Problemas Diagnósticos de la Esclerosis Múltiple en Chile

D´une maladie inconnue a une maladie en vogue

Dr. Jorge Barahona StrauchDirector Centro de Esclerosis Múltiple

Clínica Alemana de SantiagoUniversidad del Desarrollo UDD

II Jornadas Franco Chilenas de Neurología Valparaíso 14-15 de Marzo 2008

Multiple Sclerosis in Latin America

?

Latin America: An overview

• Vast continent: over 25 m sq km • Vast latitudes

– Border US and Mexico at 32o N– Southermost Argentina and Chile

at 56o S

• Vast spectrum of climate– Desert to sub-Antarctic

• Many different regions– 36 countries – 6 territories

Amerindians in Latin American population

Country % Country %

Bolivia 62 Paraguay 5

Peru 45 Argentina 3

Mexico 30 Chile 3

Ecuador 25 El Salvador 1

Honduras 7 Colombia 1

Nicaragua 5 Brazil <1

Venezuela 5 Uruguay 0

Migration routes :-The Bering Strait route

30.000 years agofrom Mongolia and Siberia

-The Trans-Pacific route20.000 years agofrom Polynesia to South

America-The Trans-Atlantic route

The origin of the Latin America populations:

The Mestizos

• Offspring of an European and an Amerindian or children of two mestizo parents

Country % Country %

Paraguay 95 Ecuador 65

El Salvador 94 Mexico 60

Honduras 90 Colombia 68

Chile 90 Peru 37

Panama 70 Argentina 13

Nicaragua 69 Brazil 12

Venezuela 67 Uruguay 8

Mulattoes and pure blacks in some Latin American countries (%)

Country Mulattoes Pure Blacks Total

Haiti 5 95 100

Martinique 0 90 90

Dominican Republic 76 11 87

Cuba 65 11 76

Venezuela 38 10 48

Brazil 38 5 43

Puerto Rico 27 10 37

Colombia 14 7 21

Peru 15 3 18

Chile 0 5 5

Uruguay 0 4 4

Argentina 0 3 3

Mexico 0 1 1

The prevalence of MS in Latin America

Country Year Prevalence per 105 Reference

Mexico Mexico City Chihuaua

19702002

1.66.3

Alter et OlivaresVelasquez et al

Cuba 1990 10.0 Cabrera-Gomez et al

Martinique 1991 17.4 Cabre et al

Colombia 2000 1.48 – 4.98 Sanchez et al

Argentina Junin B. Aires Patagonia

199419972002

12.015.6 – 17.5

17.2

MelconCristiano et alGold et al.

Brazil São Paulo São Paulo Belo Horizonte Botucatu

1992199720022002

4.315.018.117.0

Callegaro et al.Callegaro et alLana-Peixoto et alRocha et al.

Uruguay 2001 20.7 Ohninger et al

Multiple Sclerosis study (Chile) Barahona J. et al LACTRIMS 2004, Arq Neuropsiquiatr 2004 ; 62:1:11

Región Población (Muestra)

I 4.938

II 3.453

III 1.857

IV 3.760

V 14.211

VI 3.880

VII 6.444

VIII 12.802

IX 7.658

X 9.137

XI 1.289

XII 2.381

METROPOLITANA 64.808

• Population of Chile (2002) 15.050.341 inhabitants

MULTIPLE SCLEROSIS

Estimated:

• Prevalence: 11,7 : 100.000

• Incidence: 1.8 : 100.000

Distribution of patients with MS by age at the diagnosis of the disease

05101520253035404550

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70

Nu

mb

er o

f p

atie

nts

Age

Distribution of the patients

Easter Island (Isla de Pascua) Chile

Population: 3.791 inhabitants Area: 166 Km2

Multiple Sclerosis in Easter Island

AIR FLIGHT TO ISLA DE PASCUA 1984-2005

0

5000

10000

15000

20000

25000

30000

35000

YEAR

N°

PA

SS

AG

ER

No cases of MS in Easter Island

* The only case of MS in Easter Island is from a man who travelled from Chile and lived here for more than 15 years ( He died from Multiple Sclerosis 5 years ago )

Population: 3.791 inhabitants

Area : 166 Km2

Multiple Sclerosis mortality (1970-2002)MS was a prevalent disease in Chile after 1970

