Zerebrale Mikroangiopathien

Marco Düring; Christian Opherk

doi:10.1055/a-0646-3746

Aktuelle Neurologie, Inhaltsverzeichnis

Aktuelle Neurologie 2018; 45(08): 592-604
DOI: 10.1055/a-0646-3746

Übersicht

Zerebrale Mikroangiopathien

Cerebral Small Vessel Disease

Marco Düring

¹Institut für Schlaganfall- und Demenzforschung, Klinikum der Universität München, München

,

Christian Opherk

²SLK-Kliniken Heilbronn GmbH, Klinik für Neurologie, Klinikum am Gesundbrunnen, Heilbronn

› Institutsangaben

Abstract

Zusammenfassung

Zerebrale Mikroangiopathien, Erkrankungen der kleinen Gefäße (perforierende Arterien und Arteriolen, Kapillaren, Venolen) des Gehirns, sind häufige Ursachen von Schlaganfall und vaskulärer Demenz. Die häufigste Form ist alters- und hypertonieassoziiert, die genauen Pathomechanismen sind jedoch weitgehend unbekannt. Weitere relevante Formen sind die zerebrale Amyloidangiopathie und monogen vererbte Mikroangiopathien, wie bspw. CADASIL als häufigste erbliche Schlaganfallerkrankung. An klinischen Manifestationen finden sich akute (ischämischer oder hämorrhagischer Schlaganfall) und chronische Symptome. Zu letzteren zählen eine Gangstörung, affektive Symptome und eine vaskuläre kognitive Störung mit Defiziten vorwiegend im Bereich der Exekutivfunktionen. In der MRT finden sich charakteristische Gewebeläsionen, u. a. konfluierende T2-Hyperintensitäten (Leukenzephalopathie), Lakunen, Mikroblutungen und kortikale Mikroinfarkte. Zudem kommt es im Verlauf zu einer Gehirnatrophie. Differenzialdiagnostisch müssen die verschiedenen Formen der Mikroangiopathie voneinander abgegrenzt werden, da dies ggf. therapeutische Konsequenzen hat. Ferner stellen entzündliche ZNS-Erkrankungen und Leukodystrophien mögliche Differenzialdiagnosen dar. Therapeutisch steht die Optimierung des Gefäßrisikoprofils im Vordergrund.

Abstract

Cerebral small vessel disease (CSVD) is a frequent cause of stroke and vascular dementia. CSVD is characterized by alterations of the small blood vessels of the brain, i. e. penetrating arteries and arterioles, as well as capillaries and venules. The most common form of CSVD is related to aging and hypertension. The exact mechanisms are, however, poorly understood. Other important forms are cerebral amyloid angiopathy and inherited CSVD, such as CADASIL, the most common monogenic disease leading to stroke. Distinguishing between different forms of CSVD can have clinical implications. CSVD manifests with acute (ischemic or hemorrhagic stroke) and chronic symptoms. The latter include gait and mood disorders and vascular cognitive impairment. The small penetrating vessels cannot be visualized on routine MRI. Neuroimaging relies on characteristic tissue alterations, such as white matter hyperintensities, lacunes, microbleeds, cortical microinfarcts and atrophy. Especially regarding imaging findings, multiple sclerosis and leukodystrophies are relevant differential diagnoses. Current CSVD treatment is focused on the management of vascular risk factors.

Schlüsselwörter

zerebrale Mikroangiopathie - Schlaganfall - vaskuläre kognitive Störung - Magnetresonanztomografie

Keywords

cerebral small vessel disease - stroke - vascular cognitive impairment - magnetic resonance imaging

