demyelinating diseases - esnr disease - yousry.pdf · demyelinating diseases ta yousry institute of...

Demyelinating Diseases

TA Yousry

Institute of Neurology

Queen Square

Acknowledgment

Jackie Palace (Oxford) A Rovira (Barcelona)

F Barkhof (Amsterdam) N de Stefano (Siena)

F Fazekas (Graz) E Enzinger (Graz)

V Sethi D Chard (London)

R Jaeger H Chandrashekar (London)

A Thompson D Miller (London)

Overview • Autoantibodies associated CNS diseases

Neuromyelitis optica

Limbic encephalitis

NMDAR encephalitis

• ADEM

• Neuropsychiatric SLE

1. NMO Pathology

• Inflammation

• Astrocytopathy

• Myelin relatively preserved, damage 2ry

Epidemiology

Uzawa Journal of Clinical Neuroscience 2013 Prevalence (per 100,000)

Diagnosis

• Optic neuritis initial event in the young

• Acute myelitis initial event in the older

• AQP4 AB –ve 20-30%

NMO

NMO

Aquaporin 4 • most abundant CNS water channel • concentrated in astrocytic foot

processes

Lennon et al Lancet 2004; J Ex Med 2005 Antibodies to AQP4 → astrocytopathy

AQP4 Channelopathy AB Disease’ NMO

• Female > 80%

• Non-Caucasian predominance

• Relapsing if untreated

• Severe disability and high mortality

• Associated with other auto-immunity

• Onset with both ON + TM uncommon

Lennon et al Lancet 2004; J Ex Med 2005

NMO

M ON

10% - monophasic

M ON ON M

NMO

90% - relapsing

AQP4 Channelopathy’

1.AQP4-Ab-positive classical NMO

2.AQP4-Ab-positive high-risk syndromes

for NMO’ (HRS)

NMO

Isolated LETM (lesions spanning > 3segments)

Monophasic or recurrent isolated ON

Certain types of brainstem encephalitis (particularly if the

diencephalon or medulla oblongata is involved)

NMOSD

Autoimmune AQP4 Channelopathy’ NMO Revised diagnostic criteria (Wingerchuk 2006)

• Optic neuritis

• Acute myelitis

• At least 2 of 3 supportive criteria

1. SC MRI Contiguous over 3 segments

2. Onset brain MRI not meeting MS* criteria

3. NMO-IgG/AQP4 AB seropositive

Some NMO patients remain seronegative for NMO-IgG (12-24%)

• Male predominance

• Younger patients

• Milder clinical presentation: lower relapse rate, lower disability,

lower number of severe attacks

• Simultaneous occurrence of ON and transverse myelitis (33% vs 6%)

• No differences in brain MRI

• Shorter SC lesions

• Spinal cord confinement

• Some NMOneg could suffer either atypical ADEM or MS. Hyun et al. Mukt Scler J 2014; Bernard-Valnet et al. Eur J Neurol 2015

NMO-IgG Seronegative’

Jarius Journal of Neuroinflammation 2012

NMO

NMO


NMO


SC lesions

• Extent > 3 segments

• Central grey matter

• Swelling

• Partial enhancement

• Atrophy & cavity formation

Uzawa Journal of Clinical Neuroscience 2013

NMO Devic Neuromyelitis optica

Multiple sclerosis

Nakamura et al. J Neurol 2008

Preferential spinal central gray matter

involvement in neuromyelitis optica

Courtesy A Rovira


NMO

Bot et al. Radiology 2004

Nakamura et al. J Neurol 2008

Spinal cord MRI in NMO Central necrosis: pseudosyringomyelia

Courtesy A Rovira

Neuromyelitis optica

Multiple sclerosis

Courtesy A Rovira

Specific brain lesions

• Medullary periaqueductal grey

• Bilat hypothalamus


NMO

Brain lesions • Present 60%

• Location PV ( AQP4 expression)

• Extensive

• Multiple, patchy, enhancing (cloud-like enhancement) in 90% of pat with CE

• CC Splenium; diffuse; oedematous, heterogenous

NMO


NMO

NMO

Sato Arq Neuropsiquiatr 2011

NMO

Sato Arq Neuropsiquiatr 2011

NMO

Nakamura, Multiple Sclerosis 2009

Cloud-like

enhancement

Ito Ann Neurol 2009

NMO 90%

MS 8%

Cortical

lesions

Calabrese Neurol 2012

NMO 0

MS 67%

NMO

7T

Kister MSInternational 2013

7T

Sinnecker Neurology 2012

7T

Sinnecker Neurology 2012 Sinnecker Neurology 2012

Central Vein Sign

Cortese Neurology 2018

Class III evidence CVS accurately

distinguishes

MS vs sero+ve NMOSD

Central vein sign (3 T) MS vs NMO

Cortese et al. Neurology 2018

•The clinical value of the CVS in the context of the differential diagnosis between MS and NMOSD is now extended to clinical 3T scanners •Step towards the use of CVS in clinical practice. •Class III evidence that the CVS on 3T MRI accurately distinguishes patients with MS from those with seropositive NMOSD.

