of signal characteristics

bull T1

bull may show general oedema in affected region

bull if complicated by sub acute haemorrhage there may be areas of hyper intense signal

bull T1 C+ (Gd)

bull enhancement is usually absent early on

bull later enhancement is variable in pattern 5

bull gyral enhancement

bull leptomeningeal enhancement

bull ring enhancement

bull diffuse enhancement

bull T2

bull hyperintensity of affected white matter and cortex

bull more established haemorrhagic components may be hypo intense

bull DWI ADC

bull more sensitive than T2 weighted images

bull restricted diffusion is common due to cytotoxic oedema

bull GE SWI - may demonstrate blooming if haemorrhagic (rare in neonates common in older patients)

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

This 33 year-old female patient presented with agitation confusion mutism and fever

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

Vascular-

A CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia linked to a gene on

chromosome 19 which presents with multiple lacunar and subcortical white matter infarctions There

is disproportionate cortical hypometabolism Presenile dementia and migraines develop in the third-

to-fourth decades of life

B Vasculitis- can caused by a wide spectrum of entities including drug abuse collagen vascular diseases

(eg systemic lupus erythematosus) granulomatous processes (eg sarcoidosis) and infectious causes

(eg syphilis)

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

The patient a 16-year-old girl presented with headache optic neuritis and fatigue

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

MRI

bull widespread confluent white matter

hyperintensities 2

bull More circumscribed hyperintense lesions are also

seen in the basal ganglia thalamus and pons 3

bull Although the subcortical white matter can be

diffusely involved the frontal (93) and temporal

(86) lobes and subinsular white matter (93) are

classical 2

bull There is relative sparing of the occipital and

orbitofrontal subcortical white matter 2subcortical

U-fibers and cortex

CADASIL

Post-therapeutic-

This condition can follow some types of chemotherapy causing necrotizing

leukoencephalopathy (eg methotrexate) immunosuppressive agents (eg

cyclosporin A) and radiation therapy

Radiation injury can occur at any point during the post-treatment period In the acute

period (first few months) this is manifested clinically by hypersomnolence and

usually has no CT or MR findings

Early injury (occurring within the first year) is usually marked by encephalopathy

often with focal white matter lesions on CT and MR imaging

Hemorrhagic radiation injury asymptomatic

MR images through temporal lobes in patient who had received helium ion irradiation for nasopharyngeal

carcinoma 3 years earlier

DYSMYELINATING DISORDERS

LEUKODYSTROPHIES

LYSOSOMAL STORAGE DISORDERS

Lysosomes are membrane-bound cell organelles that contain a variety of hydrolytic enzymes and

aid in the digestion of phagocytosed particles

When the activity of a specific lysosomal enzyme is deficient a lysosomal storage disorder may result

These disorders are classified according to what materials show abnormal accumulation in the

lysosomes (eg sphingolipidosis glycoproteinosis mucopolysaccharidosis mucolipidosis)

The underlying disorder may be diagnosed clinically with assay for the enzyme deficiency or abnormal

accumulation of material

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is an autosomal recessive disorder caused by a deficiency

of the lysosomal enzyme arylsulfatase A

This enzyme is necessary for the normal metabolism of sulfatides which are important

constituents of the myelin sheath In metachromatic leukodystrophy sulfatides

accumulate in various tissues including the brain peripheral nerves kidneys liver and

gallbladder The accumulation of sulfatides within glial cells and neurons causes the

characteristic metachromatic reaction

Metachromatic leukodystrophy is diagnosed biochemically on the basis of an abnormally

low level of arylsulfatase A in peripheral blood leukocytes and in urine

Three different types of metachromatic leukodystrophy are recognized according to

patientrsquos age at onset

1 late infantile

2 juvenile and

3 adult

The most common type is late infantile metachromatic leukodystrophy which usually

manifests in children between 12 and 18 months of age and is characterized by motor

signs of peripheral neuropathy followed by deterioration in intellect speech and

coordination

Within 2 years of onset gait disturbance quadriplegia blindness and decerebrate

posturing may be seen Death occurs 6 months to 4 years after onset of symptoms

bull At T2-weighted MR imaging metachromatic leukodystrophy manifests as symmetric confluent

areas of high signal intensity in the periventricular white matter with sparing of the subcortical

U fibers (Fig 1a)

bull No enhancement is evident at computed tomography (CT) or MR imaging (Fig 1b)

bull The tigroid and ldquoleopard skinrdquo patterns of demyelination which suggest sparing of the

perivascular white matter can be seen in the periventricular white matter and centrum

semiovale (Fig 2)

bull The corpus callosum internal capsule and corticospinal tracts are also frequently involved

bull The cerebellar white matter may appear hyperintense at T2-weighted MR imaging

bull In the later stage of metachromatic leukodystrophy corticosubcortical atrophy often occurs

particularly when the subcortical white matter is involved

Metachromatic leukodystrophy

Metachromatic leukodystrophy

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Hemorrhagic radiation injury asymptomatic