Multiple Sclerosis Mortality

0

5

10

15

20

25

30

1970

1972

1974

1976

1978

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

MORTALITY MULTIPLE SCLEROSIS CHILE 1970-2005

00,020,040,060,080,10,120,140,160,18

1970

1972

1974

1976

1978

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

YEAR

10

0.0

00

Number Cases / Year MS Cases / 100.000

Instituto Nacional de Estadisticas, Chile

INCIDENCE OF MULTIPLE SCLEROSIS CHILE

0

10

20

30

40

50

60

70

80

90

AÑO

N°

CA

SO

S

YEAR

The effect of socioeconomic status on susceptibility to autoimmune and allergic diseases

J.Bach N Engl J Med 2002;347:12:911

The Effect of Infections on Susceptibility to Autoimmune and Allergic Diseases

J.Bach N Engl J Med 2002;347:12:911-918

J.Bach N Engl J Med 2002;347:12:911

Increase of Autoimmune Diseases in Chile

Asthma Allergic dermatitis Allergic rhinitis

1990 2005

8%

14%

25% 30% Increase of Allergic Diseases in school- children in Chile in the last 15 years

M.A. Guzman, Allergy & Immunology Society of Chile 2006

MRI in Chile ( 1988-2006)

N ° MRI

Years

First MRI in Chile

MRI : 39

0

10

20

30

40

50

60

70

80

90

N°

CA

SO

S

AÑO

Cases of Multiple Sclerosis in ChileData from register of the Corporation of Multiple Sclerosis in Chile

MS Subdiagnosis

MS Overdiagnosis

Changes in the ascertainment of Multiple Sclerosis

Marrie, Neurology 2005: 65: 1066

Multiple Sclerosis Diagnosis in Chile Time until the first MS Diagnosis

0-1 years58,4%

>5 years

12,5%

1-2 years

14,6%

2-3 years

3-4 years 6,25%

6,25%

Superintendencia de Isapres 1996-2005

ND

Review of 156 personal outpatients records

Diagnosis Numbers of cases

CIS ( ON, Transverse myelitis, Brainstem syndrome ) 13

Migraine headache 7

Small-vassel disease 5

Subcortical arteriosclerotic encephalopathy 5

ADEM 4

SLE, Sjogren 3

Stroke ( embolic ) 2

CADASIL 2

Antiphospholipid syndrome 2

HIV, HTLV-I 2

CNS Lymphoma 1

NMO 1

Psychiatric disease ( ACIS) 6

Total 53 ( 34% ) Barahona JA, Clínica Alemana MS Center 2006

Review of Personal Outpatient Records

Charles M. Poser and Callum C. Ross

Total Referrals with diagnosis of CDMS

366 100%

Correct Diagnosis 236 64.5%

Other Diagnosis 130 (101 F + 29 M)

35.5%

Other Diagnoses

Diagnosis Number Percent

Disseminated encephalomyelitis 48 36.9%

Chronic fatigue syndrome 28 21.5%

Myelopathy Posttraumatic Cervical spondylosis / HNP Acute myelitis Unknown cause

278874

20.8%

Posttraumatic syndrome 5 3.8%

Complicated migraine 5 3.8%

Psychiatric problem 3 2.3%

Miscellaneous/undiagnosed 14 10.8%

• The mean age was 42 years• 36% male and 64% female• Unexplained symptoms were a important cause of misdiagnosis

• In one large series of patients diagnosed with MS , 9% turned out not to have any organic disease

Hankey GJ et al Pseudo multiple sclerosis: a clinico-epidemiological study Clin Exp Neurol 1987 : 24 ; 15-19

Lack of comfirmation of initial MS suspicion upon expert referral

Referring Practioners Number of patients

Percent in wich MS was NOT confirmed

Reference

Patients initially diagnosed with MS by neurologist

366 35% Poser , 1977

Primary care providers 64% neurologist 25% other physicians

281 67% Carmosino, 2005

Neurologists for second opinion 377 32% Nielsen, 2005

Diagnostic Criteria for Multiple Sclerosis

Reason for Referral to a MS Center * Rate of Non - Confirmation of MS

MS possible ( Clinical findings ) 54%

MS possible ( MRI findings ) 89%

MRI are not a substitute for a good history and neurological examination in the diagnosis of MS J.Fleming AAN San Diego 2006

* Carmosino, Arch Neurol 2005;62:585-90

Reason for Referral to a MS Center * Rate of Non - Confirmation of MS

Lancet Neurol 2006 ; 5 : 841-52

Does MRI allow earlier diagnosis ?

