Presentation on theme: "CADASIL Mary Quiceno, M.D. Clinical Assistant Professor"— Presentation transcript:
1CADASIL Mary Quiceno, M.D. Clinical Assistant Professor Department of NeurologyUT Southwestern Medical Center
2Neuropathology report on NP36015 What is CADASIL?
3CADASIL Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts &Leuko-encephalopathyInherited small vessel disease causing stroke and subcortical vascular dementia that starts in early adulthood and progresses over time.This is a nonatherosclerotic, nonamyloid angiopathy involving small arteries and capillaries of the brain and other organs.Caused by missense mutations in the Notch3 gene on chromosome 19p13.Inherited small vessel disease causing stroke and subcortical vascular dementia that starts in early adulthood and progresses over time. This is a nonatherosclerotic, nonamyloid angiopathy involving small varteries and capillaries of the brain and other organs caused by missense mutations in the Notch3 gene on chromosome 19p13.
4CADASIL 1977: family w/hereditary, multi-infarct dementia syndrome Presents in mid-20s to age 45Stroke, dementia, migraine with aura, mood disordersShortened life spanMost die by age 65Unknown prevalence400 families world-wide2/100,000Largely undiagnosedA clinical syndrome consistent with CADASIL was originally described by Van Bogaert in 1955 and by Sourander and Walinder in 1977 ina case series describing the autopsy findings of 5 patients who had recurrent ischemic strokes prior to age 40. There was an autosomal dominant transmission, and 4 of the 5 had dementia. Pathologic changes were observed in the cerebral microvasculature. Also in 1977, Stevens et al described a similar syndrome which they termed chronic familial vascular encephalopathy.400 familes world-wide have mutation.Estimates at prevalance: 2/100,000.Largely uindiagnosed.
5Case Studies Most reported cases from Europe 105 people from 33 affected familiesVascular risk factors are uncommonMean age of initial symptom onset yearsMigraine in 40% ( yrs)Stroke/ TIA 43% ( yrs)Depression 8%Cognitive decline 6%Seizure 3%A pooled analysis of published cases found 105 symptomatic people from 33 families.-even split between males and females-most patients from europe, 13 from US, 2 from El Salvador, 1 from Japan-Vascular RF uncommon (8 had HTN)-mean age of symptom onset was years.-Stroke/TIA was initial symptom in 45 (mean age on onset years) (43%)-Migraine was initial symptom in 42 patients (younger mean age of onset years) (40%). Most w/aura.-9 had depression as initial symptom (8.5%) and 6 (5.7%) had cognitive decline, and 3 had seizure (2.8%)-
6overall, 67% had a TIA or stroke overall, 42% had dementia>30% with migraine w/aura and 15% w/mood d/ooverall, age of death, in the 20% of the cohort that was deceased, was yearsCourse is heterogeneous even in the same family: some remain asymptomatic until their 70s whereas others are severely affected by the age of 50.
7MIGRAINE with aura Often initial feature 1/3 of families Occurs earlier as compared to strokeConsider CADASIL in migraineur with diffuse white matter lesions on MRINot small, scattered hyperintensities, which can be seen in migraineurs (16%) who don’t have CADASIL16% have WM lesionsIf <50 years old with no stroke risk factors, then 6% have UBOsIncrease in frequency with age and RFIn study of 1000 MRIs in normals who had studies done for research purposes, 0.5% had a solitary white matter hyperintensity. Mean and median age was about 30 yrs (all subjects were 3-83 yrs old).WMLs in 10% of people in 4th decade and 80% of people in 8th decade
8STROKE TIAs and subcortical ischemic strokes Accumulating sensory, motor, and cognitive deficitsMost common featureTypical stroke risk factors NOT presentCerebral non-atherosclerotic, nonamyloid angiopathyPrimarily affecting small vessels that penetrate white matter and basal ganglia
9MOOD DISORDERS Depression Bipolar disorder Like migraine, CADASIL should only be considered when MRI changes are presentTend to predate cognitive decline
10Mood Disorders in an affected family 29 yr old son4th psychiatric hosp. admissionDepression and psychosis52 yr old fatherMigraines, strokeAntisocial and withdrawn72 yr old paternal grandmotherDepression at age 50Dementia at age 61Frontal lobe dysfunctionRetrieval deficits
11COGNITIVE DEFICITSSlowly progressive in addition to stepwise deteriorationTypically appears after stroke symptoms appearCan be presenting featureFrontal lobe dysfunctionMemory impairmentPseudobulbar palsy, gait disturbances, pyramidal signs, sphincter incontinenceSubcortical dementiaVascular dementia
