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The new england journal of

medicine

2271

case records of the

massachusetts general hospital

Founded by

Richard C. CabotNancy Lee Harris, m.d.,

Editor

Jo-Anne O. Shepard, m.d.

,Associate Editor

Stacey M. Ellender,Assistant Editor

Sally H. Ebeling,Assistant Editor

Christine C. Peters,Assistant Editor

Case 36-2005: A 61-Year-Old Womanwith Seizure, Disturbed Gait,

and Altered Mental Status

Bradford C. Dickerson, M.D., David Holtzman, M.D., Ph.D., P. Ellen Grant, M.D.,and Di Tian, M.D., Ph.D.

From the Departments of Neurology(B.C.D., D.H.) and Pediatrics (D.H.), theDivision of Pediatric Radiology, Departmentof Radiology (P.E.G.), and the Depart-ment of Pathology (D.T.), MassachusettsGeneral Hospital; the Division of Cogni-tive and Behavioral Neurology, Departmentof Neurology, Brigham and Womens Hos-pital (B.C.D.); and the Departments of Neu-rology (B.C.D., D.H.), Pediatrics (D.H.),Radiology (P.E.G.), and Pathology (D.T.),

Harvard Medical School all in Boston.

N Engl J Med 2005;353:2271-80.

Copyright 2005 Massachusetts Medical Society.

Dr. Ronan Walsh

(Department of Neurology, Brigham and Womens Hospital): A 61-year-old left-handed woman was admitted to the neurology service of this hospital because

of a seizure and altered mental status.On the morning of admission, her husband awoke at 4 a.m. to find her thrashing in

bed, with rhythmic movements of all four extremities, for two to five minutes. She sub-

sequently appeared groggy but alert, with a facial droop, garbled speech, and an inabilityto follow verbal commands. Emergency-medical-services personnel were called and

she was brought to the emergency department of this hospital and admitted to the neu-

rology service.The patient had been in good health, with the exception of mild hypertension forwhich she took no medications. She worked in retail sales, had smoked until she was35 years of age, and rarely drank alcohol. She was married with four sons, had no sib-

lings, and had no family history of stroke or other neurologic illness.Her vital signs were normal except for a blood pressure of 180/76 mm Hg. The weight

was 73 kg and the height 150 cm. The general physical examination revealed no abnor-malities. On neurologic examination, the patient was alert and pleasant but did not

follow commands or know the date. When speaking, she made frequent phonemicparaphasic errors and perseverated. She could write but not speak the names of objectson the National Institutes of Health stroke cards and could not repeat spoken words.

She read with paraphasic errors and did not follow written commands. Motor exami-nation revealed no pronator drift and full strength in the arms and legs. There was de-

creased blink reflex in response to threat on the right. Her extraocular movements werefull. A sensory examination was limited by her aphasia. Reflexes were 2+ throughout,

with the left toe going downward on plantar-reflex testing and the right equivocal. Thegait was slightly wide-based but steady with good stride. The serum levels of electrolytes,calcium, phosphorus, and magnesium were normal, as were the results of renal-func-

tion tests. The cerebrospinal fluid protein and glucose levels were normal, and the cellcounts showed no abnormalities. Other laboratory-test results are shown in Table 1.

pres en t at i on of cas e

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Phenytoin was administered intravenously. Aurinary tract infection was confirmed and treated

with levofloxacin. Computed tomographic (CT)scanning of the brain revealed a focus of low atten-

uation in the left temporal lobe. Magnetic resonanceimaging (MRI) disclosed a corresponding region

of bright signal in the left temporal lobe on T

2

-weighted and diffusion-weighted imaging. An elec-troencephalogram revealed periodic lateralizing

epileptiform discharges in the left hemisphere withmarked asymmetry in the form of low-amplitude

delta and theta waves on the left. A biopsy of theleft temporal-lobe lesion was performed on thefourth hospital day. An examination of the biopsy

specimen disclosed features that were consistentwith ischemic changes.

The patients speech gradually improved but re-mained severely impaired. She was discharged to a

rehabilitation facility on the 16th hospital day. Over

the course of the next two months, she was able toperform most activities of daily living, but language

difficulty and confusion persisted. She was readmit-ted for a repeated brain biopsy, two months later,

which showed features identical to the first.For the next six months, she remained aphasic

and confused, and she had difficulty recognizingfamily members. She read and wrote at a second-grade level. No further seizure activity occurred.