•Cutoff value of 54% of lesions with CVS was optimal in differentiating MS from NMOSD in the groups with high lesion numbers (sensitivity 94%; specificity 100%; accuracy 94%). •In patients with low lesion numbers, the cutoff point rose to 80% of lesions with CVS and produced less convincing results (sensitivity 50%; specificity 93%; accuracy 88%).

MS

NMOSD

Atypical

lesions

Pittock Arch Neurol 2006

Kim MSJ

2011

NMO


NMO-Spectrum Disorders

In addition to NMO, AQP4-Ab is found in •Isolated LETM (lesions > three segments) •Monophasic or recurrent isolated ON •Certain types of brainstem encephalitis (particularly if diencephalon or medulla oblongata involved) •Most develop NMO •Classify these symptoms—as ‘high-risk syndromes for NMO’ (HRS)

Wingerchuk DM, et al.

Neurology. 2015

NMO: 2015 diagnostic criteria

Wingerchuk DM, et al. Neurology. 2015

+ AQP4-IgG - AQP4-IgG

NMOSD with unknown AQP4-IgG status

Emphasis on clinical diagnosis rather than solely AQP4-IgG positivity:

integration of clinical, serologic, and MR imaging data


NMO

Wingerchuk et al Neurology 2015

MR requirements (AQP4-IgG -ve/unknown)

Acute optic neuritis

Brain Normal / unspecific

Optic nerve >1/2 ON length or optic chiasm

NMO: 2015 diagnostic criteria NMO


Intramedullary lesions ≥ 3 contiguos segments (LETM)

≥ 3 contiguous segments SC atrophy (history of myelitis)



Acute myelitis

NMO


Dorsal medulla/area postrema

lesions

Area postrema syndrome



NMO


Periependymal brainstem lesions

Acute brainstem syndrom



NMO NMOSD 2015

NMOSD

AQP4-Ab positive

disease

AQP4-Ab

negative

Attack(s) involves ≥ 2 sites with typical MRI:

≥ 1 from ON, SC, area postrema. Other: brainstem, diencephalic, cerebral relapsing or monophasic

1 site

ON or LETM relapsing or monophasic

Multiple sclerosis

Ab negative MOG-Ab disease

25%


Attack 1 site:ON / TM / brainstem / area

postrema Or diencephalic / narcolepsy / cerebral w typical MRI

NMOSD 2015 NMO

MOG

• Female : Male equal

• No non-caucasian predominance

• ~ 50% monophasic

• Better outcome than AQP4-Ab disease

• Not associated with other auto-immunity

• Onset with both ON + TM common

• Overlap with ADEM (monophasic & relapsing)

Myelin Oligodendrocyte

Glycoprotein (MOG)-AB Disease

NMO

Reindl et al. Nat Rev Neurol 2014

MOG-AB Disease

MOG-AB Disease

Jurynczyk Brain 2017

MOG-AB Disease


Summary

• NMOSD is a distinct entity

• Diagnosis based on clinical, lab and MRI findings

• MRI findings play a role in the Diagnostic criteria

• Overlap with ADEM, MS

• Neuroradiologist must be familiar with the radiological spectrum of

NMOSD, in order to properly distinguish this disorder from MD (different

prognosis and treatment)

Brain lesions as initial manifestation

http://www.google.co.uk/url?sa=i&rct=j&q=astrocytes+and+myelin&source=images&cd=&cad=rja&docid=oNAYPPFvzraGNM&tbnid=ounFAJe32qAr_M:&ved=0CAUQjRw&url=http://www.nature.com/nature/journal/v457/n7230/fig_tab/457675a_F1.html&ei=Z1OmUdLkH8qg0wXlkoHAAg&bvm=bv.47008514,d.d2k&psig=AFQjCNFZ0uwRQ0eoT1LBx6sutj6uYT1d8Q&ust=1369941169802671

De Seze Brain 2017

AQP4-ab vs MOG-ab NMO

MOG-ab Similar to AQP4-ab

Additionally

• conus involvement (left w isolated sphincter and

erectile dysfunction)

• fluffy lesions (adults, or ADEM attacks childhood)