JNNP 2001;70:390-93

Criterios de Barkhof (1997)

Gd juxta infra PV

Esclerosis Múltiple: Lesión Periventricular o Juxtacortical

EM EM

No EM

McDonald 2001 McDonald 2005 Nuevos Criterios DiagnósticosEspecificidad 91% 88% 87%Sensibilidad 47% 60% 72%

Lancet Neurology 2007

Clinical Symptom in Multiple Sclerosis

Symptom Porcentage at onset Porcentage Anytime

Sensory 30 - 50 90Visual loss (ON) 15.9 65Weakness legs 10.0 90 Hemiplegia 2.0 9Diplopia 6.8 30Gait disturbance 4.8 50 - 80Sensory in face 2.8 10Vertigo 1.7 - 4 5 - 50Lhermitte´s symptom 1.8 - 3 30Bladder symptoms 1.0 80Polysymptomatic onset 13.7

D.W.Paty University of British Columbia

Clinical Symptom : Optic Neuritis

Optic Neuritis

MS

ON

ON ADEM

ON

Leber

MS

Myelitis

Devic Lupus ADEM

Isolated Optic Neuritis

Mc Donald1992, Morrissey 1993, Miller 1988, Stendahl-Brondin 1983

Cerebral MRI Normal

Multiple Sclerosis

None Developed MS

36% (19/53)

10%

64%

Multiple Sclerosis

Cerebral MRI Abnormalities

(34/53)

35% (12/34)

1 year

With silent MRI lesions 75% Developed MS

(3/19)

6 year

5 year

OB

81% 5%

MS

+ -

Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical

conversion profileC Lebrun1, C Bensa2, M Debouverie3, J De Seze4, S Wiertlievski5, B Brochet6, P Clavelou7, D Brassat8, P Labauge9, E Roullet2

Journal of Neurology, Neurosurgery, and Psychiatry 2008;79:195-198

• Report a descriptive retrospective study of clinical and 5 year MRI follow-up in patients with subclinical demyelinating lesions fulfilling MRI Barkhof–Tintoré criteria with a normal neurological examination.

• 30 patients were identified and the first brain MRI was performed for various medical events: headaches (n = 14), migraine with (n = 2) or without (n = 4) aura, craniocerebral trauma (n = 3), depression (n = 3), dysmenorrhoea (n = 2), epilepsy (n = 1) and cognitive changes (n = 1).

• Mean time for the second brain MRI was 6 months (range 3–30).• 23 patients had temporospatial dissemination (eight with gadolinium enhancement). • 11 patients had clinical conversion: optic neuritis (n = 5), brainstem (n = 3), sensitive

symptoms (n = 2) and cognitive deterioration (n = 1). Eight (72%) already had criteria of dissemination to space and time before the clinical event.

• Mean time between the first brain MRI and clinically isolated syndrome (CIS) was 2.3 years. • Early treatment should be discussed in view of the predictive value on conversion of the

MRI burden of the disease.

Separating Zebras from Horses The unusual presentation of an common disease is generally more likely than

the usual presentation of an uncommon disease

When faced with an unusual clinical feature, ask first whether it can be explained by something other than a rare disease

Smith J Am Board Fam Pract 13(6):424-429, 2000

Problems with the McDonald criteria

1. Prognostic criteria not Diagnostic criteria2. Stringency of criteria ( Recurrent optic neuritis, recurrent myelitis, recurrent ADEM )

3. MRI ( Cost and the sensitivity may vary with technology; 3 Tesla MRI may create more false positives )

4. Oligoclonal bands ( Sensitivity and specificity )

5. Other diseases may meet the criteria for dissemination in time and space required for diagnosis of MS

6. Impact on treatment decisions ( Early treatment should be discussed in view of the predictive value on conversion of the MRI burden of the disease )

Multiple Sclerosis

• MS is a life-long disease• Multiple Sclerosis is a clinical diagnosis• There is no pathognomonic or perfect

laboratory test to diagnose MS• MRI is sensitive but has limited specificity

Suspected MS is not the same as established MS once diagnosed can´t easily retract

Muchas GraciasMerci

Disease is very old and nothing about it changes. Its is we who change as we learn to recognize what was formerly imperceptible

Jean Martin Charcot ( 1825-1893 )

The Three Worlds

Third World: "less developed countries", "lesser developed countries"

INCIDENCE OF MULTIPLE SCLEROSIS CHILE

0

10

20

30

40

50

60

70

80

90

AÑO

N°

CA

SO

S

MRI

CHOLERA

WATER PROCESSING PLANTS

YEAR

Large-scale field trial of live oral typhoid vaccine in Santiago, Chile (1982-1986)

** Year Vaccine Placebo

• 1982 55.238 27.305• 1983 44.549 21.904• 1984 248.544 0• 1986 84.836 0 Total 433.167 school-children

** C. Ferreccio personal comunication

Santiago of Chile

* Lancet 1987;336:891

Typhoid Fever (1980-2002)

The Lancet

The Hygiene Hypotesis

Multiple Sclerosis

The starting point for diagnosis in the individual patient is the clinical picture

A BTwins : MS & Not MS

Is the clinical history compatible with MS ?