Over a two-day period, worsening aphasia and con-fusion developed, and she was again brought to

the emergency room and admitted to the hospital.The results of the neurologic examination were un-

changed from the first admission.A repeated brain MRI revealed a new, right-

sided, temporo-occipital lesion that was bright on

T

2

-weighted and diffusion-weighted imaging. Elec-troencephalography revealed right-sided parieto-

occipital periodic lateralizing epileptiform dis-

charges, two separate bursts of activity consistent

with focal electrographic seizures, and generalizedslowing. The phenytoin level was 8 g per milliliter.Intravenous phenytoin (0.5 g) was given and clo-

nazepam was begun. The levels of cerebrospinalfluid protein and glucose and the cell counts were

normal. Other laboratory-test results are shown inTable 1. The patient was treated for a confirmed

urinary tract infection. A biopsy specimen of theleft deltoid muscle obtained on the third hospital

day (of the readmission) showed mild myofiber at-rophy and occasional fibers with abnormal NADHtetrazolium reductase (NADH-TR) staining. Testing

of a blood specimen for mitochondrial DNA muta-tions was negative for the seven most common

mutations. The patient was discharged on the fifthhospital day with her language functioning havingreturned to baseline levels.

Approximately six weeks after discharge she be-

gan to have difficulty hearing, worse on the left sidethan on the right. Two weeks later, she had an epi-sode of tremulousness in the left hand and was re-

admitted to the hospital. A new enhancing lesionin the right temporal lobe was seen on MRI. Her

symptoms resolved, and she was discharged afterthree days. Over the course of the next five months,her speech fluency and comprehension deteriorat-

ed. She had increasing difficulty with oral intake,frequently regurgitated food and pills, and lost 23

kg. Her gait became unsteady, and she could walkonly with assistance. She was readmitted to the

hospital.

The patients vital signs were normal. On neu-rologic examination, she was alert but could not

answer questions or follow verbal commands. Hergait was shuffling, with small steps, and she re-

quired the assistance of one person. The phenytoinlevel was elevated at 25.8 g per milliliter (normal,

5 to 20); phenytoin was withheld and her gaitgradually improved. During the hospital stay sheshowed some paranoid behavior and seemed to

have hallucinations or illusions, which improvedafter treatment with quietapine. Thiamine, biotin,

coenzyme Q10, folate, riboflavin, vitamin C, andvitamin E were added to the patients treatment.

Auditory evoked responses in the brain stem con-firmed dysfunction in the peripheral hearing sys-tem, worse on the left side than on the right side.

A gastrostomy tube was inserted on the 15thhospital day, and a diagnostic procedure was per-

formed.

Table 1. Laboratory-Test Results.

Variable (Normal Range)1st

Admission3rd

Admission

Creatine kinase (40150 U/liter) 230

Alkaline phosphatase (30120 U/liter) 51 179

Aspartate aminotransferase (035 U/liter) 63 28

Alanine aminotransferase (034 U/liter) 37 25

Lactic acid (0.61.7 mmol/liter) 3.2

Cerebrospinal fluid lactate (0.42.2 mmol/liter) 7.4 4.6

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Dr. Bradford C. Dickerson:

This 61-year-old womanhad an acute neurologic syndrome that began with

a seizure and was followed by residual aphasia,which was accompanied by right visual-field loss.

This set of focal neurologic deficits localizes thelesion to the left temporo-occipital region. Hyper-

tension was the only obvious element of the medi-cal history that predisposed the patient to neurolog-

ic disease. At the time of her initial presentation,the differential diagnosis was broad, including cere-brovascular, neoplastic, infectious, inflammatory,

and metabolic processes. Given the absence of ahistory of a prodrome (such as a headache, subtle

neurologic symptoms, or systemic illness) or pre-disposing conditions (such as autoimmune disease

or alcoholism), a cerebrovascular insult was highon the list of diagnostic possibilities.

Although the development of seizures soon af-ter that of ischemic cerebral infarcts was describedmore than 100 years ago,

1

seizure is the presenting

feature in only 2 to 33 percent of ischemic strokes.

2

However, seizures are common as a presenting fea-

ture of other cerebrovascular diseases, includinglobar intracerebral hemorrhage,

3

cerebral venoussinus thrombosis,

4

and hypertensive encephalopa-

thy.