12Cognitive profile CADASIL compared to normals Impaired on executive function and speed measuresDelis-Kaplan Executive Function System (D-KEFS)Trails motor speed subtest from the D-KEFSCADASIL w/stroke and cerebral small vessel disease (SVD)SVD typically olderBoth impaired similarly on executive fx and speedCADASIL worse on verbal fluency (letter)refers to a wide range of central control processes in the brain that connect, prioritize,and integrate operation of subordinate brain functionsthis central management system, often attributed to operations in the prefrontalcortex, is crucial to organizing and integrating cognitive processes over time and plays anincreasingly important role as we maturevisualize executive function as the conductor of a symphony orchestra, who does not playa musical instrument in the orchestra but does play a critical role by enabling theorchestra to produce complex music. The conductor organizes, activates, focuses,integrates, and directs the musicians as they play. The brain’s executive functions, in likefashion, organize, activate, focus, integrate, and direct, allowing the brain to perform bothroutine and creative work.Executive functions require several higher-level cognitive abilities for successful performance.These can be assessed with tasks that require:– initiation of effortful and novel thinking– isolation of a common feature or attribute from among the array of target stimuli– formation of a higher-level concept that captures the defining properties of those common features– flexibility of thinking in order to abandon one conceptual relationship in order to apprehend new onesDelis-Kaplan Executive Function System Ages 8- adulthood D-KEFS is the first nationally standardized set of tests to evaluate executive functions Assesses higher level thinking and cognitive flexibility Two forms are available to limit practice effects when used for pre- and post-testing.Comprehensive Evaluation Using 9 Tests Card Sorting Test– Evaluates problem-solving, verbal and spatial concept formation, flexibility of thinking on aconceptual task Trail Making Test– Evaluates flexibility of thinking on a visual-motor task Verbal Fluency Test– Evaluates fluent productivity in the verbal domain Design Fluency Test– Evaluates fluent productivity in the spatial domain Color-Word Interference Test– Evaluates verbal inhibition Tower Test– Evaluates planning and reasoning in the spatial modality; impulsivity 20 Questions Test– Hypothesis testing; evaluates verbal and spatial abstract thinking; impulsivity Word Context Test– Evaluates deductive reasoning; verbal abstract thinking Proverb Test– Evaluates metaphorical thinking; generating versus comprehending abstract thoughtCorrelated with Wechsler Abbreviated Scale of Intelligence (WASI) with California Verbal Learning Test Provides information concerning the role of intellectual ability and memoryon D-KEFS performance
13Executive Functionrefers to a wide range of central control processes in the brain that connect, prioritize, and integrate operation of subordinate brain functionsthis central management system, often attributed to operations in the prefrontal cortex, is crucial to organizing and integrating cognitive processes over time and plays an increasingly important role as we matureorganizes, activates, focuses, integrates, and directsExecutive functions require several higher-level cognitive abilities for successful performance.These can be assessed with tasks that require:– initiation of effortful and novel thinking– isolation of a common feature or attribute from among the array of target stimuli– formation of a higher-level concept that captures the defining properties of those common features– flexibility of thinking in order to abandon one conceptual relationship in order to apprehend new ones
14Other organ disease In some patients w/CADASIL silent retinal microvascular circulatory changes18 pts: No visual symptoms. VA was normal in all. Ophthalmologic abnormalities were found in 8 patients.FE and FA revealed silent retinal abnormalities in CADASIL patients with nerve fiber loss in 22% and cotton wool spots in 17%.may be considered as peripheral markers of this genetic disease.high frequency of myocardial infarction in a single series of Dutch patientsDistinct from CADASIL, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) is an autosomal dominant multi-infarct syndrome with systemic involvement.We describe a Chinese American family with a hereditary syndrome consisting of retinopathy, nephropathy, and stroke, affecting 11 members spanning three generations. Ophthalmologic evaluations revealed macular edema with capillary dropout and perifoveal microangiopathic telangiectases. Several members had renal abnormalities with proteinuria and hematuria. Initial manifestations were visual impairment and renal dysfunction; neurologic deficits occurred in the third or fourth decade of life. Symptoms included migraine-like headache, psychiatric disturbance, dysarthria, hemiparesis, and apraxia. Neuroimaging consistently demonstrated contrast- enhancing subcortical lesions with surrounding edema. Ultrastructural studies showed distinctive multilaminated vascular basement membranes in the brain and in other tissues, including the kidney, stomach, appendix, omentum, and skin. Genetic analysis ruled out linkage to the CADASIL locus on chromosome 19. Distinct from CADASIL, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) is an autosomal dominant multi-infarct syndrome with systemic involvement.