• bilateral cerebellar peduncle lesions

Lechner et al. JNNP 2015

AQP4-ab vs MOG-ab

NMO


• Acute monophasic course

• Immune-mediated inflammatory disorder, triggered by

inflammatory response to viral infections and vaccination

• Affects children more commonly than adults

• Best viewed as a “syndrome” rather than a specific disorder

Clinical presentation

• Headaches, vomiting, drowsiness, fever, lethargy (uncommon MS)

• Self-limiting, good outcome

Acute Disseminated Encephalomyelitis

ADEM

ADEM MS

Age Gender Prior flu Encephalopathy Symptoms Attacks CSF white blood cell count >50 CSF oligoclonal bands

≤10 years (rare in adults) male=female very frequent

required multifocal

fluctuate over 3 months frequent variable

>10 years male<female

variable rare

monofocal separated by >1 month

very rare frequent

ADEM vs MS ADEM

Periventricular lesions

Isolated subcortical lesions

Deep grey matter lesions

Poorly marginated lesions

Contrast-enhancement

Symmetrical white matter lesions

Symmetrical grey matter lesions

New lesions on follow-up

Hemorrhagic lesions

Same appearance lesions

Large and confluent lesions

Resolution of lesions

Hypointense lesions (ne)

MS

+

++

++

++

+

+

++

+

+

++

++

++

-

+++

-

+/-

+

++

++

-

+++

-

+

+

+

++

ADEM

ADEM vs MS

Evolution

ADEM

MS

ADEM vs MS

8 years old boy

SC involvement in ~30% Large and tumefactive lesions Variable enhancement

ADEM

MS if ≥ 2

• 2 or more PV lesions

• Black holes

• Absence of diffuse bilateral lesions

Callen et al. Neurology 2009

ADEM MS

ADEM

Verhey et al. Lancet Neurol 2011

•PV lesions •T1-hypointense lesions

Predictive Parameteres: Time to MS

• First polyfocal, clinical CNS event (presumend inflammatory demyelinating) • Encephalopathy (cannot be explained by fever) • No new clinical and MRI findings ≥ 3 months after onset • Brain MRI abnormal in acute phase (3 months) Typical MRI

• Diffuse, poorly demarcated, large (>1-2 cm) lesions (cerebral WM) • T1 hipointense lesions rare • Deep GM lesions can be present Krupp et al. Mult Scler J 2013

Proposed 2012 IPMSSG criteria Pediatric ADEM

• Rare (less than 4%)

• Multiphasic ADEM

2 episodes consistent with ADEM separated by 3 months,

not followed by any further events

Second episode can be new or re-emergence of first

episode

• Relapsing ADEM following ADEM beyond a 2nd episode

leads to the diagnosis of MS or NMO

Krupp et al. Mult Scler J 2013

Proposed 2012 IPMSSG criteria Pediatric ADEM

baseline 1 m

• Viral upper respiratory tract infection & fever

(38ºC)

• Cephalea and irritability

• Bilateral optic neuritis


3 requirements for 2nd clinical event • Nonencephalopathic • ≥ 3 months after incident neurologic illness •Associated with new MRI findings (disseminated in space)

MS Diagnostic Criteria After ADEM

baseline 1 m


1 year

•Right optic neuritis






•Internuclear opthalmoplejia

baseline 1 m 1 year 3 years

2-18% of children with MS present with clinical/MR features suggestive of ADEM

ADEM MS NMOSD

Age at onset Children. Median of 5–8 years. Uncommon in adults

Young adults. Median of 29 years, uncommon in children and >50 years

Middle age adults. Mean of 40–45 years, with wide distribution from young children to elderly

Gender No gender predominance Moderate female predominance: 2-3/1

High female predominance: 3-9/1

Incidence/Prevalence Incidence of 0.3 to 0.6 per 100,000 per year

Global prevalence 33 per 100,000 (91-203 (108) in Europe; 2.2 East Asia) Incidence: 3,6-9,6

Global prevalence 1-2.6 per 100,000 (1/100,000 Europe; 2.2 Asia) Incidence 0.05-0.4

Prior viral or bacterial infections, vaccination

Common May trigger relapse Not seen

Course Monophasic, rarely multiphasic (4%) Relapsing, progressive Usually relapsing (80-90%)

Serum AQP4 antibodies: not seen MOG antibodies: in up to 40% of patients; commonly transient (in monophasic ADEM) and most frequent in children between age 3 and 8 years

AQP4 antibodies: not seen

AQP4 antibodies: Sensitive and specific MOG antibodies 30% of AQP4 Ab negative cases

CSF analysis Oligoclonal bands: present in up to 29% of cases

Oligoclonal bands: Common and persistent (90-95%)