5

A neuroimaging study is an essential and ur-gent component of the workup of a patient who

presents to the hospital in this manner; the inter-pretation of the study will heavily influence man-

agement of the acute syndrome.

May we review the neuroimaging studies?

Dr. P. Ellen Grant:

The MRI obtained on the pa-

tients first admission (Fig. 1A) shows increasedT

2

-weighted signal in both gray and white matter

of the left temporal lobe, indicating increased freewater, which results in a local mass effect effacing

the sulci. On the T

1

-weighted images obtained af-ter the administration of contrast material, there isa small region of cortical enhancement, indicating

breakdown of the bloodbrain barrier (Fig. 1B).On diffusion-weighted imaging, there are areas of

abnormally bright signal in the left temporal lobe(Fig. 1C), which indicates increased T

2

-weighted

signal, decreased diffusion, or both. The corre-sponding apparent-diffusion-coefficient map (Fig.1D) indicates that the rate of diffusion in the affect-

ed cortex is only mildly decreased (10 to 15 percent),whereas the subcortical white matter has increased

diffusion (approximately twice the normal rate).

Decreased diffusion occurs when there is failure

or impairment of the sodiumpotassium pump.When there is complete failure, necrosis ensues andthe apparent-diffusion-coefficient values are typical-

ly decreased by 60 to 80 percent. In this case, the cor-tical apparent-diffusion-coefficient values are mildly

di fferen t i al di ag n os i s

Figure 1. Magnetic Resonance Images from the First Admission.

An axial fluid-attenuated inversion recovery image (Panel A) shows increased

signal and sulcal effacement involving a large portion of the left temporal lobe(arrows). The signal in this region was low on T

1

-weighted imaging and after

the administration of contrast material (Panel B); there was a small region of

cortical enhancement (arrow). Diffusion-weighted imaging is used to exam-

ine the properties of the free water to determine whether the water moleculesare moving at a slower rate than normal, as in metabolic dysfunction or fail-

ure, or at a faster rate than normal, as in vasogenic edema. Bright signal on

diffusion-weighted imaging can be due to increased T

2

-weighted signal, de-creased diffusion, or both. The diffusion-weighted image (Panel C) shows

increased cortical signal in the anterior left temporal lobe (arrows). The corre-

sponding apparent-diffusion-coefficient maps are used to determine whetherthe bright diffusion-weighted-imaging signal is due to decreased diffusion

or increased T

2

-weighted signal. Each pixel value on the apparent-diffusion-

coefficient map is the rate of water diffusion in that pixel. On the apparent-diffusion-coefficient map (Panel D), the cortical regions have diffusion that

is normal to only slightly decreased (10 to 15 percent), as compared with the

normal contralateral cortex. The subcortical white matter in the anterior left

temporal lobe (arrows) has increased diffusion (approximately twice the nor-mal rate).

A B

C D

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decreased suggesting that either a small frac-

tion of cells is undergoing necrosis or the sodiumpotassium pump is partially impaired. Increaseddiffusion occurs in vasogenic edema, and thus the

edema is probably affecting the subcortical whitematter. Magnetic resonance spectroscopy showed

almost complete loss ofN

-acetylaspartate, choline,and creatine, but with a markedly elevated lactate

peak. The perfusion study showed symmetric bloodvolume and blood flow without a clear defect in the

left temporal lobe, which would be atypical in acutestroke. The mean transit times were normal.

Eight months later, the left temporal-lobe abnor-

mality had evolved into an area of encephalomala-cia, but there was now a right temporo-occipital

abnormality similar in appearance to the left tem-poral-lobe lesion at presentation. The lesion was

bright on diffusion-weighted imaging, and theapparent diffusion coefficient indicated that diffu-

sion was only approximately 10 percent decreased.Therefore, much of the bright signal seen on diffu-sion-weighted imaging was due to increased T

2

-

weighted signal and only a small amount was dueto a decrease in the apparent diffusion coefficient.

Four days later, this lesion had enlarged in size(Fig. 2A and 2B), and on the apparent-diffusion-coefficient map, increased diffusion was evident in

the subcortical white matter, probably owing tovasogenic edema (Fig. 2C). The diffusion in the

cortex was normal to approximately 10 to 15 per-cent decreased. Perfusion-weighted imaging, as be-

fore, showed no focal deficit, but there was mildly

increased cerebral blood flow and decreased meantransit time. A proton magnetic resonance spec-

trograph in the affected regions (Fig. 2D) showedreduction of all normal metabolites and a large lac-

tate peak indicative of cell loss and anaerobic metab-olism.