Volltext

Referenzen

Literatur
1 Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9: 689-701
2 Filomena J, Riba-Llena I, Vinyoles E. et al. Short-term blood pressure variability relates to the presence of subclinical brain small vessel disease in primary hypertension. Hypertension 2015; 66: 634-640 ; discussion 445
3 Yamaguchi Y, Wada M, Sato H. et al. Impact of ambulatory blood pressure variability on cerebral small vessel disease progression and cognitive decline in community-based elderly Japanese. Am J Hypertens 2014; 27: 1257-1267
4 Diaz KM, Veerabhadrappa P, Kashem MA. et al. Visit-to-visit and 24-h blood pressure variability: association with endothelial and smooth muscle function in African Americans. J Hum Hypertens 2013; 27: 671-677
5 Shah IM, Ghosh SK, Collier A. Stroke presentation in Type 2 diabetes and the metabolic syndrome. Diabetes Res Clin Pract 2008; 79: e1-4
6 Jackson CA, Hutchison A, Dennis MS. et al. Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy?. Stroke 2010; 41: 624-629
7 Jackson C, Sudlow C. Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts. Stroke 2005; 36: 891-901
8 Kalaria RN. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimerʼs disease. Acta Neuropathol 2016; 131: 659-685
9 Craggs LJ, Yamamoto Y, Deramecourt V. et al. Microvascular pathology and morphometrics of sporadic and hereditary small vessel diseases of the brain. Brain Pathol 2014; 24: 495-509
10 Thal DR, Grinberg LT, Attems J. Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain. Exp Gerontol 2012; 47: 816-824
11 Ghosh M, Balbi M, Hellal F. et al. Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann Neurol 2015; 78: 887-900
12 Shoamanesh A, Kwok CS, Benavente O. Cerebral microbleeds: histopathological correlation of neuroimaging. Cerebrovasc Dis 2011; 32: 528-534
13 Keith J, Gao FQ, Noor R. et al. Collagenosis of the deep medullary veins: an underrecognized pathologic correlate of white matter hyperintensities and periventricular infarction?. J Neuropathol Exp Neurol 2017; 76: 299-312
14 Gouw AA, Seewann A, van der Flier WM. et al. Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J Neurol Neurosurg Psychiatry 2011; 82: 126-135
15 Highley JR, Gebril OH, Simpson JE. et al. Axonal preservation in deep subcortical white matter lesions in the ageing brain. J Aging Sci 2014; 2: 118
16 Westover MB, Bianchi MT, Yang C. et al. Estimating cerebral microinfarct burden from autopsy samples. Neurology 2013; 80: 1365-1369
17 Wardlaw JM, Valdes Hernandez MC, Munoz-Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J Am Heart Assoc 2015; 4: 001140
18 Pantoni L. Pathophysiology of age-related cerebral white matter changes. Cerebrovasc Dis 2002; 13 (Suppl. 02) 7-10
19 Fisher CM. The arterial lesions underlying lacunes. Acta neuropathologica 1968; 12: 1-15
20 Brun A, Englund E. A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 1986; 19: 253-262
21 Poggesi A, Pasi M, Pescini F. et al. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: a review. J Cereb Blood Flow Metab 2016; 36: 72-94
22 Nezu T, Hosomi N, Aoki S. et al. Endothelial dysfunction is associated with the severity of cerebral small vessel disease. Hypertens Res 2015; 38: 291-297
23 Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis. Neurobiol Aging 2009; 30: 337-352
24 Wardlaw JM, Makin SJ, Valdés Hernández MC. et al. Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study. Alzheimers Dement 2016; 13: 634-643
25 Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013; 12: 483-497
26 Cognat E, Cleophax S, Domenga-Denier V. et al. Early white matter changes in CADASIL: evidence of segmental intramyelinic oedema in a pre-clinical mouse model. Acta Neuropathol Commun 2014; 2: 49
27 Rosenberg GA, Wallin A, Wardlaw JM. et al. Consensus statement for diagnosis of subcortical small vessel disease. J Cereb Blood Flow Metab 2016; 36: 6-25
28 Chauhan G, Debette S. Genetic risk factors for ischemic and hemorrhagic stroke. Curr Cardiol Rep 2016; 18: 124
29 Falcone GJ, Malik R, Dichgans M. et al. Current concepts and clinical applications of stroke genetics. Lancet Neurol 2014; 13: 405-418
30 Duering M, Zieren N, Herve D. et al. Strategic role of frontal white matter tracts in vascular cognitive impairment: a voxel-based lesion-symptom mapping study in CADASIL. Brain 2011; 134: 2366-2375
31 Duering M, Gesierich B, Seiler S. et al. Strategic white matter tracts for processing speed deficits in age-related small vessel disease. Neurology 2014; 82: 1946-1950
32 Duering M, Gonik M, Malik R. et al. Identification of a strategic brain network underlying processing speed deficits in vascular cognitive impairment. Neuroimage 2012; 66C: 177-183
33 Lawrence AJ, Chung AW, Morris RG. et al. Structural network efficiency is associated with cognitive impairment in small-vessel disease. Neurology 2014; 83: 304-311
