CADASIL MAIN CLINICAL FEATURES AND NATURAL HISTORY

H Chabriat CERVCO, INSERM U740, DHU NeuroVasc, Universit Denis Diderot, APHP Paris, France

Executive Dysfunction

Dementia

Motor Disability Apathy Mood Disturbances 20 % 60-85% 40%

Ischemic Stroke Migraine with aura

20-40 %

T2 WM abnormalities

10

20

30

40

50

60

70

80 Age (years)

Chabriat et al, Lancet Neurol, 2009

Executive Dysfunction

Dementia

Motor Disability Apathy Mood Disturbances 20 % 60-85% 40%

Ischemic Stroke Migraine with aura

20-40 %

T2 WM abnormalities

10

20

30

40

50

60

70

80 Age (years)

Chabriat et al, Lancet Neurol, 2009

Migraine with aura

Migraine with aura occurs earlier in women than in men in CADASIL

Vahedi et al, Arch Neurol, 2004

Migraine with aura in CADASIL: age of onset

60

N = 378 patients
50 40 30 20

percentage

women men

10
0

5 to 15

16 to 30

31 to 40 41 to 50 age (years)

51 to 60

> 60

Paris-Munnich Cohort (2013)

Recurrent episodes of headache in 102 CADASIL patients

pts (%)
Migraine Migraine with aura Basilar migraine Hemiplegic migraine Aura without headache Migraine without aura Other types of headache 38 33

6 5 7
26 9

Dichgans et al. Ann Neurol 1996

TIAs and stroke

Ischemic stroke
6085% of patients mean age of first stroke: 49 years (range from 19 to 70 years) average incidence: 104 per 100 patient-years (95% CI 5.6 to 15.2) average number: 2 to 5 recurrent strokes over several years ischemic events invariably subcortical lacunar syndrome in about 2/3 of cases (pure motor or sensory deficit, ataxic hemiparesis, sensory-motor deficit, dysarthriaclumsy hand syndrome) in most cases no conventional vascular risk factors but HT present in 20% of patients and high cholesterol and smoking present in 50% of patients in some series
Chabriat et al, Lancet, 1995 Dichgans et al, Ann Neurol, 1998 Peters et al, Stroke, 2004

Multiple punctiform DWI positive lesions

Case 1 51 yo man, no vasc risk factor, 3rd stroke: left hemiplegia BP 100/50 mmHg

Case 2 44 yo man, no vasc risk factor episodes of instability and paresthesias; sudden right sided dysarthria and hemiparesis BP 100-130/60-85 mmHg with episodes of hypotension 80/45 mm Hg Case 3 54 yo woman, no vasc risk factor, 4th stroke, acute right hemiparesis BP 105-130/60-75 mmHg

Gobron et al Cerebrovasc Dis, 2006

Multiple widespread DWI positive lesions

Case 1 48 yo woman, acute short term memory loss and word finding difficulty BP normotensive but no detail

Case 2 42 yo woman, sudden fall and abulia BP 98/50 mm Hg

Gordhan et al, Radiology Case, 2013 Saito et al, J Neurol, 2011

Intracerebral hemorrhage in CADASIL

DWI+ ICH

Case 1: BP 220-120 mm Hg Ragoschke et al, JNNP, 2004

ICH

Case 2: BP: 100/63 mm Hg, use of steroids MacLean et al, JNNP, 2005
4 hypertensive cases Rinnocciet al, J Neurol Sciences, 2013