What disorders present acutely as bright lesionsinvolving cortex and white matter with T

2

-weightedimaging and diffusion-weighted imaging? In an

acute stroke, the lesion apparent-diffusion-coeffi-cient values are typically markedly reduced, whereas

here the apparent-diffusion-coefficient values wereelevated in the white matter. Also in acute stroke,

there is typically a perfusion deficit in the area of theabnormality on diffusion-weighted imaging, where-as here there was no perfusion defect. Occasionally

status epilepticus can cause increased diffusion-weighted imaging, but typically only the cortex is

involved and there is at most only minimal corticaledema without mass effect. In status epilepticus,

ipsilateral thalamic involvement is often seen, prob-

ably owing to involvement of cortical thalamicloops. Therefore, the imaging findings do not fitwell either with a focal arterial ischemic event or

with status epilepticus.These asynchronous lesions, which presented

acutely with cortical and subcortical edema withmildly decreased cortical apparent-diffusion-coef-

ficient values and elevated white-matter apparent-diffusion-coefficient values, no perfusion deficit,

and marked lactate elevation, are evidence of corti-cal injury, white-matter vasogenic edema, and an-aerobic metabolism in the presence of maintained

perfusion. These findings are strongly suggestive ofa metabolic disorder.

Dr. Dickerson:

During this patients first hospital-ization, the neuroimaging findings confirmed the

clinical localization of the left temporo-occipitallesion, and its characteristics suggested focal meta-

bolic dysfunction. In addition, the background elec-trophysiological rhythm in this region was slowed,and there was evidence of persistent cortical irrita-

bility. This neurologic syndrome occurred in thecontext of a urinary tract infection, and lumbar

puncture revealed only elevated lactate levels, with-out evidence of a central nervous system infectionor inflammatory response. The unusual constella-

tion of findings prompted additional workup, in-cluding magnetic resonance spectroscopy which

provided evidence of derangement of cellular energywithin the lesion and, subsequently, brain biopsy.

Eight months later, an acute deterioration of

neurologic function, again in the setting of urinarytract infection, was accompanied by similar find-

ings on neuroimaging and electroencephalograph-ic study and similar cerebrospinal fluid data. A

muscle-biopsy specimen revealed biochemical ab-normalities suggestive of mitochondrial myopathy,

but typical morphologic features were not seen.This patients clinical course was one of pro-

gressive dementia, marked by intercurrent acute

neurologic episodes and the serial development ofmultifocal brain lesions. Dysfunction occurred pri-

marily in the left perisylvian network for languageand in the occipito-temporal network for object

recognition.

6

This pattern is not typical of the com-mon degenerative dementias, such as Alzheimersdisease, but would potentially be consistent with

cerebrovascular dementia.

7,8

The stepwise courseof this patients clinical decline was also consistent

with vascular dementia,

9

but the imaging charac-teristics of the lesions and their extreme electro-

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physiological irritability suggested that the disease

mechanism was one of cellular energy failure rath-er than ischemia. Moreover, the development of thelesions in the setting of increased systemic meta-

bolic demand due to urinary tract infection support-ed this hypothesis.

Finally, the additional clinical findings, includ-ing the patients short stature and hearing loss; the

laboratory findings of mildly elevated serum crea-tine kinase and elevated lactate in the serum, cere-

brospinal fluid, and the brain lesions; and the pres-ence of a myopathy with an oxidative metabolicabnormality all provided further signs suggesting

a primary abnormality of mitochondrial function.Although this patient had no family history of such

a condition and symptoms developed much later inlife than is usual for patients with this disease, we

suspected a diagnosis of mitochondrial encephalo-myopathy specifically, mitochondrial encephalo-

myopathy, lactic acidosis, and stroke-like episodes(the MELAS syndrome).

Mitochondrial encephalomyopathies are a diversegroup of disorders that have been known since

the 1960s; they are usually diseases of childhoodand young adulthood.

10

Since the first disease-

related mitochondrial mutations were identified in1988,

11,12

more than 150 pathogenic mutations

have been reported in patients with a variety of clin-

ical disorders (www.mitomap.org/). Most of theseare maternally inherited and multisystemic, al-

though some are sporadic and tissue-specific.