34 Duering M, Righart R, Wollenweber FA. et al. Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts. Neurology 2015; 84: 1685-1692
35 Duering M, Righart R, Csanadi E. et al. Incident subcortical infarcts induce focal thinning in connected cortical regions. Neurology 2012; 79: 2025-2028
36 Benavente OR, Hart RG. The SPS3 Investigators. et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367: 817-825
37 Valdes Hernandez MC, Maconick LC, Munoz Maniega S. et al. A comparison of location of acute symptomatic vs. ‘silent’ small vessel lesions. Int J Stroke 2015; 10: 1044-1050
38 Fisher CM. Lacunar strokes and infarcts: a review. Neurology 1982; 32: 871-876
39 Potter GM, Doubal FN, Jackson CA. et al. Counting cavitating lacunes underestimates the burden of lacunar infarction. Stroke 2010; 41: 267-272
40 Duering M, Csanadi E, Gesierich B. et al. Incident lacunes preferentially localize to the edge of white matter hyperintensities: insights into the pathophysiology of cerebral small vessel disease. Brain 2013; 136: 2717-2726
41 Dichgans M, Leys D. Vascular cognitive impairment. Circ Res 2017; 120: 573-591
42 Szirmai I, Vastagh I, Szombathelyi E. et al. Strategic infarcts of the thalamus in vascular dementia. J Neurol Sci 2002; 203-204: 91-97
43 Tatemichi TK, Desmond DW, Prohovnik I. Strategic infarcts in vascular dementia. A clinical and brain imaging experience. Arzneimittelforschung 1995; 45: 371-385
44 Moreton FC, Razvi SS, Davidson R. et al. Changing clinical patterns and increasing prevalence in CADASIL. Acta neurologica Scandinavica 2014; 130: 197-203
45 Joutel A, Corpechot C, Ducros A. et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 383: 707-710
46 Joutel A, Vahedi K, Corpechot C. et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997; 350: 1511-1515
47 Rutten JW, Dauwerse HG, Gravesteijn G. et al. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Ann Clin Transl Neurol 2016; 3: 844-853
48 Guey S, Mawet J, Herve D. et al. Prevalence and characteristics of migraine in CADASIL. Cephalalgia 2016; 36: 1038-1047
49 Schon F, Martin RJ, Prevett M. et al. „CADASIL coma“: an underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry 2003; 74: 249-252
50 Chabriat H, Joutel A, Dichgans M. et al. Cadasil. Lancet Neurol 2009; 8: 643-653
51 Opherk C, Gonik M, Duering M. et al. Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL. Stroke 2014; 45: 968-972
52 Wollenweber FA, Hanecker P, Bayer-Karpinska A. et al. Cysteine-sparing CADASIL mutations in NOTCH3 show proaggregatory properties in vitro. Stroke 2015; 46: 786-792
53 Dichgans M, Markus HS, Salloway S. et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol 2008; 7: 310-318
54 Lukas J, Scalia S, Eichler S. et al. Functional and Clinical Consequences of Novel alpha-Galactosidase A Mutations in Fabry Disease. Hum Mutat 2016; 37: 43-51
55 Mehta A, Beck M, Elliott P. et al. Enzyme replacement therapy with agalsidase alfa in patients with Fabry’s disease: an analysis of registry data. Lancet 2009; 374: 1986-1996
56 Hara K, Shiga A, Fukutake T. et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 2009; 360: 1729-1739
57 Nozaki H, Nishizawa M, Onodera O. Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2014; 45: 3447-3453
58 Verdura E, Herve D, Scharrer E. et al. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain 2015; 138: 2347-2358
59 Haffner C, Vinters HV. CADASIL, CARASIL, CARASAL: The linguistic subtleties of cerebral small vessel disease. Neurology 2016; 87: 1752-1753
60 Tan RY, Markus HS. Monogenic causes of stroke: now and the future. J Neurol 2015; 262: 2601-2616
61 Charlton RA, Morris RG, Nitkunan A. et al. The cognitive profiles of CADASIL and sporadic small vessel disease. Neurology 2006; 66: 1523-1526
62 Freitas S, Simoes MR, Alves L. et al. Montreal Cognitive Assessment (MoCA): validation study for vascular dementia. J Int Neuropsychol Soc 2012; 18: 1031-1040
63 Pendlebury ST, Mariz J, Bull L. et al. MoCA, ACE-R, and MMSE versus the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards Neuropsychological Battery after TIA and stroke. Stroke 2012; 43: 464-469
64 Tombaugh TN. Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol 2004; 19: 203-214
65 Taillia H, Chabriat H, Kurtz A. et al. Cognitive alterations in non-demented CADASIL patients. Cerebrovasc Dis 1998; 8: 97-101
66 Jouvent E, Reyes S, De Guio F. et al. Reaction time is a marker of early cognitive and behavioral alterations in pure cerebral small vessel disease. J Alzheimers Dis 2015; 47: 413-419
67 Wardlaw JM, Smith EE, Biessels GJ. et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013; 12: 822-838
68 Zwanenburg JJM, van Osch MJP. Targeting Cerebral Small Vessel Disease With MRI. Stroke 2017; 48: 3175-3182