MR images through temporal lobes in patient who had received helium ion irradiation for nasopharyngeal

carcinoma 3 years earlier

DYSMYELINATING DISORDERS

LEUKODYSTROPHIES

LYSOSOMAL STORAGE DISORDERS

Lysosomes are membrane-bound cell organelles that contain a variety of hydrolytic enzymes and

aid in the digestion of phagocytosed particles

When the activity of a specific lysosomal enzyme is deficient a lysosomal storage disorder may result

These disorders are classified according to what materials show abnormal accumulation in the

lysosomes (eg sphingolipidosis glycoproteinosis mucopolysaccharidosis mucolipidosis)

The underlying disorder may be diagnosed clinically with assay for the enzyme deficiency or abnormal

accumulation of material

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is an autosomal recessive disorder caused by a deficiency

of the lysosomal enzyme arylsulfatase A

This enzyme is necessary for the normal metabolism of sulfatides which are important

constituents of the myelin sheath In metachromatic leukodystrophy sulfatides

accumulate in various tissues including the brain peripheral nerves kidneys liver and

gallbladder The accumulation of sulfatides within glial cells and neurons causes the

characteristic metachromatic reaction

Metachromatic leukodystrophy is diagnosed biochemically on the basis of an abnormally

low level of arylsulfatase A in peripheral blood leukocytes and in urine

Three different types of metachromatic leukodystrophy are recognized according to

patientrsquos age at onset

1 late infantile

2 juvenile and

3 adult

The most common type is late infantile metachromatic leukodystrophy which usually

manifests in children between 12 and 18 months of age and is characterized by motor

signs of peripheral neuropathy followed by deterioration in intellect speech and

coordination

Within 2 years of onset gait disturbance quadriplegia blindness and decerebrate

posturing may be seen Death occurs 6 months to 4 years after onset of symptoms

bull At T2-weighted MR imaging metachromatic leukodystrophy manifests as symmetric confluent

areas of high signal intensity in the periventricular white matter with sparing of the subcortical

U fibers (Fig 1a)

bull No enhancement is evident at computed tomography (CT) or MR imaging (Fig 1b)

bull The tigroid and ldquoleopard skinrdquo patterns of demyelination which suggest sparing of the

perivascular white matter can be seen in the periventricular white matter and centrum

semiovale (Fig 2)

bull The corpus callosum internal capsule and corticospinal tracts are also frequently involved

bull The cerebellar white matter may appear hyperintense at T2-weighted MR imaging

bull In the later stage of metachromatic leukodystrophy corticosubcortical atrophy often occurs

particularly when the subcortical white matter is involved

Metachromatic leukodystrophy

Metachromatic leukodystrophy

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

DYSMYELINATING DISORDERS

LEUKODYSTROPHIES

LYSOSOMAL STORAGE DISORDERS

Lysosomes are membrane-bound cell organelles that contain a variety of hydrolytic enzymes and

aid in the digestion of phagocytosed particles

When the activity of a specific lysosomal enzyme is deficient a lysosomal storage disorder may result

These disorders are classified according to what materials show abnormal accumulation in the

lysosomes (eg sphingolipidosis glycoproteinosis mucopolysaccharidosis mucolipidosis)

The underlying disorder may be diagnosed clinically with assay for the enzyme deficiency or abnormal

accumulation of material

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is an autosomal recessive disorder caused by a deficiency

of the lysosomal enzyme arylsulfatase A

This enzyme is necessary for the normal metabolism of sulfatides which are important

constituents of the myelin sheath In metachromatic leukodystrophy sulfatides

accumulate in various tissues including the brain peripheral nerves kidneys liver and

gallbladder The accumulation of sulfatides within glial cells and neurons causes the

characteristic metachromatic reaction

Metachromatic leukodystrophy is diagnosed biochemically on the basis of an abnormally

low level of arylsulfatase A in peripheral blood leukocytes and in urine

Three different types of metachromatic leukodystrophy are recognized according to

patientrsquos age at onset

1 late infantile

2 juvenile and

3 adult

The most common type is late infantile metachromatic leukodystrophy which usually

manifests in children between 12 and 18 months of age and is characterized by motor

signs of peripheral neuropathy followed by deterioration in intellect speech and

coordination

Within 2 years of onset gait disturbance quadriplegia blindness and decerebrate

posturing may be seen Death occurs 6 months to 4 years after onset of symptoms

bull At T2-weighted MR imaging metachromatic leukodystrophy manifests as symmetric confluent

areas of high signal intensity in the periventricular white matter with sparing of the subcortical

U fibers (Fig 1a)

bull No enhancement is evident at computed tomography (CT) or MR imaging (Fig 1b)

bull The tigroid and ldquoleopard skinrdquo patterns of demyelination which suggest sparing of the

perivascular white matter can be seen in the periventricular white matter and centrum

semiovale (Fig 2)

bull The corpus callosum internal capsule and corticospinal tracts are also frequently involved

bull The cerebellar white matter may appear hyperintense at T2-weighted MR imaging

bull In the later stage of metachromatic leukodystrophy corticosubcortical atrophy often occurs

particularly when the subcortical white matter is involved

Metachromatic leukodystrophy

Metachromatic leukodystrophy

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

LYSOSOMAL STORAGE DISORDERS

Lysosomes are membrane-bound cell organelles that contain a variety of hydrolytic enzymes and

aid in the digestion of phagocytosed particles

When the activity of a specific lysosomal enzyme is deficient a lysosomal storage disorder may result

