MS clinical forms and variantsMS clinical forms and variantsMS clinical forms and variantsMS...

O.O. FernFernáándezndez

MS clinical forms and variantsMS clinical forms and variants

Instituto de Neurociencias Clínicas – Hospital Regional Universitario Carlos Haya – Málaga

Updating Knowledge in MS - Barcelona - June 1 - 2010

30´

Introduction

MS International classification of clinical patterns

• Relapsing- Remitting

• Secondary Progressive MS

• Primary progressive MS

• Progressive relapsing MS

MS variants

Conclusions


CHARCOTCHARCOT(1825(1825--1893)1893)

LA PITIÉ - SALPETRIÈRE

NistagmusScanning speechIntentional tremor

IntroductionIntroduction

Problems to make a diagnosis of MS

Problems to classify phenotypically the patients (clinical clasif.)

• Classification according to the type of evolution

• Classification according to the severity


Fred D. Lublin, M.D. isProfessor of Neurology atMount Sinai School ofMedicine and Director of thenewly endowed CorinneGoldsmith Dickinson Centerfor Multiple Sclerosis at MountSinai.

Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey.Neurology 1996;46:906-911

Classification according to the type of evolution


Relapsing-Remitting

PrimaryProgressive

SecondaryProgressive

Progressive-Relapsing

or

or

or

or

Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey.Neurology 1996;46:906-911

Clinical classification according to the type of evolution


Marburg Variant

ADEM

RRMS

Neuromyelitis optica(Devic´s disease)

Baló´s concentric sclerosis

Acute transverse myelitis

Recurrent optic neuritisIsolated optic neuritis

PPMS

Severity

Type of EvolutionIdiopathic demyelinating diseases of the CNS

PRMS

IntroductionIntroductionA two dimensional classification (Type of evolution and severity)

SPMSBening MS

Psedotumoral MSShilder´s diffuse sclerosis

Introduction






MS variants

Conclusions


Serie EM completa (N=634)

2,1%

31,4%

6,9%

59,6%

PR

PS

PP

RR

Serie EM completa (N=634)

2,1%

31,4%

6,9%

59,6%

PR

PS

PP

RR

Fernández V, 2001

SP

(12 y evolution)


1317939360N =

PRPSPPRR

Age

ofdi

seas

eon

set-

Mea

nan

d95

%IC 50

45

40

35

30

25

20

Fernández V, 2001

Distribution of Pts according to Int. Classification

(12 y evolution)


Transitional Progresive MS – TPMS

“Essentially a progressive course with a single relapse before or duringthe progressive phase”. (1)

“This clinical form is defined by a progressive course beginning manyyears after an isolated bout”. (2)

“In conclusion, this study gives some evidence that TPMS is very similarto SPMS from a clinical point of view at the beginning, but suggests thatat the progressive stage it shares similar features with PPMS in terms ofpathological activity and increase in disability”.

1. Ingle, G. T. Stevenson, V. L. Miller, D. H. Leary, S. M. Rovaris, M. Barkhof, F. Brochet, B. Dousset, V. Filippi, M.Montalban, X. Kalkers, N. F. Polman, C. H. Rovira, A. Thompson, A. J. wo-year follow-up study of primary and transitionalprogressive multiple sclerosis. Mult Scler 2002;8:108-1142. Gayou, A. Brochet, B. Dousset, V. Transitional progressive multiple sclerosis a clinical and imaging study. J Neurol NeurosurgPsychiatry 1997;63:396-398



Montalbán X. Curr Opin Neurol 2005:18:261–266..