13-15

Population-based studies suggest that mitochon-

drial disorders may be at least as common (preva-lence, 1 in 8500 population) as other sporadic and

inherited neurologic disorders, such as amyotro-phic lateral sclerosis and Huntingtons disease.

16-18

The symptoms of mitochondrial disorders arise

from dysfunction of tissue types that are thought tobe vulnerable because of their high rate of oxidative

metabolism, including tissue in the brain and pe-ripheral nerves, skeletal and cardiac muscle, retina

and organ of Corti, and the renal tubule.

19

The indexof suspicion for a mitochondrial disorder shouldbe high when there is apparently unrelated symp-

tomatic involvement of two or more tissues. In theproper context, the suspicion that an illness involves

mitochondrial dysfunction should be raised whenthe individual or family history includes any of the

following: short stature, migraine-like headaches,

sensorineural hearing loss, progressive externalophthalmoplegia, axonal neuropathy, diabetes mel-

litus, hypertrophic cardiomyopathy, or renotubularacidosis.

m i t och on dri al

en ceph alom yopat h i es

Figure 2. Magnetic Resonance Images from Day 4 of the Third Admission,Eight Months after the Initial Seizure.

In the images from the third admission, the left temporal tip is normal, butthe remainder of the left temporal region has progressed to cystic encephalo-

malacia and gliosis with volume loss (Panels A, B, and C, arrows). A new re-

gion of abnormality is seen in the cortex of the right posterior temporal region

on the T

2

-weighted image (arrowheads, Panel A), with abnormal increasedT

2

-weighted signal caused by increased fluid, and with a mild local mass

effect; this has increased in size since the day of admission, and increased

T

2

-weighted signal is evident in the subcortical white matter. There is a corre-sponding region of abnormally bright cortical signal on diffusion-weighted

imaging (arrowheads, Panel B) that has also increased in size in the interval

since the study was performed at the patients first admission. The apparent-diffusion-coefficient map (Panel C) shows normal to slightly decreased cor-

tical apparent-diffusion coefficient values and increased apparent-diffusion

coefficient in the subcortical region (arrowheads). Magnetic resonance spec-troscopy (Panel D) shows a large lactate peak and decreased N

-acetylaspar-

tate (NAA), choline (cho), and creatine (cr).

A B C

D

cho cr

NAA

lactate

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Of the variety of clinical syndromes associated

with mitochondrial dysfunction (Table 2),

20

thispatients illness is best characterized as the MELASsyndrome.

21

Previously established diagnostic cri-

teria for the MELAS syndrome specified the pres-ence of stroke-like episodes before the age of 40

years, encephalopathy with seizures or dementia,and either lactic acidosis or so-called ragged-red

fibers (subsarcolemmal accumulation of red-stain-ing material on muscle biopsy), along with at least

two of the following: normal early development, re-

current headache, or recurrent vomiting.

22,23

Asdata have accumulated on the breadth of pheno-types in patients harboring genetic mutations as-

sociated with the MELAS syndrome, some authori-ties have suggested an approach to the diagnostic

workup that would broaden the identification ofmitochondrial encephalomyopathy even when strict

diagnostic criteria are not met.

20

As was the casewith the approach to this patient, the workup in-

* Data in table are from DiMauro et al.

20

Plus signs denote present, minus signs absent, and the plusminus signs possible.

Table 2. Clinical Features of Mitochondrial Diseases Associated with Mitochondrial DNA Mutations.*

Tissue or Area Symptom or SignKearnsSayre

Syndrome

MyoclonusEpilepsy withRagged-Red

Fibers

MitochondrialEncephalomyopathy,Lactic Acidosis, andStroke-like Episodes

Neuropathy,Ataxia, Retinitis

Pigmentosa

MaternallyInherited

LeighSyndrome

Central nervoussystem

Seizures + + + +

Ataxia + + + +

Myoclonus +

Psychomotor retardation +

Psychomotor regression + +

Hemiparesis or hemianopia +

Cortical blindness +

Migraine-like headache +

Dystonia + +

Peripheral ner-vous system

Peripheral neuropathy +

Muscle Weakness or exercise intolerance + + + + +

Ophthalmoplegia +

Ptosis +

Eye Pigmentary retinopathy + +

Optic atrophy

Blood Sideroblastic anemia

Endocrine Diabetes mellitus

Short stature + + +

Hypoparathyroidism

Heart Conduction block +

Cardiomyopathy

Gastrointestine Exocrine pancreatic dysfunction

Ear, nose, throat Sensorineural hearing loss + +

Kidney Fanconis syndrome

Laboratory results Lactic acidosis + + +

Ragged-red fibers on musclebiopsy

+ + +

Inheritance Maternal + + + +

Sporadic +

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cludes a detailed history and family history (with

