eMedicine Specialties > Neurology > Neuro-vascular Diseases

CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)

Reza Behrouz, DO, Assistant Professor of Vascular and Critical Care Neurology, Department of Neurology, University of South Florida College of Medicine
Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Contributor Information and Disclosures

Updated: Aug 20, 2008

Introduction

Background

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral angiopathy. As the name implies, it is dominantly inherited. The condition was first described more than 30 years ago in a Swedish family1, although the acronym CADASIL did not emerge until the early 1990s2. Clinically, CADASIL is associated with progressive dementia, mood disorders, migraine, and recurrent subcortical cerebral infarctions.

Pathophysiology

CADASIL is caused by a mutation in the NOTCH3 gene on chromosome 19q12. The gene mutation was first identified in 1996.3 NOTCH3 codes for a transmembrane receptor protein whose function is not precisely known. The NOTCH3 receptor is located on the surface of smooth muscle cells surrounding arteries. Mutations are typically located within epidermal growth factor–like repeat domains in the extracellular part of the NOTCH3 receptor.4 Accumulation of the pathologic NOTCH3 receptor protein in small and medium-sized cerebral arteries is responsible for the pathogenesis and phenotypic presentation of CADASIL.5 Cerebral infarctions result from thickening and fibrosis of the walls of small and medium-sized arteries.

Frequency

United States

The incidenceand prevalence of CADASIL in the United States are not known.

International

The incidence and prevalence of CADASIL worldwide are not known.

Mortality/Morbidity

The exact mortality rate in patients with CADASIL is unknown. The age at onset for stroke is 45-50 years. The mean age at death has been reported to be 61 years after a mean disease duration of approximately 23 years.6 Men tend to die earlier than women.7 Fewer than half of patients older than age 60 could walk without assistance.5 Close to 80% of patients are completely dependent immediately before death.7

Race

Although CADASIL was first reported in European families, it has been observed in American, Middle Eastern, African, and Asiatic pedigrees.8

Sex

CADASIL appears to be equally distributed between men and women.

Age

The onset of clinical symptoms usually occurs in the fourth decade of life9, with a mean age at presentation of 46.1 years6.

Clinical

History

CADASIL is characterized by the clinical tetrad of dementia, psychiatric disturbances, migraine, and recurrent strokes.10 All components may not be present and the severity of associated symptoms and mode of presentation are highly variable.

The most frequent presentation is recurrent ischemic cerebrovascular episodes (transient ischemic attacks or cerebral infarctions).6 The condition may begin with migraine attacks in young adulthood, some of which may be associated with focal neurologic deficits or complicated migraine.11 Migraine with aura is more common than without.6 This is later followed by recurrent transient ischemic attacks and eventually, clinically overt strokes. Cognitive impairment associated with CADASIL is progressive and takes the form of subcortical dementia. A profile of frontal lobe dysfunction, declarative memory impairment suggestive of a retrieval deficit, and relatively preserved language is often evident.12

Other related symptoms that tend to occur late in the disease are gait apraxia, pseudobulbar palsy, and urinary incontinence. CADASIL progresses in a stepwise fashion and the level of disability from the disease is quite heterogeneous, even within pedigrees.5 Mood disturbances are reported in 10-20% of patients.13 Seizures6 and intracerebral hemorrhage14 have also been described.

For more information, see Medscape's Headache, Stroke/Cerebrovascular Disease, and Epilepsy Resource Centers.

Physical

Physical features that may be present with CADASIL are as follows: 

  • Variable degrees of weakness
  • Variable degrees of sensory deficit
  • Gait apraxia
  • Pseudobulbar palsy
  • Parkinsonism/movement disorders
  • Psychomotor retardation
  • Apathy
  • Depressed affect
  • Psychosis

Causes

CADASIL is a genetic disorder due to mutations in the NOTCH3 gene.

Contents

Overview: CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)
Differential Diagnoses & Workup: CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)
Treatment & Medication: CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)
Follow-up: CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)
Multimedia: CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)
[ CLOSE WINDOW ]

References

  1. Sourander P, Walinder J. Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol. Aug 31 1977;39(3):247-54. [Medline].

  2. Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet. Mar 1993;3(3):256-9. [Medline].

  3. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. Oct 24 1996;383(6602):707-10. [Medline].

  4. Peters N, Freilinger T, Opherk C, Pfefferkorn T, Dichgans M. Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL. J Neurol Sci. Sep 15 2007;260(1-2):100-5. [Medline].

  5. Meschia JF, Brott TG, Brown RD Jr. Genetics of cerebrovascular disorders. Mayo Clin Proc. Jan 2005;80(1):122-32. [Medline].

  6. Dichgans M, Mayer M, Uttner I, Bruning R, Müller-Hocker J, Rungger G, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. Nov 1998;44(5):731-9. [Medline].

  7. Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. Nov 2004;127:2533-9. [Medline].

  8. Ruchoux MM, Maurage CA. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol. Sep 1997;56(9):947-64. [Medline].

  9. Arboleda-Velasquez JF, Lopera F, Lopez E, Frosch MP, Sepulveda-Falla D, Gutierrez JE, et al. C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology. Jul 23 2002;59(2):277-9. [Medline].

  10. Davous P. CADASIL: a review with proposed diagnostic criteria. Eur J Neurol. May 1998;5(3):219-233. [Medline].

  11. Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr JP. The natural history of CADASIL: a pooled analysis of previously published cases. Stroke. Jun 1999;30(6):1230-3. [Medline].