Probably strict adherence to the Lublin and Reingoldclassification should be advised (always same bias)



Kutzelnigg A; Brain 2005

NeuropathologyNeuropathology

Inflammation Demyelination Neurodegeneration

EDSS and evolution time

Evolution time (years)

50403020100

Pre

sent

ED

SS

scor

e

10

8

6

4

2

0 Rsq = 0,1922

r=0,44

EDSS and evolution time

Evolution time (years)

50403020100

Pre

sent

ED

SS

scor

e

10

8

6

4

2

0 Rsq = 0,1922

r=0,44

Fernández O, 98

58º CONGRESO CHILENO DE NEUROLOGÍA – XI CONGRESO PANAMERICANO DE NEUROLOGÍA - SANTIAGO DE CHILE 9-11 OCTUBRE - 2003

Instituto de Neurociencias – Hospital Regional Universitario Carlos Haya – Málaga

Progression Index: 0,30 - 0,40 / year

ClinicClinic

00,5

11,5

22,5

33,5

44,5

1 2 3 4 5 6 7 8 9

Years

No. Of years in each EDSS point (Weinshenker et al. 1991)

EDSS

10 years of evolution

ClinicClinic

Disabilityprogression

-Mean time to EDSS 6-(1 cane) since onset is 10-15 years

- 87% alive after 40 years

Weinshenker B.G., et al.The natural history of multiple sclerosis: A geographically base study. Brain 1989;112:133-14658º CONGRESO CHILENO DE NEUROLOGÍA – XI CONGRESO PANAMERICANO DE NEUROLOGÍA - SANTIAGO DE CHILE 9-11 OCTUBRE - 2003


ClinicClinic

Disabilityprogression

-Mean time to EDSS 6-(1 cane) since onset is25 years

58º CONGRESO CHILENO DE NEUROLOGÍA – XI CONGRESO PANAMERICANO DE NEUROLOGÍA - SANTIAGO DE CHILE 9-11 OCTUBRE - 2003


Pittock, S. J. et al. Disability profile of MS did not change over 10 years in a population-based prevalence cohort. Neurology 2004

ClinicClinic

Confavreux C, et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438.

ClinicClinic

Degeneraciónaxonal

(Total BrainN-Acetilaspartate)

WBNAA in patients andcontrols. There is anannual reduction of 0.8% inpatients.

Gonen O, et al. Total brain N-acetylaspartate: A new measure of disease load in MS. Neurology 2000;54:15-19

NeuroimageNeuroimage

De Stefano, N. Narayanan, S. Francis, G. S. Arnaoutelis, R. Tartaglia, M. C. Antel, J. P. Matthews, P. M. Arnold, D. L. Evidence ofaxonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 2001;58:65-70


fMRI as a surrogate of efficacy of neurorehabilitation

Control

MS patient

Rocca MA. Is a Preserved Functional Reserve a Mechanism Limiting Clinical Impairment in Pediatric MS Patients?.Human Brain Mapping 30:2844–2851 (2009

Hopefully fMRI will help, in the near future, to evaluate the effects of neurorehabilitation


METHODS: visual, acoustic brainstem, somatosensory and motor evokedpotentials; global evoked potential score

EDSS significantly correlated with global evoked potential score severityPatients with severe baseline global evoked potential score (higher than themedian value) had a risk of 72.5% to progress on disability at follow-up, whereaspatients with multiple sclerosis with lower scores had a risk of 36.3%

CONCLUSION: evoked potential is a good marker of the severity of nervousdamage in multiple sclerosis and may have a predictive value regarding theevolution of disability.

Leocani L, et al. Multimodal evoked potentials to assess the evolution of multiple sclerosis: a longitudinal study.J Neurol Neurosurg Psychiatry. 2006

Evoked potentialsEvoked potentials

Response to therapyResponse to therapy

Clinically isolated syndrome

p = 0.034, log rank testHR = 0.69

Pro

bab

ility

ofC

DM

S

0 1 2 30.0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo

IFNB-1a IM

Year

p = 0.002Risk Ratio = 0.56

.