particular attention to potentially associated con-ditions described above), laboratory tests (especial-ly measurement of serum and cerebrospinal fluid

lactate and serum creatine kinase), MRI studies (in-cluding the specific sequences used in this case),

exercise physiology, muscle biopsy for morphologyand biochemistry, and molecular genetic screening.

Although mitochondrial encephalomyopathywas the leading diagnosis, both health care provid-

ers and the patients family were frustrated by thedifficulty of obtaining a definitive tissue and geneticdiagnosis. Genetic screening performed on the first

muscle-biopsy specimen for the seven most com-mon mitochondrial DNA mutations was negative.

The diagnostic procedure was a second musclebiopsy.

Mitochondrial encephalomyopathy, lactic acidosis,and stroke-like episodes (the MELAS syndrome).

Mitochondrial encephalomyopathy, lactic acidosis,

and stroke-like episodes (the MELAS syndrome).

Dr. Di Tian:

Both of the muscle-biopsy specimens

were taken from the right deltoid. The first showedmildly increased variation in myofiber size and rare

myocytes with increased subsarcolemmal and cyto-plasmic NADHtetrazolium reductase enzyme ac-

tivity. However, there was no subsarcolemmal ac-cumulation of red-staining material (ragged-red

fibers, which characterize mitochondrial myopa-thy) on trichrome staining. Stain for ATP revealedoccasional small atrophic myofibers of both types

without fiber-type grouping. Electron microscopi-cal examination did not reveal morphologically ab-

normal mitochondria.The second muscle-biopsy specimen showed

moderately increased variation in myofiber size andsome atrophic myocytes displaying coarse cytoplas-mic and subsarcolemmal staining with hematox-

ylin and eosin (Fig. 3A). These fibers containedsubsarcolemmal accumulation of linear, irregular

material that stained red, indicating ragged-redfibers (Fig. 3B). Abnormal subsarcolemmal and cy-

toplasmic accumulations of mitochondria were also

highlighted by NADH-TR (Fig. 3C), succinyl dehy-drogenase, and cytochrome c

oxidase stains and on

electron microscopy (Fig. 3D). These morphologicfeatures were highly suggestive of mitochondrialmyopathy.

Tissue was sent to Columbia Universitys labo-ratory for biochemical and genetic testing. Electron-

transport-chain assays on both biopsy samples re-vealed a defect in complex I, with normal activities

in complexes II, III, and IV. DNA sequencing dis-closed a G13513A missense mutation in the ND5

mitochondrial gene, a subunit of complex I, result-

ing in alteration from aspartic acid to asparagine atamino acid residue 393 (D393 N), which is predict-

ed to cause a secondary structural change.

24,25

Thismutation has been described in patients with vari-

ous clinical phenotypes that are associated withmitochondrial dysfunction, including cases of both

childhood and adult-onset MELAS syndrome,

26-29

Lebers hereditary optic neuropathy and MELASoverlap syndromes,

26,29

adult-onset encephalomy-

cli n i cal di ag n os i s

dr. b radford c. di ck ers on s

di ag n os i s

pat h olog i cal di s cus s i on

Figure 3. Biopsy Specimen of the Right Deltoid Muscle Showing Features

of Mitochondrial Myopathy.

A myocyte shows clumped cytoplasmic staining on a hematoxylin-and-eosin

stain (Panel A) and subsarcolemmal accumulation of red-staining material,

so-called ragged-red fibers, on a modified Gomoris trichrome stain (arrow,Panel B). NADHtetrazolium reductase stain (Panel C) highlights markedly

increased enzymatic activity (dark blue staining) in the subsarcolemmal com-

partment of some fibers. Electron microscopy reveals subsarcolemmal and

interfibrillary accumulation of mitochondria. Some mitochondria (Panel D)are enlarged, with complex internal structure, and some contain abnormal

electron-dense material.