Characteristics of CADASIL patients with ICH

Rinnocci et al, J Neurol Sciences, 2013

Neuropsychiatric manifestations Mood disturbances

Neuropsychiatric manifestations are frequent in CADASIL

NPI

Reyes et al, Neurology, 2009

Apathy: a major symptom associated with cognitive decline

reduction of voluntary (or goal-directed) behavior
APATHETIC (40%) n = 54 58.7 (9.9) 3477 66.7 (36) 9.2 (0.5) 23.0 (0.6) 119.7 (2.4) 42.6 (23) 3.9 (0.3) 77.4 (41) 55.6 (30) 40.0 (20) 79.6 (43) 16.7 (9) 51.9 (28) 35.2 (19) NONAPATHETIC n = 78 50.5 (11.8) 2574 34.6 (27) 11 (0.4) 28.4 (0.5) 139.9 (1.9) 7.7 (6) 7.6 (0.3) 75.3 (58) 40.3 (31) 46.6 (34) 57.4 (44) 5.2 (4) 9.1 (7) 0.0 (0) p*
0.0001 0.0004 0.0038 0.0001 0.0001 0.0001 0.0001 0.07 0.27 0.79 0.46 0.62 0.008 0.0001

Age, y, mean (SD) Range Men,%(n) Years of school, mean (SD) MMSE/30, mean (SD) MDRS/144, mean (SD) Modified Rankin Scale >3,%(n) IADL/8, mean (SD) Presence of vascular risk factors,%(n) History of psychiatric disorders,%(n) Migraine with aura,%(n) History of TIA or stroke,%(n) Presence of seizures,%(n) Presence of gait disorders,%(n) Dementia,%(n)

Reyes et al, Neurology, 2009

Mood disturbances in CADASIL

Can be inaugural High frequency: between 20-40% in the largest series Most frequently severe depression (9/10 cases) Sometimes dysphoria and manic episodes as observed in bipolar disorders (1/10)

Structured Clinical Interview for DSMIV criteria by psychiatrists - N = 23 pts (mean age 53y, demented subjects excluded) - Lifetime episode of depression: n = 17 (74%)
- Main symptom: depressed mood, feelings of guilt, insomnia

- Lifetime manic episode: n = 6 (26%)

- Main symptoms: increased motor activity-energy, sleep disturbances, irritability

Chabriat et al, Lancet Neurol, 2009 Valenti et al, Acta Neurol Scand, 2008 &2011

Cognitive decline

Alteration of speed processing is the earliest cognitive manifestation of CADASIL

22 CADASIL pts (mean age 53 y, MMSE 25-30, mRS 0-1) vs 29 healthy age-matched controls
Executive functions Inhibition errors Flexibility errors (number letter) Verbal fluency phonological task, n (letter p, 2 min) Verbal fluency category task, n (fruits, 2 min) Divided attention errors (visual and auditory) Planning errors (clock drawing executive task) Executive functions time measures (ms) Inhibition Flexibility (number letter) Divided attention (visual item in dual task) Divided attention (auditory item in dual task) Speed reaction time task (ms) Without warning With warning p value 0.34 0.88 0.06 0.35 0.38 0.41

0.001 0.02 0.002 <10-4

0.02 0.04

Jouvent & Reyes et al, VasCog 2011

Impaired cognitive functions in CADASIL

patients

100% 80% 60%

Visuospatial abilities Reasoning Verbal fluency Attention Memory Executive functions < 50 ]50 60] > 60
Buffon F et al, JNNP, 2006

Percentage of

40%
20% 0%

Age

Memory impairment
INFORMATION
ENCODING immediate recall N = 44
Age (years) High educationlevel Sex male Cardiovascularrisk History of stroke or TIA Focal neurologica l deficit MADRS Barthel Index Rankin score MDRS <5th percentile,%(n) IADL, mean(S.E.) MMSE *adjustment for age, sex and education level 54.7(1.9) 13.0% 68.8% 67.5% 66.6% 42.9% 13.5(3.8) 91.6(3.2) 1.1(0.3) 42.3 (11) 6.7 (0.3) 28.3 (0.3)

INFORMATION STORAGE RETRIEVAL delayed recall recall with cues N = 96

49.2(1.2) 34.1% 41.0% 84.4% 72.4% 24.5% 9.1(2.1) 96.8(1.8) 0.6(0.2) 8.2 (5) 7.4 (0.2) 28.1 (0.2)