69 Bouvy WH, Biessels GJ, Kuijf HJ. et al. Visualization of perivascular spaces and perforating arteries with 7 T magnetic resonance imaging. Invest Radiol 2014; 49: 307-313
70 van Veluw SJ, Shih AY, Smith EE. et al. Detection, risk factors, and functional consequences of cerebral microinfarcts. Lancet Neurol 2017; 16: 730-740
71 Wollenweber FA, Baykara E, Zedde M. et al. Cortical superficial siderosis in different types of cerebral small vessel disease. Stroke 2017; 48: 1404-1407
72 Lummel N, Wollenweber FA, Demaerel P. et al. Clinical spectrum, underlying etiologies and radiological characteristics of cortical superficial siderosis. J Neurol 2015; 262: 1455-1462
73 Linn J, Halpin A, Demaerel P. et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 2010; 74: 1346-1350
74 Pichler M, Vemuri P, Rabinstein AA. et al. Prevalence and natural history of superficial siderosis: a population-based study. Stroke 2017; 48: 3210-3214
75 Arboix A, Massons J, Garcia-Eroles L. et al. Clinical predictors of lacunar syndrome not due to lacunar infarction. BMC Neurol 2010; 10: 31
76 Baumgartner RW, Sidler C, Mosso M. et al. Ischemic lacunar stroke in patients with and without potential mechanism other than small-artery disease. Stroke 2003; 34: 653-659
77 Shi Y, Wardlaw JM. Update on cerebral small vessel disease: a dynamic whole-brain disease. Stroke Vasc Neurol 2016; 1: 83-92
78 Petrone L, Nannoni S, Del Bene A. et al. Branch atheromatous disease: a clinically meaningful, yet unproven concept. Cerebrovasc Dis 2016; 41: 87-95
79 Charidimou A, Imaizumi T, Moulin S. et al. Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: a meta-analysis. Neurology 2017; 89: 820-829
80 Brownlee WJ, Hardy TA, Fazekas F. et al. Diagnosis of multiple sclerosis: progress and challenges. Lancet 2017; 389: 1336-1346
81 Hajj-Ali RA, Singhal AB, Benseler S. et al. Primary angiitis of the CNS. Lancet Neurol 2011; 10: 561-572
82 Ahmed RM, Murphy E, Davagnanam I. et al. A practical approach to diagnosing adult onset leukodystrophies. J Neurol Neurosurg Psychiatry 2014; 85: 770-781
83 Lynch DS, Rodrigues Brandao de Paiva A, Zhang WJ. et al. Clinical and genetic characterization of leukoencephalopathies in adults. Brain 2017; 140: 1204-1211
84 Gattringer T, Pinter D, Enzinger C. et al. Serum neurofilament light is sensitive to active cerebral small vessel disease. Neurology 2017;
85 Jonsson M, Zetterberg H, van Straaten E. et al. Cerebrospinal fluid biomarkers of white matter lesions – cross-sectional results from the LADIS study. Eur J Neurol 2010; 17: 377-382
86 Mattsson N, Andreasson U, Zetterberg H. et al. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol 2017;
87 Piehl F, Kockum I, Khademi M. et al. Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod. Mult Scler 2017;
88 Steinacker P, Semler E, Anderl-Straub S. et al. Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias. Neurology 2017; 88: 961-969
89 Weydt P, Oeckl P, Huss A. et al. Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. Ann Neurol 2016; 79: 152-158
90 De Guio F, Jouvent E, Biessels GJ. et al. Reproducibility and variability of quantitative magnetic resonance imaging markers in cerebral small vessel disease. J Cereb Blood Flow Metab 2016; 36: 1319-1337
91 Jokinen H, Schmidt R, Ropele S. et al. Diffusion changes predict cognitive and functional outcome: the LADIS study. Ann Neurol 2013; 73: 576-583
92 Baykara E, Gesierich B, Adam R. et al. A novel imaging marker for small vessel disease based on skeletonization of white matter tracts and diffusion histograms. Ann Neurol 2016; 80: 581-592
93 Mustanoja S, Meretoja A, Putaala J. et al. Outcome by stroke etiology in patients receiving thrombolytic treatment: descriptive subtype analysis. Stroke 2011; 42: 102-106
94 Barnett HJ, Meldrum HE, Eliasziw M. et al. The appropriate use of carotid endarterectomy. CMAJ 2002; 166: 1169-1179
95 Smith EE, Rosand J, Knudsen KA. et al. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002; 59: 193-197
96 Benavente OR, Coffey CS. et al. The SPS3 Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382: 507-515
97 Rombach SM, Smid BE, Bouwman MG. et al. Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain. Orphanet J Rare Dis 2013; 8: 47
98 Rutten JW, Dauwerse HG, Peters DJ. et al. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain 2016; 139: 1123-1135
99 Ngandu T, Lehtisalo J, Solomon A. et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 2015; 385: 2255-2263
100 Moll van Charante EP, Richard E, Eurelings LS. et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet 2016; 388: 797-805
101 Ferro DA, van Veluw SJ, Koek HL. et al. Cortical cerebral microinfarcts on 3 Tesla MRI in patients with vascular cognitive impairment. J Alzheimers Dis 2017; 60: 1443-1450