These disorders are classified according to what materials show abnormal accumulation in the

lysosomes (eg sphingolipidosis glycoproteinosis mucopolysaccharidosis mucolipidosis)

The underlying disorder may be diagnosed clinically with assay for the enzyme deficiency or abnormal

accumulation of material

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is an autosomal recessive disorder caused by a deficiency

of the lysosomal enzyme arylsulfatase A

This enzyme is necessary for the normal metabolism of sulfatides which are important

constituents of the myelin sheath In metachromatic leukodystrophy sulfatides

accumulate in various tissues including the brain peripheral nerves kidneys liver and

gallbladder The accumulation of sulfatides within glial cells and neurons causes the

characteristic metachromatic reaction

Metachromatic leukodystrophy is diagnosed biochemically on the basis of an abnormally

low level of arylsulfatase A in peripheral blood leukocytes and in urine

Three different types of metachromatic leukodystrophy are recognized according to

patientrsquos age at onset

1 late infantile

2 juvenile and

3 adult

The most common type is late infantile metachromatic leukodystrophy which usually

manifests in children between 12 and 18 months of age and is characterized by motor

signs of peripheral neuropathy followed by deterioration in intellect speech and

coordination

Within 2 years of onset gait disturbance quadriplegia blindness and decerebrate

posturing may be seen Death occurs 6 months to 4 years after onset of symptoms

bull At T2-weighted MR imaging metachromatic leukodystrophy manifests as symmetric confluent

areas of high signal intensity in the periventricular white matter with sparing of the subcortical

U fibers (Fig 1a)

bull No enhancement is evident at computed tomography (CT) or MR imaging (Fig 1b)

bull The tigroid and ldquoleopard skinrdquo patterns of demyelination which suggest sparing of the

perivascular white matter can be seen in the periventricular white matter and centrum

semiovale (Fig 2)

bull The corpus callosum internal capsule and corticospinal tracts are also frequently involved

bull The cerebellar white matter may appear hyperintense at T2-weighted MR imaging

bull In the later stage of metachromatic leukodystrophy corticosubcortical atrophy often occurs

particularly when the subcortical white matter is involved

Metachromatic leukodystrophy

Metachromatic leukodystrophy

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is an autosomal recessive disorder caused by a deficiency

of the lysosomal enzyme arylsulfatase A

This enzyme is necessary for the normal metabolism of sulfatides which are important

constituents of the myelin sheath In metachromatic leukodystrophy sulfatides

accumulate in various tissues including the brain peripheral nerves kidneys liver and

gallbladder The accumulation of sulfatides within glial cells and neurons causes the

characteristic metachromatic reaction

Metachromatic leukodystrophy is diagnosed biochemically on the basis of an abnormally

low level of arylsulfatase A in peripheral blood leukocytes and in urine

Three different types of metachromatic leukodystrophy are recognized according to

patientrsquos age at onset

1 late infantile

2 juvenile and

3 adult

The most common type is late infantile metachromatic leukodystrophy which usually

manifests in children between 12 and 18 months of age and is characterized by motor

signs of peripheral neuropathy followed by deterioration in intellect speech and

coordination

Within 2 years of onset gait disturbance quadriplegia blindness and decerebrate

posturing may be seen Death occurs 6 months to 4 years after onset of symptoms

bull At T2-weighted MR imaging metachromatic leukodystrophy manifests as symmetric confluent

areas of high signal intensity in the periventricular white matter with sparing of the subcortical

U fibers (Fig 1a)

bull No enhancement is evident at computed tomography (CT) or MR imaging (Fig 1b)

bull The tigroid and ldquoleopard skinrdquo patterns of demyelination which suggest sparing of the

perivascular white matter can be seen in the periventricular white matter and centrum

semiovale (Fig 2)

bull The corpus callosum internal capsule and corticospinal tracts are also frequently involved

bull The cerebellar white matter may appear hyperintense at T2-weighted MR imaging

bull In the later stage of metachromatic leukodystrophy corticosubcortical atrophy often occurs

particularly when the subcortical white matter is involved

Metachromatic leukodystrophy

Metachromatic leukodystrophy

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Three different types of metachromatic leukodystrophy are recognized according to

patientrsquos age at onset

1 late infantile

2 juvenile and

3 adult

The most common type is late infantile metachromatic leukodystrophy which usually

manifests in children between 12 and 18 months of age and is characterized by motor

signs of peripheral neuropathy followed by deterioration in intellect speech and

coordination

Within 2 years of onset gait disturbance quadriplegia blindness and decerebrate

posturing may be seen Death occurs 6 months to 4 years after onset of symptoms

bull At T2-weighted MR imaging metachromatic leukodystrophy manifests as symmetric confluent

areas of high signal intensity in the periventricular white matter with sparing of the subcortical