30%
0.01 0.01 0.004 0.15 0.65 0.1 0.05 0.14 0.14 0.01 0.01 0.001 *

S Epelbaum et al, Neurobiol Aging, 2009

Hippocampic memory impairment is observed in one out of five CADASIL patients with memory deficit
INFORMATION
ENCODING STORAGE RETRIEVAL INFORMATION

poor free and delayed recall adequate encoding little or no improvement by cueing Hippocampic memory impairment (8) Mean age IADL Barthel index Rankin 56.8 5 (0.7) 77 (8) 2 (0.8) Other types of memory impairment (36) 55.1 6.8 (0.4) 92 (3) 1.1 (0.3)

MMSE

22.9 (0.8)

27 (0.4)
S Epelbaum et al, Neurobiol Aging, 2009

The cognitive profile does not differ between CADASIL pts with stroke and sporadic SVD

N = 20 N = 54 N = 14

Clarton et al, Neurology, 2006

Disability

Main factors of disability in CADASIL

Rankin scale
0 - No symptoms at all 1 - No significant disability despite symptoms; able to carry out all usual duties and activities 2 - Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 - Moderate disability; requiring some help, but able to walk without assistance 4 - Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 - Severe disability; bedridden, incontinent and requiring constant nursing care and attention
From 220 CADASIL patients

Dementia 11%

1/3

1/3
1/10

Yao et al, Cerebrovasc Dis, 2012

Dementia
20-30% pts mean age = 58 9 years subcortical dementia
frontal-like symptoms (poor attention, perseverations, apathy) and memory impairment

stepwise or progressive deterioration isolated (no history of stroke) in 10% often associated with pseudobulbar palsy present in 90% of cases before death

Main symptoms associated with dementia

Demented CADASIL patients can present without any history of stroke and without any focal symptoms

Benisty et al, Stroke, 2008

Gender effect

Severe disability and/or dementia is nearly constant before death

Sign/symptom No. of subjects* (%)

Spastic tetra-/hemiparesis Urinary incontinence Constant nursing care and attention Dementia Dysarthria Dysphagia Faecal incontinence Bedridden Pathological laughing or crying Decubital ulcer Transcutaneous gastric feeding Suprapubic catheter

55/62 (89) 48/60 (80) 51/65 (78) 49/64 (77) 47/61 (77) 41/56 (73) 42/58 (72) 41/65 (63) 30/56 (54) 18/55 (33) 18/59 (31) 12/58 (21)
C Opherk et al, Brain, 2004

Other clinical manifestations

Seizures (partial of GM) focal, generalized, refractory status epilepticus Rare or coincidental manifestations 10%

- Parkinsonism - Vestibular manifestation - Hemiballism

Peripheral sensory symptoms with abnormal nerve conduction Myopathy Spinal cord manifestations with associated lesions Visual loss

Conclusion
CADASIL is a severe condition progressing over several decades the most frequent clinical manifestations are migraine with aura, TIAs and stroke, gait disturbances, mood disorders, cognitive decline from executive dysfunction to severe dementia associated with apathy, seizures can be also observed severe disability is more frequent in men than in women after 50y and can occur at different age from 45 to 80y, although > 75% pts are severely disabled after 65y

Acknowledgements Clinical team

Dominique Herv Nassira Alili Jerome Mawet Frederique Buffon Marie Germaine Bousser

Lab
E Tournier Lasserve A Joutel and their team

Support Logistics
Jocelyne Ruffie Solange Hello

Imaging
Jean Pierre Guichard (MRI team) Eric Jouvent Franois De Guio

Neuropsychologists
Annie Kurtz Sonia Reyes Aude Jabouley

Patients, families +++

Association CADASIL France

Main collaborators
Martin Dichgans Marco During Nicola Zieren Niels Peters Chahin Pachai

Clinical researchers and PostDoc

Anand Viswanathan (USA) Stephane Epelbaum (France) Claire Gobron (France) Sarah Benisty (France) Bence Gunda (Hungary) Zhu YiCheng (China) Yao Ming (China)

Acknowledgements

ARNEVA

Fondation Leducq

Fondation Singer Polignac