  12. Harris JG, Filley CM. CADASIL: neuropsychological findings in three generations of an affected family. J Int Neuropsychol Soc. Sep 2001;7(6):768-74. [Medline].

  13. Chabriat H, Bousser MG. Neuropsychiatric manifestations in CADASIL. Dialogues Clin Neurosci. 2007;9(2):199-208. [Medline].

  14. Choi JC, Kang SY, Kang JH, Park JK. Intracerebral hemorrhages in CADASIL. Neurology. Dec 12 2006;67(11):2042-4. [Medline].

  15. Ito D, Tanahashi N, Murata M, Sato H, Saito I, Watanabe K, et al. Notch3 gene polymorphism and ischaemic cerebrovascular disease. J Neurol Neurosurg Psychiatry. Mar 2002;72(3):382-4. [Medline].

  16. Chabriat H, Levy C, Taillia H, Iba-Zizen MT, Vahedi K, Joutel A, et al. Patterns of MRI lesions in CADASIL. Neurology. Aug 1998;51(2):452-7. [Medline].

  17. Lesnik Oberstein SA, van den Boom R, Middelkoop HA, Ferrari MD, Knaap YM, van Houwelingen HC, et al. Incipient CADASIL. Arch Neurol. May 2003;60(5):707-12. [Medline].

  18. Dichgans M, Filippi M, Bruning R, Iannucci G, Berchtenbreiter C, Minicucci L, et al. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology. Apr 22 1999;52(7):1361-7. [Medline].

  19. O'Sullivan M, Jarosz JM, Martin RJ, Deasy N, Powell JF, Markus HS. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology. Mar 13 2001;56(5):628-34. [Medline].

  20. Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, et al. Diagnostic strategies in CADASIL. Neurology. Oct 22 2002;59(8):1134-8. [Medline].

  21. Jouvent E, Viswanathan A, Mangin JF, O'Sullivan M, Guichard JP, Gschwendtner A, et al. Brain atrophy is related to lacunar lesions and tissue microstructural changes in CADASIL. Stroke. Jun 2007;38(6):1786-90. [Medline].

  22. Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. Dec 15 2001;358(9298):2049-51. [Medline].

  23. LaPoint SF, Patel U, Rubio A. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Adv Anat Pathol. Sep 2000;7(5):307-21. [Medline].

  24. Malandrini A, Gaudiano C, Gambelli S, Berti G, Serni G, Bianchi S, et al. Diagnostic value of ultrastructural skin biopsy studies in CADASIL. Neurology. Apr 24 2007;68(17):1430-2. [Medline].

  25. Kusaba T, Hatta T, Kimura T, Sonomura K, Tanda S, Kishimoto N, et al. Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Clin Nephrol. Mar 2007;67(3):182-7. [Medline].

  26. Oh JH, Lee JS, Kang SY, Kang JH, Choi JC. Aspirin-associated intracerebral hemorrhage in a patient with CADASIL. Clin Neurol Neurosurg. Apr 2008;110(4):384-6. [Medline].

  27. Dichgans M, Markus HS, Salloway S, Verkkoniemi A, Moline M, Wang Q. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol. Apr 2008;7(4):310-8. [Medline].

  28. Forteza AM, Brozman B, Rabinstein AA, Romano JG, Bradley WG. Acetazolamide for the treatment of migraine with aura in CADASIL. Neurology. Dec 11 2001;57(11):2144-5. [Medline].

  29. Weller M, Dichgans J, Klockgether T. Acetazolamide-responsive migraine in CADASIL. Neurology. May 1998;50(5):1505. [Medline].

  30. Lesnik Oberstein SA, van den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E, et al. Cerebral microbleeds in CADASIL. Neurology. Sep 25 2001;57(6):1066-70. [Medline].

  31. Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. Jul 2005;62(7):1091-4. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL, hereditary cerebral angiopathy, vascular dementia, multi-infarct dementia, cerebral angiopathy, progressive dementia, mood disorders, migraine

recurrent subcortical cerebral infarctions, transient ischemic attacks, ischemic cerebrovascular episodes, gene, clinically overt strokes, cognitive impairment, subcortical dementia, frontal lobe dysfunction, declarative memory impairment suggestive of a retrieval deficit, preserved language, gait apraxia, pseudobulbar palsy, urinary incontinence, sensory deficit, pseudobulbar palsy, parkinsonism, movement disorders, psychomotor retardation

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Reza Behrouz, DO, Assistant Professor of Vascular and Critical Care Neurology, Department of Neurology, University of South Florida College of Medicine
Reza Behrouz, DO is a member of the following medical societies: American Academy of Neurology, Neurocritical Care Society, and Society for Vascular Medicine and Biology
Disclosure: Nothing to disclose

Coauthor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose

Medical Editor

Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center
Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association
Disclosure: Nothing to disclose

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose

Managing Editor

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: Nothing to disclose

CME Editor

Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center
Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association
Disclosure: Nothing to disclose

Chief Editor

Helmi L Lutsep, MD, Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center
Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology and American Stroke Association
Disclosure: Co-Axia Consulting fee for Review panel membership; Talecris Consulting fee for Review panel membership; AGA Medical Consulting fee for Review panel membership; Boehringer Ingelheim Honoraria for Speaking and teaching; Boston Scientific Honoraria for Speaking and teaching; Concentric Medical None for Review panel membership; Northstar Neuroscience Consulting fee for Review panel membership; ev3 Consulting fee for Review panel membership

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.