Cerebral Autosomal Dominant Arteriopathy (CADASIL)


Article Author:
Justin Cramer


Article Editor:
Matthew White


Editors In Chief:
Linda Lindsay


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/9/2019 9:12:36 PM

Introduction

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an aptly-named inherited disease with almost exclusively neurological manifestations, primarily migraines and premature onset of small vessel ischemic disease. It has a relatively characteristic appearance on MRI and diagnosis is made via genetic testing or skin biopsy. No disease-modifying therapies are yet available, and treatment is targeted mainly at cardiovascular risk reduction.

Etiology

Originally, CADASIL was recognized as a heritable early-onset microvascular disease of unknown etiology. The genetic cause of CADASIL was identified by Joutel et al. in 1996 as multiple mutations involving genes encoding for the NOTCH3 protein on chromosome 19.[1] CADASIL is the most common small vessel disease caused by mutations involving a single gene. It is inherited in an autosomal-dominant fashion.

Epidemiology

At a minimum, the prevalence of CADASIL has been estimated at approximately 5:100,000. Actual prevalence is likely higher due to under-diagnosis. There is no gender predilection, though men tend to be slightly more severely affected than women. No definite regional or ethnic predilection has been identified.[2]

Pathophysiology

The NOTCH3 gene mutation causes a vasculopathy predominantly affecting small cerebral vessels. The most common manifestations are migraines, transient ischemic attacks (TIAs) and lacunar infarcts, vascular dementia, and psychiatric diseases such as depression and apathy. The pathophysiology accounts for the clinical findings of lacunar infarcts, vascular dementia, and psychiatric disease. It is not clear how CADASIL accounts for migraine headaches.[2]

Histopathology

Skin biopsy is the gold standard for diagnosing CADASIL in cases where no genetic mutation is found. Accumulation of granular osmiophilic material (GOM) around smooth muscle in small arteries is the characteristic appearance. These findings are most prevalent in the brain, but can also be seen in skin and muscle samples throughout the body, thus the diagnosis via skin biopsy. On histopathology, the appearance is typical of any small vessel disease, with degeneration of vascular smooth muscle cells, endothelium, and basal lamina. Notably, atherosclerosis is absent. Again, changes are most prominent in small cerebral vessels as opposed to elsewhere in the body.[3]

History and Physical

Age of onset and disease course is widely variable, with case reports describing onset in children to older adults. Nonetheless, the average age of onset is around 30 years. A migraine with aura is the most common initial symptom, present in about 55% of people diagnosed with CADASIL, and slightly more common in women. Less commonly CADASIL may present as an acute encephalopathy. After roughly a decade, TIAs and subcortical/lacunar infarcts manifest with typical clinical syndromes such as a pure motor or sensory deficits or brainstem infarcts. Later still, patients manifest with vascular dementia. Psychiatric diagnoses such as depression and apathy are also common.[2]

Evaluation

CADASIL should be suspected in patients with a strong family history of early strokes and dementia, keeping in mind that CADASIL is likely under-diagnosed. Though definitive diagnosis is via genetic testing or skin biopsy, a CADASIL scale has been proposed by Pescini et al. as a less expensive initial clinical screening measure.[4] This scale includes typical symptoms of the disease such as migraines and TIA, typical imaging features, and family history, all with various weightings. In patients where CADASIL is strongly suspected, definitive diagnosis begins with serum genetic testing for a NOTCH3 mutation. Approximately 4% of patients with CADASIL will have a negative genetic test, likely related to unidentified genetic mutations. Thus, for those patients with a high clinical suspicion, the next step is a skin biopsy with histopathologic examination for GOM accumulation.[5]

Alternatively, CADASIL has a somewhat characteristic appearance on MRI, and a radiologist may suggest the diagnosis. Abnormal T2/FLAIR white matter hyperintensities, similar in appearance to those seen with the chronic microvascular disease, are present in CADASIL in the anterior temporal, external capsule, and paramedian superior frontal subcortical white matter. Importantly, these findings are present in younger patients (younger than approximately 60). Though this distribution is reported to be specific for CADASIL, older patients with the severe microvascular disease may have lesions in these locations because they have the diffuse disease. As expected, lacunar or subcortical infarcts can also be seen with CADASIL, which manifest as foci of restricted diffusion on DWI/ADC sequences (bright on diffusion, dark on ADC) typically measuring less than 1.5 cm. Finally, microbleeds are seen with a greater prevalence in CADASIL patients. These are best seen on a T2*-GRE MRI sequence as multiple punctate foci of susceptibility/hypointensity. These findings of lacunar infarcts and microbleeds in younger patients are less specific but suggestive MRI findings.[2]

There are numerous differential considerations to keep in mind. Age-advanced traditional microvascular disease in the setting of diabetes and/or hypertension should be the first consideration. Besides the expected clinical findings, the traditional microvascular disease would not be expected to have the same MRI distribution of lesions. Multiple sclerosis is another consideration with a different MRI appearance and involvement of the optic nerves and spinal cord that would not be expected with CADASIL. Fabry disease is another heritable cause of early-onset microvascular disease and strokes that also features basal ganglia calcifications and is X-linked. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a similar entity to CADASIL that presents with early-onset spinal degenerative disease and hair loss but typically does not feature migraines. More broadly, other causes of strokes and hemorrhage in younger individuals include primary CNS vasculitis, reversible cerebral vasoconstriction syndrome (RCVS), inflammatory amyloid angiopathy, venous thrombosis, septic emboli, metastatic disease, and toxic/metabolic exposures. These entities may demonstrate subtly different findings on CT or MRI that are beyond the scope of this discussion. Finally, other heritable conditions such as leukoencephalopathies and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) should be considered.