15Brain Imaging in CADASIL Diffuse white matter hyperintensities on T2 and FLAIR weighted imagesSubcortical white matterBasal gangliaChanges on MRI may be evident in persons who are in their 20sPenetrance complete by age 35 and all will have MRI findingsThe syndrome may not be suspected until affected individuals are in their 50s or olderLesion volume is inversely correlated with cognitive function
16MRI Changes Axial FLAIR images 59 yr old woman Multiple confluent hyperintensities in deep and periventricular white matter
17MRIMost specific finding to differentiate CADASIL from ischemic leukoaraiosisT2 hyperintenisties in anterior temporal pole
18MRI in CADASIL w/characteristic MRI findings of involvement of the external capsule and anterior temporal lobes.
19Differentiating CADASIL from other diseases affecting the white matter Ischemic small-vessel diseaseUsually occurs after fifth decadeVascular risk factors presentMultiple SclerosisMore likely to see spinal cord and corpus callosum lesionsPeriventricular lesions are ovoid and/or oriented perpendicular to lateral ventriclesOthers in the differentialADEMBinswnger’s disease (hypertensive atherosclerotic encephalopathy)Amyloid angiopathyProgressive multifocal leurkoencephalopathyMitochondrial disprdersvasculitis
20When to consider MRI in migraineur Consider MRI ifMigraine attacks with aura begin in mid-adulthoodAtypical auraHemiplegic, basilar, prolongedFamily history of stroke, dementia, depressionFocal neurological signsIn 771 migraineurs with nl exam, significant abnormalities on MRI were found in <1%.26% with “complicated migraines” (prolonged aura that was difficult to distinguish from a TIA/CVA, had an abnormal MRI.White matter hyperintense lesions (multiple, small, punctate lesions in deep white matter as seen on T2 or FLAIR imaging are common in general population (up to 10% in fourth decade and 80% in eight decade). There is an increased prevelance in people with vascular disease risk factors, h/o CAD, stroke, dementia, and advancing age. People with migraine are four times more likely to have WMH than non-migraine, age-matched controls, independent of vascular risk factors. Aura or no aura are the same. Women with more than 1 migraine a month may be at higher risk for the development of WMH. Putative mechanisms include migraine-related hypoperfusion and embolism.
21When to Suspect CADASIL Recurrent subcortical ischemic strokesEsp. <60 yrs oldEsp. in absence of vascular risk factorsEarly cognitive declineMigraine with auraComorbid psychiatric symptomsDepressionBipolar
22When to Suspect CADASIL Abnormal MRISignificant white matter lesions before age 35Multiple T2 hyperintensities w/o vascular risk factorsBilateral T2 hyperintensities in white matter, esp. w/lesions in ant. Temporal polesFamily historyStroke, dementia, depression, migraine w/aura, other white matter diseases (which may be misdiagnosed)Premature CAD
23Diagnostic Approach History MRI with involvement of anterior temporal poles OR external capsule ***&Positive gene testing ***Sensitivity of 100% with Hx, MRI, & gene test in one study from EnglandFigure. Fluid-attenuated inversion recovery MRI scans from a patient with a notch3 mutation shows typical involvement of the anterior temporal poles (arrow in A) and the external capsule (arrow in B), and characteristic images at the level of the lateral ventricles
24BiopsySkin biopsy was positive in approximately half of the 18 patients testedSkin biopsy was negative in all of the gene negative patientsSensitivity of 100%Granular osmiophilic material seen on EMSensitivity 50%, specificity 100%Tissue samples stained with monoclonal Ab top Notch3 proteinSensitivity 96%, specificity 100%
25The hallmark of the disease is the presence of granular osmiophilic material which is seen adjacent to the basement membrane of the smooth muscle cells of arterioles on electron microscopy.This is pathognomic for CADASIL.The deposition of GOM in skin arterioles may vary depending on the exact mutation involved.The vascular defects are present in every tissue and may be detected histologically by examining arterioles in skin biopsy, where accumulation of granular and osmiophilic material within the smooth muscle cell basement membrane and the surrounding extracellular matrix.
26Blood vessels in CADASIL w/ basophilic granular material (below)EM (to right)The hallmark of the disease is the presence of granular osmiophilic material which is seen adjacent to the basement membrane of the smooth muscle cells of arterioles on electron microscopy. This is pathognomic for CADASIL. The deposition of GOM in skin arterioles may vary depending on the exact mutation involved.The vascular defects are present in every tissue and may be detected histologically by examining arterioles in skin biopsy, where accumulation of granular and osmiophilic material within the smooth muscle cell basement membrane and the surrounding extracellular matrix.