U fibers (Fig 1a)

bull No enhancement is evident at computed tomography (CT) or MR imaging (Fig 1b)

bull The tigroid and ldquoleopard skinrdquo patterns of demyelination which suggest sparing of the

perivascular white matter can be seen in the periventricular white matter and centrum

semiovale (Fig 2)

bull The corpus callosum internal capsule and corticospinal tracts are also frequently involved

bull The cerebellar white matter may appear hyperintense at T2-weighted MR imaging

bull In the later stage of metachromatic leukodystrophy corticosubcortical atrophy often occurs

particularly when the subcortical white matter is involved

Metachromatic leukodystrophy

Metachromatic leukodystrophy

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

bull At T2-weighted MR imaging metachromatic leukodystrophy manifests as symmetric confluent

areas of high signal intensity in the periventricular white matter with sparing of the subcortical

U fibers (Fig 1a)

bull No enhancement is evident at computed tomography (CT) or MR imaging (Fig 1b)

bull The tigroid and ldquoleopard skinrdquo patterns of demyelination which suggest sparing of the

perivascular white matter can be seen in the periventricular white matter and centrum

semiovale (Fig 2)

bull The corpus callosum internal capsule and corticospinal tracts are also frequently involved

bull The cerebellar white matter may appear hyperintense at T2-weighted MR imaging

bull In the later stage of metachromatic leukodystrophy corticosubcortical atrophy often occurs

particularly when the subcortical white matter is involved

Metachromatic leukodystrophy

Metachromatic leukodystrophy

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Metachromatic leukodystrophy

Metachromatic leukodystrophy

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Metachromatic leukodystrophy

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Metachromatic leukodystrophy with involvement of the corticospinal tract

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Krabbe Disease

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder

caused by a deficiency of galactocerebroside -galactosidase an enzyme that degrades

cerebroside a normal constituent of myelin

As soon as myelination commences and myelin turnover becomes necessary

cerebrosides accumulate in the lysosomes of macrophages within the white matter

forming the globoid cells characteristic of the disease

The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty

gene on chromosome 14

The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood

leukocytes

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

The clinical manifestation of Krabbe disease varies with patient age at onset

Infantile late infantile juvenile and adult forms are recognized

The infantile form is the most common and manifests as hyperirritability increased muscle

tone fever and developmental arrest and regression

Disease progression is characterized by cognitive decline myoclonus and opisthotonus and

nystagmus

Typically Krabbe disease is rapidly progressive and fatal

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

bull CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci

in the thalami caudate nuclei corona radiata posterior limbs of the internal capsule and brainstem

bull The centrum semiovale periventricular white matter and deep gray matter demonstrate high signal

intensity at T2-weighted MR imaging

bull The subcortical U fibers are spared until late in the disease course

bull Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the

disease course

bull Severe progressive atrophy occurs as the disease advances

bull Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with

the underlying abnormal white matter despite the absence of an inflammatory reaction in the

pathologic specimen

bull Optic nerve hypertrophy may also occur in Krabbe disease

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Krabbe disease in a 2-year-old boy

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

KRABBES DISEASE

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Mucopolysaccharidosis

Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the

degradation of glycosaminoglycans

Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected

bull CT and MR imaging usually reveal delayed myelination atrophy varying degrees of hydrocephalus and

white matter changes

bull These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at

CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal

intensity on T2-weighted images (Fig 6)

bull The sharply defined foci are commonly present in the corpus callosum basal ganglia and cerebral white

matter

bull They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent

mucopolysaccharide-filled perivascular spaces (16)

bull As the disease progresses the lesions become larger and more diffuse reflecting the development of

infarcts and demyelination

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Mucopolysaccharidosis in a 4-year-old boy with Hurler disease

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

A patient with MPS II at 21 years of age

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Peroxisomal Disorders

Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and

monounsaturated fatty acids

Peroxisomal enzymes are also involved in gluconeogenesis lysine metabolism and glutaric acid

metabolism

Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more

of these enzymes

ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency whereas Zellweger

syndrome and neonatal ALD are caused by multiple enzyme defects

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

X-linked Adrenoleukodystrophy

bull X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system adrenal

cortex and testes (17)

bull The genetic defect responsible for X-linked ALD is located in Xq28 the terminal segment of the long arm of the X

chromosome

bull X-linked ALD is caused by a deficiency of a single enzyme acyl-CoA synthesase This deficiency prevents the

breakdown of very long chain fatty acids which then accumulate in tissue and plasma (17)

bull In the early stages of classic ALD symmetric white matter demyelination occurs in the peritrigonal regions and

extends across the corpus callosum splenium (Figs 7 8)

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

bull Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white

matter is affected

bull The subcortical white matter is relatively spared in the early stage but often becomes involved in the later

stages

bull The affected cerebral white matter typically has three different zones

The central or inner zone appears moderately hypointense at T1-weighted MR imaging and

markedly hyperintense at T2-weighted imaging This zone corresponds to irreversible gliosis and

scarring

The intermediate zone represents active inflammation and breakdown in the blood-brain barrier At