Oligoclonal bands: Rare; if present at presentation tend to disappear later on

Differences between MS, ADEM and NMOSD

MS-NMO-MOG

Weber TAND 2018

Weber TAND 2018

Diagnostic Algorithm

Hacohen Neurology 2017

MS

NMOSD (NMO/LETM/atyp

ON)

AQP4-

Ab

disease ADE

M

Autoantibodies Associated CNS Diseases

• Onconeural AB Paraneoplastic No improvement with immunotherapies

• Neuronal “cell surface” protein AB Improve with immunotherapies Prev “autoimmune channelopathies”

Vincent Lancet Neurol 2011 Rosenfeld Neurol Clin Practice 2012

Vincent Lancet Neurol 2011

Vincent Lancet

Neurol 2011

3. Limbic Encephalitis

Inflammatory process

• 1960 rare paraneoplastic syn

• 1980s onconeural AB

• 2000s Cell-surface AB

LGI1LE most common Autoimmune E

Asztely Acta Neurol Scand 2012

Graus Lancet Neurol 2012

Association with

• Onconeural AB (intracellular) Often tu

• Surface/synaptic surface AB Often no tu

• No known AB Often tu

Asztely Acta Neurol Scand 2012

Limbic Encephalitis

VGKC AB POSITIVE

Limbic Encephalitis Anti-NMDAR (N-methyl D-aspartate receptor) Encephalitis

Autoimmune disorder 1st described in 2005

• Prominent psychiatric symptoms

• 2nd most common cause of autoimmune encephalitis (after ADEM)

• 80% improve after immunotherapy a/or tumour removal

Titulaer Lancet Neurol 2013

NMDAR Encephalitis

• 80% females

• 37% <18y

• 38% tumour (97% f)

• 94% ovarian teratomas

• Higher frequency of teratomas in Asian

Titulaer, Lancet Neurol 2013

NMDAR Encephalitis MR

• 50% normal

• 50% T2/FLAIR hyperintensity hippocampi, cortex, cerebellar cortex, BG, BS, insula, fronto-basal, cord

mild/transient

focal meningeal enhancement

Ho Dev Med Child Neurol 2017

NMDAR Encephalitis First Criterion

• Rapid onset (<3mo) of at least 4/6

• (1) psychiatric behaviour or cog dysfunction

• (2) speech dysfunction

• (3) seizures

• (4) movement disorders

• (5) decreased level of consciousness

• (6) autonomic dysfunction or central hypoventilation. Ho Dev Med Child Neurol 2017

Diagnostic Criteria

Second criterion

At least one of the following lab results

• (1) abnormal EEG or

• (2) CSF with pleocytosis or oligoclonal bands.


Diagnostic Criteria Third criterion

• Reasonable exclusion of other disorders

All three criteria should be fulfilled for a probable diagnosis of anti-NMDAR encephalitis.


Diagnostic Criteria

• Cumulative % of patients satisfying anti-

NMDAR encephalitis diagnostic criteria over

time


Diagnostic Criteria


Diagnostic Criteria

Encephalitis

New Disease

•Novel cell surface auto antigen

• DPPX antibodies

Boronat Ann Neurol 2013

NMDAR Encephalitis

Boronat Ann Neurol 2013

4. SLE Primary pathophysiology

• Rheumatic disorder; Autoantibodies

• Inflammation

• Small vessel infarction

• Thrombosis

Scolding Neuropath App Neurobio 2002

• Chronic relapsing-remitting

• Neuropsychiatric SLE in 50%

• Woman>man


SLE

Diagnostic criteria • Malar rash Discoid rash

• Photosensitivity Oral ulcers

• Arthritis Serositis

• Renal disorder Neurological disorder

• Haematological disorder Immunological dis

• Antinuclear AB


SLE Clinical presentation (112)

• Woman 92%

• Age 41 (±14)

• Headache 28%

• CV disease 16%

• Cog dysfunction 12% Multicentre study 2014

SLE

MR abnormalities in 60%

• SVD 56%

• LVD 13%

• Inflammation 7%

• Atrophy 19%

Multicentre study 2014

SLE MR –Clinical correlation

• Headache Normal MR

• CV syndrome LVD, WML, MicroH

• Cog dysfunction WML

• Low C4 Inflammatory pattern

Multicentre study 2014

SLE

Conclusions

NPSLE (6M diagnosis)

• T2 lesions (SVD+LVD) 48%

• Inflammatory only 6%

• MRI is important for monitoring active NPSLE

Summary • NMOSD/AQP4/MOG

± typical MR pattern

• NMDAR E Frequent; ± tumours

• Membrane surface encephalitis are a growing field ± typical MR pattern

• SLE Inflammatory changes possible

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