27Blood vessels in CADASIL 2 types of changes in arteries, veins in bodyBasophilic degeneration and thickening of the media (top picture)Fibrinoid necrosis of the media sometimes associated with delicate perivascular inflammatory infiltrates (bottom picture)Basophilic degeneration and fibrinoid necrosis have been found in arteries and veins of internal organs as well as vessels from skin, muscle, and nerve biopsy.The nature of the granular basophilic changes in vessel walls has not been identified. It may be debris of degenerated smooth muscles cells and/or basal lamina.In some cases of CADASIL, eosinophilc necrosis of tunica media and perivascular inflammatory infiltrates have been seen. Notch 3 gene may influence the development or reactivity of the immune system. Notch signalling directs early development of T and B cell lineages and is involved in the maturation of CD4 and CD8 T cells in the thymus. The notch pathway contributes to the regulation of the peripheral immune system and regulates the decision between immunity and tolerance.
28Notch3 ab in brain blood vessels Notch3 immunoreactivity in vascular smooth muscle cellsNormal controls on left (a, c, e)CADASIL patients on right (b, d, f)
29What leads to CADASIL? Mutations in notch3 gene Odd number of cysteine residues in Notch3 receptor extracellular domainImpaired clearance of cleavage productAlterations of vascular smooth musclePresence of granular osmiophilic deposits
30Notch3 gene mutation Usually missense mutation More than 50 have been foundSpontaneous mutations have been describedThe protein folds incorrectlyLeads to accumulation of protein in membranes of smooth muscles and, ultimately, fibrosis and luminal narrowing of them
31Notch3 gene Mutation in Notch3 gene on chromosome 19 Just downstream from a mutation found in familial hemiplegic migraineNotch 3 gene encodes a transmembrane receptorFunctions in signaling pathways essential for maturation of blood vesselsIn adults, it is maximally expressed in vascular smooth muscle in small to medium arteriesInteraction of notch receptor with its ligand leads to cleavage of the transmembrane receptor which migrates into the nucleus and, associated with a transcription factor, activates transcription of primary target genes.Notch genes code for large transmembrane receptors involved in cell fate decision during embryonic development.Interaction of notch receptor with its ligand leads to cleavage of the transmembrane receptor which migrates into the nucleus and, associated with a transcription factor, activates transcription of primary target genes. (fig 2b)Like all notch receprtos, notch3 contains a large number of tandemly arranged epidermal growth factor-like repeat domains which account for most of the extracellular portion. The gene has 34 exons and all of them may have pathogenetic mutations. No geneotype-phenotype relationship has been observed.All CADASIL related mutations occur in exons that encode one of the EGF-repeat domains. 100 different nutations in Notch3 have been reported. 95% are missense point mutations. Almost all mutations result in an odd number of cysteine residues which may cause protein misfolding, causing changes in receptor activation and abnormal signal trasnduction. The mechanism by which CADASIL mutations become pathogenic are unknown.
32The notch in the Drosophila wing In fruit fly heterozygotes for Notch3 gene have a “notch” in their wingThe mutation is lethal in homozygotesNotch proteinsEncode transmembrane receptors involved in determination of cell fate during developmentProliferation, differentiation, apoptosis
33Pathogenic Hypothesis Notch 3 expression is limited to vascular smooth muscle cellsMature vascular smooth muscle cells require continued function of the Notch 3 pathwayContinued survivalBlood vessels are narrowed and weak and do not react to fluctuations of CO2 and BPCapillaries, veins are involvedGeneralized vasculopathy
34Brain PredilectionCerebral vessels have fewer smooth muscle cells than vessels of other organsIncreased susceptibilityLimited ability for regeneration of CNS tissueWhite matter predilectionInsufficient collateral circulationDensity less than in grey matter
35What can be done for these patients? TreatmentControl vascular disease risk factorsBPIncreased SBP independent risk factor for progression of CADASILCholesterolDMSmokingObesityAvoid OCP, HRT
36Treatment Antiplatelet therapy Cholinesterase inhibitors Investigate for other causes of stroke (cardiac, afib, hypercoag state, etc.)Cholinesterase inhibitorsWork in vascular dementiaScreen for mood disorders, cognitive decline, seizureLife expectancy may be shortened by 6 years
37NP36015 The key finding Differential diagnosis Abundant basophilic (blue on H&E), PAS positive, osmiophilic (black on EM) granular material seen in the markedly thickened blood vessel wallsDifferential diagnosisAtheroscerotic diseaseBlood vessel walls are also thickenedGranular material is not usually present (if present, it differs from that seen in CADASIL)
38No treatmentScreening not indicated, unless family member is affectedFamily may wish to seek genetic counselingControl vascular risk factorsDo not smokeScreen for mood disorders, cognitive decline, focal neurologic signs, seizure