T2-weighted MR imaging this zone may appear isointense or slightly hypointense and readily

enhances after intravenous administration of contrast material (Fig 7c)

The peripheral or outer zone represents the leading edge of active demyelination it appears

moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19ndash21)

bull Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-

weighted MR imaging (Fig 9a 9b) (21)

bull Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22)

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

ALD in a 5-year-old boy

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

ALD with preferential involvement of the descending pyramidal tract

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Atypical ALD

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Zellweger Syndrome

Zellweger syndrome or cerebrohepatorenal syndrome is an autosomal recessive disorder caused

by multiple enzyme defects and characterized by liver dysfunction with jaundice marked mental

retardation weakness hypotonia and craniofacial dysmorphism (23)

It may lead to death in early childhood The severity of disease varies and is determined by the

degree of peroxisomal activity

Ultrasonography of the kidneys reveals small cortical cysts

MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the

perisylvian and perirolandic regions (Fig 11) The pattern of gyral abnormality is similar to that

seen in polymicrogyria or pachygyria

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Zellweger syndrome in a 5-month-old girl

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

Diseases Caused by Mitochondrial Dysfunction

bull Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular

disorders caused by a proved or proposed defect in the oxidative metabolic

pathways of energy production probably owing to a structural or functional

mitochondrial defect (24ndash27)

bull Some reasonably well-defined disorders include MELAS syndrome Kearn-Sayre

syndrome Leigh disease and MERRF syndrome (Table 1)

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

MELAS Syndrome

(mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes)

bull Patients with MELAS syndrome usually appear healthy at birth with normal early development then

exhibit delayed growth episodic vomiting seizures and recurrent cerebral injuries resembling stroke

bull These stroke like events probably the result of a proliferation of dysfunctional mitochondria in the

smooth muscle cells of small arteries may give rise to either permanent or reversible deficits

bull The disease course is progressive with periodic acute exacerbation (27ndash29)

bull Serum and cerebrospinal fluid lactate levels are usually elevated

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

General features include multiple infarcts involving multiple vascular territories which may be either symmetrical

or asymmetrical Parieto-occipital and parieto-temporal involvement is most common Basal ganglia calcification

is seen These features are more prominent feature in older patients Atrophy also present

MRI

chronic infarcts

bull involving multiple vascular territories

bull may be either symmetrical or asymmetrical

bull parieto-occipital and parieto-temporal (most common)

acute infarcts

bull swollen gyri with increased T2 signal

bull may enhance

bull subcortical white matter involved

bull increased signal on DWI (T2 shine through) with little if any change on ADC thought to

represent vasogenic rather than cytotoxic oedema 3

MR spectroscopy may demonstrate elevated lactate 3

MELAS syndrome in a 10-year-old boy with migrating infarction

Sequential MR images of a female patient with MELAS at ages 8 and 13 years

Leighs Disease

bull Leigh disease or subacute necrotizing encephalomyelopathy is an inherited progressive

neurodegenerative disease of infancy or early childhood with variable course and prognosis (30)

bull Affected infants and children typically present with hypotonia psychomotor deterioration ataxia

ophthalmoplegia ptosis dystonia and swallowing difficulties

bull Characteristic pathologic abnormalities include micro-cystic cavitation vascular proliferation

neuronal loss and demyelination of the midbrain basal ganglia and cerebellar dentate nuclei and

occasionally of the cerebral white matter (31)

Typical MR imaging findings include symmetric putaminal involvement which may be associated

with abnormalities of the caudate nuclei globus pallidi thalami and brainstem and less frequently of

the cerebral cortex (Fig 13)

The cerebral white matter is rarely affected

Enhancement may be seen at MR imaging and may correspond to the onset of acute necrosis (31)

LEIGHS DISEASE

LEIGHS DISEASE

Canavan Disease

Canavan disease or spongiform leukodystrophy is an autosomal recessive disorder

caused by a deficiency of N-acetylaspartylase which results in an accumulation of N-

acetylaspartic acid in the urine plasma and brain

It usually manifests in early infancy as hypotonia followed by spasticity cortical

blindness and macrocephaly (2)

Canavan disease is a rapidly progressive illness with a mean survival time of 3 years

Definite diagnosis usually requires brain biopsy or autopsy

bull Canavan disease is characterized at pathologic analysis by extensive vacuolization that initially

involves the subcortical white matter then spreads to the deep white matter (Fig 14c)

bull Electron microscopy demonstrates increased water content within the glial tissue described as

having the texture of a wet sponge as well as dysmyelination (3233)

bull T1-weighted MR imaging demonstrates symmetric areas of homogeneous diffuse low signal

intensity throughout the white matter whereas T2-weighted imaging shows nearly homogeneous

high signal intensity throughout the white matter

bull The subcortical U fibers are preferentially affected early in the course of the disease

bull In rapidly progressive cases the internal and external capsules are involved and the cerebellar

white matter is usually affected as well

bull As the disease progresses atrophy becomes conspicuous

Canavan disease in a 6-month-old boy with macrocephaly

CANAVAN DISEASE

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Sequential MR images of a female patient with MELAS at ages 8 and 13 years