28%

45%

Placebo

IFNB-1b sc

Risk reduction* of50% over 2 years(Hazard ratio= 0.5)

*by adjusted proportionalhazards regression

days

p<0.0001

Clin

ical

lyD

efin

ite

MS

(%)

Placebo

GA

Day 336 Day 722

+ 386 days: + 115%

Risk Reduction of45%Hazard Ratio= 0.55[95% CI] 0.40-0.77p=0.0005

ETOMS CHAMPS

PRECISEBENEFIT


RRMS

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0 200 400 600 800 1,000 1,200

Glatiramer AcetatePlacebo

p = 0.004

Time to Worsening (days)

Su

rviv

alF

un

ctio

nE

stim

ate

Patients (%) WorsenedBy 1.5 EDSS StepsGlatiramer Acetate: 21.6%Placebo: 41.6%

p = 0.001

IFNB-1ª imIFNB-1b sc

IFNB-1ª sc AG


SPMS

IFNB-1b sc

IFNB-1a sc

ALEMTUZUMABEMRR EMSP

Coles AJ, et al (J Neurol 2005)

Response to TherapyResponse to Therapy

IFNB response is not determined by demographic or HLA variables. The onlyvariable associated with response was the EDDS at onset of therapy (Cuttingpoint = 3), which suggest that early herapy is the best therapeutic strategy


3066N =

Response to IFNB therapy

Non-responderResponder

ED

SS

atbe

ginn

ing

ofIF

NB

treat

men

t8

6

4

2

0

-2

Clinical form

SPRR

Nº

ofpa

tient

s

60

50

40

30

20

10

0

Responder

Non-responder

17

13

18

48

Fernández O, et al. Responders and non-responders to interferon beta treatment in multiple sclerosis. Mult Scler2001;7:S52. Fernández O, et al. Rev Neurol 2006

Compensatory Phase• Adaptative Immune S.• Altered BBB

• Restricted focal lesions• High remyelinative capability (80%)• OPC differentiation

MS: a disease in twophases

Non- Compensatory Phase• Innate immune S (mycroglia)• Trapped inflammation behind BBB• B cell follicles• CNS global inflammation• Low remyelinative capability (20%)• Restricted OPC differentiation• Cortical demyelination

Fernández O. 2009

CIS

40-70%

30%

5-10%0%

MS: a disease in two phasesMS: a disease in two phases

Thompson A, et al (2000)

ClinicClinic

Polman, C. H. et al Diagnostic criteria for multiple sclerosis 2005 revisions to the "McDonald Criteria“ Ann Neurol 2005

ClinicClinic


• In patients experiencing a progressive course, median ageat onset of progressive phase was similar in secondaryprogressive cases (SP) and in cases who were progressivefrom onset (PP) (39.1 versus 40.1 years; P = 0.47).1

• The proportion of cases with superimposed relapses duringprogression was 40% in both categories (SP,PP).1

• Relapses in PPMS occurred in 27.8% of patients at somepoint event two to three decades after onset.2

1. Confavreux Ch, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain (2006), 129, 606–616

2. Kremechutzki et al. Brain 1999.

ClinicClinic

Kutzelnigg A; Brain 2005

Inflammation Demyelination Neurodegeneration

PPMS showed a lower load offocal demyelinated plaques inthe white matter and lowernumbers of inflammatoryinfiltrates in the global whitematter in comparison withSPMS.

Diffuse white matter injuryand cortical demyelination inprogressive MS invariablyoccurred on a background ofmeningeal, perivascularand parenchymalinflammation.

NeuropathologyNeuropathology

Confavreux CH and Vukusic . Natural history of multiple sclerosis: a unifying concept. Brain (2006), 129, 606–616

ClinicClinic

Lycklama à Nijeholt GJ, et al (1998)

Introduction






MS variants

Conclusions


Concept: MS whose onset, evolution, clinical, pathologic and imagingcharacteristics.differ from the common patterns of conventional MS

Types:

•ADEM (Acute disseminatedencephalomyelitis)

•Fulminant MS or Marburg´s disease•Pseudotumoral MS•Concentric Sclerosis of Baló•Diffuse mielinoclastic sclerosis of Schilder•Neuromielitis óptica (enfermedad de Dévic)

