problemas diagnósticos de la esclerosis múltiple en chile d´une maladie inconnue a une maladie en...
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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
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