Leighs Disease

bull Leigh disease or subacute necrotizing encephalomyelopathy is an inherited progressive

neurodegenerative disease of infancy or early childhood with variable course and prognosis (30)

bull Affected infants and children typically present with hypotonia psychomotor deterioration ataxia

ophthalmoplegia ptosis dystonia and swallowing difficulties

bull Characteristic pathologic abnormalities include micro-cystic cavitation vascular proliferation

neuronal loss and demyelination of the midbrain basal ganglia and cerebellar dentate nuclei and

occasionally of the cerebral white matter (31)

Typical MR imaging findings include symmetric putaminal involvement which may be associated

with abnormalities of the caudate nuclei globus pallidi thalami and brainstem and less frequently of

the cerebral cortex (Fig 13)

The cerebral white matter is rarely affected

Enhancement may be seen at MR imaging and may correspond to the onset of acute necrosis (31)

LEIGHS DISEASE

LEIGHS DISEASE

Canavan Disease

Canavan disease or spongiform leukodystrophy is an autosomal recessive disorder

caused by a deficiency of N-acetylaspartylase which results in an accumulation of N-

acetylaspartic acid in the urine plasma and brain

It usually manifests in early infancy as hypotonia followed by spasticity cortical

blindness and macrocephaly (2)

Canavan disease is a rapidly progressive illness with a mean survival time of 3 years

Definite diagnosis usually requires brain biopsy or autopsy

bull Canavan disease is characterized at pathologic analysis by extensive vacuolization that initially

involves the subcortical white matter then spreads to the deep white matter (Fig 14c)

bull Electron microscopy demonstrates increased water content within the glial tissue described as

having the texture of a wet sponge as well as dysmyelination (3233)

bull T1-weighted MR imaging demonstrates symmetric areas of homogeneous diffuse low signal

intensity throughout the white matter whereas T2-weighted imaging shows nearly homogeneous

high signal intensity throughout the white matter

bull The subcortical U fibers are preferentially affected early in the course of the disease

bull In rapidly progressive cases the internal and external capsules are involved and the cerebellar

white matter is usually affected as well

bull As the disease progresses atrophy becomes conspicuous

Canavan disease in a 6-month-old boy with macrocephaly

CANAVAN DISEASE

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Leighs Disease

bull Leigh disease or subacute necrotizing encephalomyelopathy is an inherited progressive

neurodegenerative disease of infancy or early childhood with variable course and prognosis (30)

bull Affected infants and children typically present with hypotonia psychomotor deterioration ataxia

ophthalmoplegia ptosis dystonia and swallowing difficulties

bull Characteristic pathologic abnormalities include micro-cystic cavitation vascular proliferation

neuronal loss and demyelination of the midbrain basal ganglia and cerebellar dentate nuclei and

occasionally of the cerebral white matter (31)

Typical MR imaging findings include symmetric putaminal involvement which may be associated

with abnormalities of the caudate nuclei globus pallidi thalami and brainstem and less frequently of

the cerebral cortex (Fig 13)

The cerebral white matter is rarely affected

Enhancement may be seen at MR imaging and may correspond to the onset of acute necrosis (31)

LEIGHS DISEASE

LEIGHS DISEASE

Canavan Disease

Canavan disease or spongiform leukodystrophy is an autosomal recessive disorder

caused by a deficiency of N-acetylaspartylase which results in an accumulation of N-

acetylaspartic acid in the urine plasma and brain

It usually manifests in early infancy as hypotonia followed by spasticity cortical

blindness and macrocephaly (2)

Canavan disease is a rapidly progressive illness with a mean survival time of 3 years

Definite diagnosis usually requires brain biopsy or autopsy

bull Canavan disease is characterized at pathologic analysis by extensive vacuolization that initially

involves the subcortical white matter then spreads to the deep white matter (Fig 14c)

bull Electron microscopy demonstrates increased water content within the glial tissue described as

having the texture of a wet sponge as well as dysmyelination (3233)

bull T1-weighted MR imaging demonstrates symmetric areas of homogeneous diffuse low signal

intensity throughout the white matter whereas T2-weighted imaging shows nearly homogeneous

high signal intensity throughout the white matter

bull The subcortical U fibers are preferentially affected early in the course of the disease

bull In rapidly progressive cases the internal and external capsules are involved and the cerebellar

white matter is usually affected as well

bull As the disease progresses atrophy becomes conspicuous

Canavan disease in a 6-month-old boy with macrocephaly

CANAVAN DISEASE

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

LEIGHS DISEASE

LEIGHS DISEASE

Canavan Disease

Canavan disease or spongiform leukodystrophy is an autosomal recessive disorder

caused by a deficiency of N-acetylaspartylase which results in an accumulation of N-

acetylaspartic acid in the urine plasma and brain

It usually manifests in early infancy as hypotonia followed by spasticity cortical

blindness and macrocephaly (2)

Canavan disease is a rapidly progressive illness with a mean survival time of 3 years