MS variantsMS variants

Clasification according to clinical form and age

Acute fulminant

• Pediatric age : < 16 yearsSchilder´s diseaseADEM

• Young adult: 20-40 yearsBaló´s diseaseMarburg´s disease

SubacutePseudotumoral MS: > 30 años


Classification accordingTopography

Monofocal:• Marburg´s disease• Pseudotumoral MS• Baló´s disease

Multifocal• ADEM: asymmetric distribution• Schilder´s disease: symmetric distribution


• Acute onset• Symptoms of intracraneal hipertension• Monophasic course• Severe vital prognosis• Cortical signs: conciousness, seizures, psychiatric symptoms,

aphasia, hemianopsia

General clinical characteristics


– Frequent and marked pleocitosis ( 50-100 c/mm3)– Total proteins in CSF > than in MS– Low frequency of OB in CSF

General CSF characteristics


• Extense lesions, predominantly in WM• Moderate mass effect• Frequent Gad enhancement• Asymmetric distribution• GM affected frequently• Concentric circles in Baló´disease

Rovira A et al. Neuroradiology 2007

General image characteristics


• Pathologic overlap– In brains with concentric sclerosis of Baló there are sometimes

contigous typical MS plaques– In some patients there are, at the same time, lesions typical of

ADEM and MS• Clinical overlap

– Some RRMS patients evolve to fulminant form of Marburg andviceversa

– One third of patients with Schilder´s disease evolve later to classicalRRMS

– Two thirds of pseudotumoral forms evolve to classical MS• Image overlap

– Is relatively frequent to find pseudotumoral lesions close to typicalMS plaques

Lucchinetti CF et al. Brain 2008; 131:1759-1775

Nosologic frontiers


Malignant and acute MS (1)

Marburg´s Disease: Monophasic, fulminant course. Paraclinical andpathological features similar to common MS, causes death due tobrainstem involvement.

Other cases, not so acute, but severe, causing death in 5 years canalso be considered malignant.

Benign MS (2)

Normal life after 15-20 years of evolution (EDSS≤3) – 20% pts.Eventually they can evolve to produce disability.

1. Marburg O. Die sogennante "acute multiple sklerose". Jahrbucher fur Psychiatre und Neurologie 1906; 27:211-312.2. Hawkins SA, McDonnell GV. Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors.J Neurol Neurosurg Psychiatry 1999; 67(2):148-52.

Classification according to the severity


Benign MS is rare

Sayao A, Devonshire V, Tremlett H. NEUROLOGY 2007;68:496–500

Mild (EDSS 0-3)

Moderate (EDSS 3.5-5.5)

Severe (EDSS >6)

• At 10 years: 200 patients diagnosed of benign MS with EDSS<3• At 20 years: Follow up of 84.5% of patients


Is “Benign Multiple Sclerosis” really benign?

D. J. Rigotti and O. Gonen Department of Radiology. New York University School of Medicine.Revista Española de Esclerosis Múltiple Nº 14 - Junio de 2010. www.revistaesclerosis.es


Box plots showing the first, second(median)and third quartiles (box),±95% (whiskers) and outliers (*)of the WBNAA distributions of the17 controls (solid), 24 benign(hatched) and 30 non-benign MSpatients (cross-hatched) groups.Note that both patients groups aresignificantly lower in WBNAA thanthe controls but not statisticallydifferent from each other.

Is “Benign Multiple Sclerosis” really benign?

D. J. Rigotti and O. Gonen Department of Radiology. New York University School of Medicine.Revista Española de Esclerosis Múltiple Nº 14 - Junio de 2010. www.revistaesclerosis.es


MarburgMarburg´s fulminant form of MSs fulminant form of MS

• It´s MS with an acute evolution and course rapidly progressive.