A B

C D

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opathy with blindness,

29

and Leigh or Leigh-like

(atypical) syndrome with isolated complex I defi-ciency in childhood.

24,30

Among the six reported patients with the MELAS

syndrome and G13513A mutation, all had clinicalfeatures of the MELAS syndrome, including hear-

ing loss, by their mid-40s and most were in theirsecond decade. The patient under discussion was

in her early 60s at the onset of her illness, makingher the oldest patient with the MELAS syndrome

known to carry the G13513A mutation.

Dr. Dickerson:

The patient was discharged home from

her third admission on the 19th hospital day. Thelevel of diagnostic specificity imparted by the results

of the genetic testing, which were returned twomonths after the patients discharge, provided re-

lief to the patients husband and sons and madepossible both a discussion of the heritability of dis-

eases associated with mutations in mitochondrial

DNA and optimal planning for end-of-life care forthe patient.

Therapeutic options for mitochondrial enceph-

alomyopathies are currently limited.

18,20

Symptom-atic and palliative approaches include the treatment

of seizures, hearing loss, ophthalmoplegia, diabe-tes, and cardiac-conduction block. The mainstay of

treatment, which was used with this patient, is theuse of metabolite and cofactor supplements, includ-

ing coenzyme Q10 (an oxygen-radical scavenger)and l

-carnitine (to restore secondarily lowered lev-els of free carnitine). Although there are few data to

support the efficacy of these supplements, the risksare minimal. Exercise and physical therapy, once

thought to be detrimental to patients with mito-chondrial disorders, is now the subject of investi-

gations, with recent evidence indicating that aero-bic training increases work tolerance and oxidative

capacity in patients with mitochondrial DNA mu-tations.

31

Finally, new approaches to genetic ther-apy are being studied.

Over the course of several home visits, I workedwith the patients husband and sons and the hos-

pice team to develop a palliative care program thatincluded pain management and other symptommanagement, psychosocial support, and the co-

ordination of services, including autopsy arrange-ments.

32,33

Dr. Walsh:

Over the eight months after dischargethe patient continued to decline. She became almost

mute and spent most of her time sleeping. She died

at home two years after the onset of her illness.

Dr. Tian:

The autopsy showed bronchopneumo-

nia to be the immediate cause of death. The brainweighed 1070 g (normal, 1300 to 1400 g). The left

temporal lobe, the left inferior parietal lobe, andthe anterior aspect of the left occipital lobe, as well

as the right inferior parietal lobe, were soft withyellowish discoloration (Fig. 4A). These lesionswere asymmetric and did not fall into the vascular

territories or border zones of any major cerebral ar-teries. Coronal sections revealed laminar cortical

necrosis in these areas (Fig. 4B). Microscopical ex-amination showed severe neuronal loss in the mid-

dle and deep cortical layers, with the accumulationof hemosiderin-laden macrophages and reactiveastrocytes (Fig. 4C). The underlying white matter

was gliotic. Scattered foci of isolated cortical necro-sis were present.

Some cerebellar Purkinje cells had marked swell-

di s cus s i on of m an ag em en t

Figure 4. Autopsy Findings in the Brain.

A gross external photograph of the brain shows that the left temporal, parietal,and anterior occipital lobes are soft and yellow (arrows, Panel A). A coronal

section of the left cerebral hemisphere shows laminar cortical disruption in

the inferior parietal lobule and lateral temporal cortexes (arrows, Panel B).A low-magnification photomicrograph of the left superior and middle tem-

poral gyri reveals laminated cortical disruption (arrows, Panel C). Markedneuronal loss, reactive gliosis, and the accumulation of hemosiderin-ladenmacrophages are seen on higher magnification (inset). Some cerebellar

Purkinje cells have marked swelling of the proximal dendrites, the so-called

cactus dendrites (arrows, Panel D). (Panels C and D, Luxol fast blue

hematoxylin and eosin stain).

A B

C D

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2279

ing of the proximal dendrites (Fig. 4D), referred to

as cactus dendrites by some authors,

34

whichhave been described in patients with mitochondrialdiseases. Arteriosclerosis and arteriolosclerosis and

a small putamenal infarct were present, consistentwith the patients history of hypertension. The skel-

etal muscles demonstrated changes similar to thosenoted in her second muscle biopsy.

The postmortem findings of multifocal corticallaminar necrosis and isolated cortical necrosis are

consistent with mitochondrial encephalomyopathy.