Definite diagnosis usually requires brain biopsy or autopsy

bull Canavan disease is characterized at pathologic analysis by extensive vacuolization that initially

involves the subcortical white matter then spreads to the deep white matter (Fig 14c)

bull Electron microscopy demonstrates increased water content within the glial tissue described as

having the texture of a wet sponge as well as dysmyelination (3233)

bull T1-weighted MR imaging demonstrates symmetric areas of homogeneous diffuse low signal

intensity throughout the white matter whereas T2-weighted imaging shows nearly homogeneous

high signal intensity throughout the white matter

bull The subcortical U fibers are preferentially affected early in the course of the disease

bull In rapidly progressive cases the internal and external capsules are involved and the cerebellar

white matter is usually affected as well

bull As the disease progresses atrophy becomes conspicuous

Canavan disease in a 6-month-old boy with macrocephaly

CANAVAN DISEASE

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

LEIGHS DISEASE

Canavan Disease

Canavan disease or spongiform leukodystrophy is an autosomal recessive disorder

caused by a deficiency of N-acetylaspartylase which results in an accumulation of N-

acetylaspartic acid in the urine plasma and brain

It usually manifests in early infancy as hypotonia followed by spasticity cortical

blindness and macrocephaly (2)

Canavan disease is a rapidly progressive illness with a mean survival time of 3 years

Definite diagnosis usually requires brain biopsy or autopsy

bull Canavan disease is characterized at pathologic analysis by extensive vacuolization that initially

involves the subcortical white matter then spreads to the deep white matter (Fig 14c)

bull Electron microscopy demonstrates increased water content within the glial tissue described as

having the texture of a wet sponge as well as dysmyelination (3233)

bull T1-weighted MR imaging demonstrates symmetric areas of homogeneous diffuse low signal

intensity throughout the white matter whereas T2-weighted imaging shows nearly homogeneous

high signal intensity throughout the white matter

bull The subcortical U fibers are preferentially affected early in the course of the disease

bull In rapidly progressive cases the internal and external capsules are involved and the cerebellar

white matter is usually affected as well

bull As the disease progresses atrophy becomes conspicuous

Canavan disease in a 6-month-old boy with macrocephaly

CANAVAN DISEASE

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Canavan Disease

Canavan disease or spongiform leukodystrophy is an autosomal recessive disorder

caused by a deficiency of N-acetylaspartylase which results in an accumulation of N-

acetylaspartic acid in the urine plasma and brain

It usually manifests in early infancy as hypotonia followed by spasticity cortical

blindness and macrocephaly (2)

Canavan disease is a rapidly progressive illness with a mean survival time of 3 years

Definite diagnosis usually requires brain biopsy or autopsy

bull Canavan disease is characterized at pathologic analysis by extensive vacuolization that initially

involves the subcortical white matter then spreads to the deep white matter (Fig 14c)

bull Electron microscopy demonstrates increased water content within the glial tissue described as

having the texture of a wet sponge as well as dysmyelination (3233)

bull T1-weighted MR imaging demonstrates symmetric areas of homogeneous diffuse low signal

intensity throughout the white matter whereas T2-weighted imaging shows nearly homogeneous

high signal intensity throughout the white matter

bull The subcortical U fibers are preferentially affected early in the course of the disease

bull In rapidly progressive cases the internal and external capsules are involved and the cerebellar

white matter is usually affected as well

bull As the disease progresses atrophy becomes conspicuous

Canavan disease in a 6-month-old boy with macrocephaly

CANAVAN DISEASE

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

bull Canavan disease is characterized at pathologic analysis by extensive vacuolization that initially

involves the subcortical white matter then spreads to the deep white matter (Fig 14c)

bull Electron microscopy demonstrates increased water content within the glial tissue described as

having the texture of a wet sponge as well as dysmyelination (3233)

bull T1-weighted MR imaging demonstrates symmetric areas of homogeneous diffuse low signal

intensity throughout the white matter whereas T2-weighted imaging shows nearly homogeneous

high signal intensity throughout the white matter

bull The subcortical U fibers are preferentially affected early in the course of the disease

bull In rapidly progressive cases the internal and external capsules are involved and the cerebellar

white matter is usually affected as well

bull As the disease progresses atrophy becomes conspicuous

Canavan disease in a 6-month-old boy with macrocephaly

CANAVAN DISEASE

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Canavan disease in a 6-month-old boy with macrocephaly

CANAVAN DISEASE

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

CANAVAN DISEASE

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Pelizaeus-Merzbacher Disease

bull PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid

protein

bull This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival

bull PMD has traditionally been divided into classic and connatal forms (3435)

bull Classic PMD begins during late infancy with X-linked recessive inheritance

bull Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy The connatal

form has either X-linked or autosomal recessive inheritance

bull Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye

movements nystagmus extrapyramidal hyperkinesias spasticity and slow psychomotor

development

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

T2-weighted MR imaging reveals a nearly total lack of normal myelination with

diffuse high signal intensity that extends peripherally to involve the subcortical U

fibers along with early involvement of the internal capsule (Fig 15)

Sometimes the white matter demonstrates high signal intensity with small scattered

foci of more normal signal intensity a finding that may reflect the tigroid pattern of

myelination (36)