• Some authors consider this as a pseudotumoral form of MS by its

clinical characteristics (headache, nausea, vomiting, somnolence,

hemiplegia, seizures) and image characteristics (edema, necrosis,

compromise of adjacent structures), afecting generally one

hemisphere, afecting the brainstem and showing diffuse

Gadolinium enhancing

Kleinschmidt-Demaster BK. 2005:181-222. Simon JH. Neuroimag Clin N Am 2008

Pathology

• Massive infiltrate of mononuclear cells and macrophages in the centerand hypertrophic astrocytes in the periphery of the great lesions,particularly in the periventricular WM , with the same chronologic age.Frequent deposit of immunocomplexes with complement activation

• Acute axonal lesions and necrosis. Mild remyelination

Hu W; Lucchinetti C. The pathological spectrum of CNS inflamatory demyelinating diseases. Semin Immunopathol 2009


• Treatment in the acute phase

– Support measures

– Bad response to steroids

– Plasmapheresis (42% response)

• Maintenance therapy : immunosupressants

– Ciclophosphamyde

– Natalizumab,

– Rituximab can be an alternative

Gladstone DE. AJTherapy 2009


Treatment

• Marburg´s disease:– Humoral immunity disfunction,

deposit of immunocomplexes andcomplement activation

– ¿ By abnormal myelin?

• Baló´s concentric sclerosis:– Mitochondrial disfunction of

olygodendrocytes (Pattern III ofLucchinetti)

• ¿By hypoxia?• ¿Toxics?

Stadelman. Brain 2005;128:979-987. Mahad Brain 2008

Atypical forms of MSAtypical forms of MS

Pathogenic theories

Refers to the presentation of MS plaques as large space-occupyingmass lesions that mimic brain tumors clinically and radiologically.

Lesions are typically supratentorial and thus may result in hemiparesis,hemisensory loss, visual field deficits, decreased consciousness, orseizures.

Often presents with atypical imaging features including size >2 cm, masseffect, edema, open-ring enhancement

Differentiation from a neoplastic process is more problematic when theinitial presentation is with a solitary mass lesion.

Lucchinetti CF, et al. Brain (2008), 131, 1759-1775

Pseudotumoral MS (Tumefactive MS)Pseudotumoral MS (Tumefactive MS)

Presents the classic features of active inflammatory demyelinatingdisease including hypercellular confluent demyelinating lesions,inflammatory infiltrates dominated by myelin-laden foamy macrophagesclosely intermingled with reactive astrocytes, variable perivascular andparenchymal lymphocytic inflammation, and ‘relative’ axonal preservation

Biopsy can help confirm the demyelinating nature of the lesion;however, the presence of Creuztfelt–Peters cells (astrocytes withfragmented nuclear inclusions) can be mistaken for mitotic glialcells.

Most patients presenting with tumefactive features later develop typicalRRMS, although monophasic cases have also been reported.

Tumefactive MS cases represent a part of the heterogeneous clinicaland radiographic spectrum of MS,



Callen DJA, et al. Role of MRI in the differentiation of ADEM from MS in children. Neurology 2009;72:968–973

ADEM criteriaADEM criteria

ADEM criteriaADEM criteria

Krupp LB, et al. Consensus definitions proposed for pediatric multiple sclerosis and related disorders.NEUROLOGY 2007;68(Suppl 2):S7–S12

• Schilder´s diffuse sclerosis has been confounded with cases ofleukodystropy because it appears at earlier ages than MS

• Typically there are headache, afasia, cortical blindness and deafnesswhich are unfrequent in MS

• Pathologically is characterised by great demyelinating plaques,particularlly in the posterior part of the brain hemyspheres

• In the acute phase there is an inflammatory infiltrate totally similar to theacute plaques of MS, and in some cases there are transitional forms withother plaques of small size typical of MS.

Schilder P. Zur Kenntnis der sogenannten difusen Sklerose (uber Encephalitis periaxialis diffusa). Zeitschrift furdie gesamte. Neurologie und Psychiatrie 1912;10:1-60.