Treatment / Management

No disease-modifying treatment is available. Therapy is very similar to that of traditional chronic microvascular ischemic disease, targeting cardiovascular risk reduction with blood pressure control, smoking cessation, statins, and antiplatelet therapy. However, given that CADASIL is non-atherosclerotic, the role of thrombosis in causing strokes with CADASIL is in question. Thus, antiplatelet therapy may fall out of favor. Moreover, given that CADASIL patients have a higher incidence of microhemorrhages any anticoagulation therapy must be considered with caution. In addition, therapy for other disease manifestations such as migraines and depression are similar to the general population. Clinical symptoms progress from migraines to infarcts to vascular dementia over decades.[2] Life expectancy is reported to be reduced by five years for men and 1 to 2 years in women.[6] As an additional note, genetic counseling should be offered to patients diagnosed with CADASIL.[7][8][9][10]

Enhancing Healthcare Team Outcomes

CADASIL is a rare genetic disorder with no cure. The condition is best managed by a multidisciplinary team that includes pharmacists, nurses and geneticists. It often causes ischemia but in the absence of atherosclerosis. The key is to reverse the modifable risk factors for heart and stroke disease. Most patients are treated symptomatically. 

The overall outcome for patients with CADASIL is guarded and life expectacy is reduced. Once dignosed, genetic counseling should be offered to patients diagnosed with CADASIL.


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Cerebral Autosomal Dominant Arteriopathy (CADASIL) - Questions

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Which of the following is least likely associated with Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy?



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A 30-year-old female presents to the emergency department with migraine headaches. As a part of her diagnostic workup, MRI on the brain is ordered. The MRI findings are shown in the following image. Also, additional genetic testing is negative. Which of the following body part is biopsied to test for the suspected diagnosis?

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Which of the following can be used to diagnose CADASIL?



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Which gene mutation is associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)?



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Select the characteristic finding on MRI in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).



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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) associated cognitive decline correlates best with which of the following?



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Which of the following is characteristically seen on MRI in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)?



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A 30-year-old female presents to the emergency department with complicated migraine symptoms. She is previously healthy with no relevant medical history. A brain magnetic resonance imaging (MRI) was obtained, and 3 axial fluid-attenuated inversion recovery (FLAIR) images are shown. Which of the following could confirm the most likely diagnosis?

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A 32-year-old male with neurologic symptoms received a brain MRI. Findings on that MRI prompted testing for a Notch Receptor 3 (NOTCH3) mutation, for which he tested positive. What symptom is the most likely to initially experience from the condition associated with this mutation?



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What is the gold standard for diagnosing cerebral autosomal dominant arteriopathy (CADASIL)?



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A 35-year-old male who presented with acute encephalopathy tested positive for a NOTCH3 mutation. What will be the best long-term management of this patient's condition?



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A 35-year-old male has recently been diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and undergoes a brain MRI. Which of the following imaging findings is least likely to be seen?



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Cerebral Autosomal Dominant Arteriopathy (CADASIL) - References

References

Microvascular pathology and morphometrics of sporadic and hereditary small vessel diseases of the brain., Craggs LJ,Yamamoto Y,Deramecourt V,Kalaria RN,, Brain pathology (Zurich, Switzerland), 2014 Sep     [PubMed]
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects., Di Donato I,Bianchi S,De Stefano N,Dichgans M,Dotti MT,Duering M,Jouvent E,Korczyn AD,Lesnik-Oberstein SA,Malandrini A,Markus HS,Pantoni L,Penco S,Rufa A,Sinanović O,Stojanov D,Federico A,, BMC medicine, 2017 Feb 24     [PubMed]
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia., Joutel A,Corpechot C,Ducros A,Vahedi K,Chabriat H,Mouton P,Alamowitch S,Domenga V,Cécillion M,Marechal E,Maciazek J,Vayssiere C,Cruaud C,Cabanis EA,Ruchoux MM,Weissenbach J,Bach JF,Bousser MG,Tournier-Lasserve E,, Nature, 1996 Oct 24     [PubMed]
Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients., Opherk C,Peters N,Herzog J,Luedtke R,Dichgans M,, Brain : a journal of neurology, 2004 Nov     [PubMed]
Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies., Peters N,Opherk C,Bergmann T,Castro M,Herzog J,Dichgans M,, Archives of neurology, 2005 Jul     [PubMed]
Pescini F,Nannucci S,Bertaccini B,Salvadori E,Bianchi S,Ragno M,Sarti C,Valenti R,Zicari E,Moretti M,Chiti S,Stromillo ML,De Stefano N,Dotti MT,Federico A,Inzitari D,Pantoni L, The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke. 2012 Nov;     [PubMed]
Anamnart C,Songsaeng D,Chanprasert S, A large number of cerebral microbleeds in CADASIL patients presenting with recurrent seizures: a case report. BMC neurology. 2019 May 30;     [PubMed]
Jokumsen-Cabral A,Aires A,Ferreira S,Azevedo E,Castro P, Primary involvement of neurovascular coupling in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Journal of neurology. 2019 Apr 26;     [PubMed]
Su J,Wang M,Ban S,Wang L,Cheng X,Hua F,Tang Y,Zhou H,Zhai Y,Du X,Liu J, Relationship between changes in resting-state spontaneous brain activity and cognitive impairment in patients with CADASIL. The journal of headache and pain. 2019 Apr 17;     [PubMed]
Koizumi T,Mizuta I,Watanabe-Hosomi A,Mukai M,Hamano A,Matsuura J,Ohara T,Mizuno T, The CADASIL Scale-J, A Modified Scale to Prioritize Access to Genetic Testing for Japanese CADASIL-Suspected Patients. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2019 Jun;     [PubMed]

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