At pathologic analysis the involved white matter demonstrates patchy distribution of

dysmyelination with preserved myelin islands

These findings are frequently seen along the perivascular area thus giving rise to the

characteristic tigroid appearance (3536)

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

PMD in a 7-month-old boy

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Alexander Disease

bull Alexander disease or fibrinoid leukodystrophy is characterized at pathologic analysis by massive

deposition of Rosenthal fibers (dense eosinophilic rodlike cytoplasmic inclusions found in astrocytes)

in the subependymal subpial and perivascular regions (Fig 16b) (37)

bull Three clinical subgroups are recognized

bull The infantile subgroup is characterized by early onset of macrocephaly psychomotor retardation and

seizure Death occurs within 2ndash3 years The diagnosis is made on the basis of a combination of

macrocephaly early onset of clinical findings and imaging findings but definite diagnosis usually

requires brain biopsy or autopsy

bull In the juvenile subgroup onset of symptoms occurs between 7 and 14 years of age Progressive bulbar

symptoms with spasticity are common

bull In the adult subgroup onset of symptoms occurs between the 2nd and 7th decades The symptoms and

disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

bull Alexander disease has a predilection for the frontal lobe white matter early in its course CT

demonstrates low attenuation in the deep frontal lobe white matter

bull Enhancement is often seen near the tips of the frontal horns early in the disease course (39) The

characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging

bull These hyperintense areas progress posteriorly to the parietal white matter and internal and external

capsules (Fig 16a)

bull The subcortical white matter is affected early in the disease course

bull In the late stages of the disease cysts may develop in affected regions of the brain

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Alexander disease in a 5-year-old boy with macrocephaly

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Early MR imaging studies in a patient with presumed juvenile Alexander disease obtained at the age of 4

years

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

VANISHING WHITE MATTER DISEASE

Childhood ataxia with central hypomyelination (CACH)

bull Vanishing white matter disease is an autosomal recessive disease due to mutations in all five gene

subunits encoding the eukaryotic translation initiation factor eIF2B

bull This factor is a regulator of the final step of proteins production in which mRNA is translated into

proteins under circumstances of mild stress

bull Clinically after an initial normal or mildly delayed psychomotor development patients show a

neurological picture whose course is chronic and progressive with additional episodes of rapid

deterioration following minor infection and minor head trauma that may lead to lethargy or coma

bull Cerebellar ataxia and spasticity are the main neurological signs

bull Optic atrophy and seizures may occur

bull Mental impairment is relatively mild and usually less severe than motor dysfunction

bull Pathological abnormalities primarily involve the axons

bull It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins

within oligodendrocytes leading to hypomyelination loss of myelin and subsequent cystic degeneration

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

bull MRI of vanishing white matter disease (VWMD) also has a characteristic pattern

bull It shows features of confluent cystic degeneration white matter signal appears CSF-like with

progressive loss of white matter over time on proton density and FLAIR images

bull Regions of relative sparing include the U-fibers corpus callosum internal capsule and the

anterior commissure

bull The cerebellar white matter and brainstem show variable degrees of involvement but do not

undergo cystic degeneration

bull MRS shows complete absence of all metabolites within cystic white matter

bull Few authors opine that MRI of the brain is usually diagnostic in VWM It shows an abnormal

signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and

cystic degeneration of the affected white matter that is replaced by fluid

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

VANISHING WHITE MATTER DISEASE

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

MEGALENCEPHALIC LEUKOENCEPHALOPATHY

bull Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first

described by van der Knaap et al in 1995

bull Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of

neurodegenerative disorder characterized by infantile onset macrocephaly cerebral

leukoencephalopathy and mild neurological symptoms and an extremely slow course of

functional deterioration

bull It is a rare disease with autosomal recessive inheritance

bull In typical cases the MR findings are often diagnostic of MLC

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

bull MR shows swollen white matter and diffuse supratentorial symmetrical white matter

changes in the cerebral hemispheres with relative sparing of central white matter

structures like the corpus callosum internal capsule and brain stem

bull Subcortical cysts are almost always present in the anterior temporal region and are also

frequently noted in frontoparietal region

bull Grey matter is usually spared

bull Gradually the white matter swelling decreases and cerebral atrophy may set in

bull The subcortical cysts may increase in size and number

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Predominance of the white matter abnormalities

Alexander frontal WM ALD parieto occipital WM KSS sparing of PV WM MLD PV amp deep WM leopard skin

Cortical neuronal disorder illdefined broad PV rim

Hypo VMD diffuse cerebral WM

CerebrotendinousXanthomatosis cerebellargt cerebral

Adult onset ALD middle cerebellar peduncles

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

Conclusions

There are many different white matter diseases each of which has distinctive features

MR imaging is highly sensitive in determining the presence and assessing the severity

of underlying white matter abnormalities

Although the findings are often non-specific systematic analysis of the finer details of

disease involvement may permit a narrower differential diagnosis which the clinician

can then further refine with knowledge of patient history clinical testing and

metabolic analysis

MR imaging has also been extensively used to monitor the natural progression of

various white matter disorders and the response to therapy

THANK YOU

THANK YOU