Dr. Nancy Lee Harris

(Pathology): Dr. Holtzman,can you explain the peculiarities of mitochondrial

DNA as they relate to this patient and her family?

Dr. David Holtzman:

Mitochondria are present in

the cytoplasm of the ovum and are thus all inheritedfrom the mother. There are multiple DNA molecules

in each mitochondrion and multiple mitochondria

in each cell.

35

The mitochondria are randomly sort-

ed when daughter cells are formed. Thus, when amitochondrial mutation is present, the mutationload in any given organ of any single person is high-

ly variable a condition known as heteroplasmy.It cannot be predicted whether the mutation load

will reach a threshold for clinical expression. Thisrandom sorting of mitochondrial DNA and its mu-

tations explains why no one in the patients moth-ers family had a similar clinical phenotype and

limits the value of genetic testing in other familymembers. Other factors, such as toxins and aging,also may affect the clinical expression.

Mitochondrial encephalomyopathy, lactic acidosis,

and stroke-like episodes (the MELAS syndrome).

an at om i cal di ag n os i s

references

1.

Jackson JH. Epileptiform convulsionsfrom cerebral disease. In: Taylor J, HolmesGL, Walshe FMR, eds. Selected writings of

John Hughlings Jackson. London, Hodderand Stoughton, 1931:30-340.

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Hirano M, Pavlakis SG. Mitochondrialmyopathy, encephalopathy, lactic acidosis,and strokelike episodes (MELAS): currentconcepts. J Child Neurol 1994;9:4-13.

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Holt IJ, Harding AE, Morgan-HughesJA. Deletions of muscle mitochondrial DNAin patients with mitochondrial myopathies.Nature 1988;331:717-9.

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Wallace DC, Singh G, Lott MT, et al. Mi-tochondrial DNA mutation associated withLebers hereditary optic neuropathy. Science1988;242:1427-30.

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Andreu AL, DiMauro S. Current classifi-cation of mitochondrial disorders. J Neurol2003;250:1403-6.

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Johns DR. Mitochondrial DNA and dis-ease. N Engl J Med 1995;333:638-44.

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Majamaa K, Moilanen JS, Uimonen S,et al. Epidemiology of A3243G, the muta-tion for mitochondrial encephalomyopa-thy, lactic acidosis, and strokelike episodes:prevalence of the mutation in an adultpopulation. Am J Hum Genet 1998;63:447-54.

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Chinnery PF, Johnson MA, Wardell TM,et al. The epidemiology of pathogenic mito-chondrial DNA mutations. Ann Neurol 2000;48:188-93.

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Kirby DM, Boneh A, Chow CW, et al.Low mutant load of mitochondrial DNAG13513A mutation can cause Leighs dis-ease. Ann Neurol 2003;54:473-8.

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Santorelli FM, Tanji K, Kulikova R, et al.Identification of a novel mutation in themtDNA ND5 gene associated with MELAS.Biochem Biophys Res Commun 1997;238:326-8.

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Pulkes T, Eunson L, Patterson V, et al.The mitochondrial DNA G13513A transitionin ND5 is associated with a LHON/MELASoverlap syndrome and may be a frequentcause of MELAS. Ann Neurol 1999;46:916-9.[Erratum, Ann Neurol 2000;47:841.]

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30. Chol M, Lebon S, Benit P, et al. The mito-chondrial DNA G13513A MELAS mutationin the NADH dehydrogenase 5 gene is a fre-quent cause of Leigh-like syndrome withisolated complex I deficiency. J Med Genet2003;40:188-91.31. Taivassalo T, Shoubridge EA, Chen J,et al. Aerobic conditioning in patients withmitochondrial myopathies: physiological,

biochemical, and genetic effects. Ann Neu-rol 2001;50:133-41.32. Morrison RS, Meier DE. Palliative care.N Engl J Med 2004;350:2582-9.33. Schulz R, Mendelsohn AB, Haley WE,et al. End-of-life care and the effects of be-reavement on family caregivers of persons

with dementia. N Engl J Med 2003;349:1936-42.

34. Iizuka T, Sakai F, Suzuki N, et al. Neuro-nal hyperexcitability in stroke-like episodesof MELAS syndrome. Neurology 2002;59:816-24.35. Scheffler IE. Mitochondria. New York:Wiley-Liss, 1999.Copyright 2005 Massachusetts Medical Society.

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