Epigenetic differences arise during the life time of monozigotic twins

M. Fraga PNAS 2005;26:10604-09

3 years old twins 50 years old twins

Explain why different phenotypes can be originated from the same genotype

Epigenetic profiles may represent the link bewteen an environmental factor and phenotypic differences in MZ twins

Multiple Sclerosis in the Faroe Islands

• The Faroe are a group of 18 Islands in the North Atlantic Ocean, in a semi-independent status, part of the Kindgdon of Denmark

• British troops invaded the Faroe Islands in World War II (1940-1945) • The population was 26.232 inhabitant (1943)• Multiple Sclerosis did not exist among resident Faroese before 1943

( Except 2 Faroese who lived in Denmark and return to Faroe Islands before the War )

British troops in the Faroe Islands in World War II Encampments of 1500 troops & Residence of MS patients

J.F. Kurtzke, Clinical Microbiology Reviews 1993;6:4:384-427

Epidemiologic Evidence for Multiple Sclerosis as an Infection

J.F. Kurtzke, Clinical Microbiology Reviews 1993;6:4:384-427

1943-1961 : 32 cases

4 cases*

* Two patients died from MS and two Faroese which lived 3 years outside Faroe Islands and return before the War

J.Benedikz Ann Neurol 1994; 36 (S2).S175-179

Epidemic I

The Hygiene Hypothesis can explain the outbreak of Multiple Sclerosis in Chile

• The “ Hygiene Hypothesis” , propose an inverse relation between the incidence of some infectious diseases or foodborne pathogens and the subsequent decreased risk of the development of Multiple Sclerosis

The Western lifestyle has succeeded in terms of decreasing the incidence of infections in early life but these infections would have had a protective effect on the

development of autoimmune diseases

Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of

Multiple SclerosisDalton CM Ann Neurol 2002 ; 52 : 47-53

Performance of McDonald Criteria

• Sensitivity 83%• Specificity 83%• Posititive Predictive Value 75%• Negative Predictive Value 89%• Accuracy 83%

• Diagnosis of MS achieved by McDonald recommendations (test criteria) applied to CIS patients at one year after presentation, when compared to re-analysis of these patients by Poser criteria (golden standard) at three years.

Multiple Sclerosis convertion after a Optic Neuritis

Optic Neuritis ( Patients in the hospital )

0 15 years 30 years

35% EM 40% EM

18 years

17% MS

Optic Neuritis (Ambulatory patients )

Rizzo1988, Nilsson 2005, Sandberg-Wollheim 1990

What is the most common mistake during MS diagnosis ?

• The biggest problem in MS diagnosis is the false positives ( overdiagnosis of MS )

• We believe that the problem in MS diagnosis is one of false negatives ( MS is not present when in fact the patient has MS )

Fleming JO The diagnosis of Multiple Sclerosis AAN 2007

The lack of a specific laboratory test for MS

Multiple Sclerosis ultimately is a histopathological diagnosis, and the clinical criteria have been developed for the diagnosis of Multiple Sclerosis during life.

Barkhof, Brain 1997,120;2059-2069

Enfermedades Diseminadas en Tiempo/Espacio RNM (+)

• Enfermedad Cerebrovascular• ADEM ; recurrente, multifasica*• Linfoma SNC • CADASIL• Enfermedad de Sjöegren*• Vasculitis SNC• Sarcoidosis*• Encefalopatia Mitocondrial ; MELAS, MERFF• Enfermedad de Lyme *• Lupus SNC *

MR (+) : Age-related changes, Binswanger`s disease,Progressive multifocal leukoencephalopathy, Inherited white matter diseases, HIV, HTLV-I, Metastatic neoplasm

* OB (+) : Lupus, Syphilis, HTLV-I, Sjögren`s disease, ADEM, Lyme disease, Sarcoid, Behcet`s disease

MRI and false positive in MS

• MRI scan for migraine or head trauma has the potential for generating data that the physician does not know how to interpret.

• This may compel both the patient and his physician to do something