Kotil K, Kalayci M, Koseoglu T, Tugrul A. Myelinoclastic diffuse sclerosis (Schilder's disease): report of a caseand review of the literature. Br J Neurosurg 2002 Oct;16(5):516-9.

SchilderSchilder´s diffuse sclerosiss diffuse sclerosis

SchilderSchilder´s diffuse sclerosiss diffuse sclerosis

Diagnosis Clínicla symptoms Diagnosticcriteria

Neuroimage Treatment

ADEM Normallymonophasic andpostinfectious

In childrenyes, no inadults

Multifocal,asymmetricSimultaneous Gdenhancement

CorticoidsPLEX

Marburg Mono o multiphasic,Fulminant onset andevolution

No GreatpseudotumorallesionGM++

CorticoidsPLEX

Baló´sconcentricsclerosis

Monophasic andprogressive

No Alteration of signalin concentriccirclesGM ++

CorticoidsPLEX

Schilder sdiffusesclerosis

Almost alwaysmonophasic andalteration ofconciousness

No Bilateral alterationof WM, symmetric,diffuse, infiltrativeGM ++

CorticoidsPLEX

Atypical forms of MSAtypical forms of MS –– Differential diagnosisDifferential diagnosis

Patología Características

ADEMrecurrente

Nuevo episodio de ADEM, con los mismos síntomas y signos,al menos 3 meses después del inicial, sin relación con laretirada de esteroides

ADEMmultifásica

Nuevos episodios clínicos que cumplan criterios de ADEM,pero implicando zonas ≠clínica o radiológicamente

NMOrecurrente

Brotes de mielitis transversa y neuritis óptica, sin episodios deafectación fuera de la vía óptica o medular

EM pediátrica Dos o más episodios separados en tiempo y espacio, y elprimero no debe ser ADEM. Si el primero fue clínicamentecompatible con ADEM, deben seguir dos después distintos. Enla RM deben aparecer lesiones nuevas al menos 3 mesesdespués.

Krupp LB, Banwel lB, Tenembaum S. International Pediatric MS Study Group. Neurology 2007;68 (sppl 2):S7-S12.

FA: diagnóstico diferencial con otras EIDI:definiciones de consenso

•• Epidemiology• Pathophysiology• Pathology• Clinical features• MRI abnormalities• CSF abnormalities• Outcome• Treatment

responsivenessE. DEVIC(1858 – 1930)

Devic’s NMO and MS are different regarding

NeuromyelitisNeuromyelitis OpticaOptica


• Optic nerves• Spinal cord• Brainstem• Hypothalamus• Periventicular regions

Pathogenesis: NMO lesions occur at sites of high AQP4 expression


• Uni or bilateral optic neuritis

• Acute myelitis

• Usually not simultaneous

• Mostly relapsing

• NMO spectrum disorder

Clinic Characteristics

Courtesy of Regina Papais


• Extension of spinal cord lesions

• Severity of optic nerve lesions

• Severity of brain involvement

• Clinical improvement and stabilization

• Beneficial effect of plasmapheresis

Correlation of serum AQP-4 Abs titers with:

In MS several patterns can be recognized, both from the clinical,pathological and paraclinical point of view.

There exist a certain amount of variability in clinical classification ofprototypic MS (20-40%).

This variability can affect the results of clinical, epidemiological, genetic,paraclinical and therapeutic studies

In the near future, paraclinical or biological markers, will permit to reducethe variability

There are atypical forms which are necessary to know, becauseoccasionally they represent a diagnostic and therapeutic dilemma

Neuromyelitis optica is a disease different from MS

ConclusionsConclusions

Instituto de Neurociencias Clínicas – Hospital Regional Universitario Carlos Haya – Málaga

Thanks for your attention

Updating Knowledge in MS - Barcelona - June 1 - 2010

MS clinical forms and variantsMS clinical forms and variantsMS clinical forms and variantsMS...

Documents

Transcript of MS clinical forms and variantsMS clinical forms and variantsMS clinical forms and variantsMS...