Continuing Education Activity

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease with almost exclusively neurological manifestations, primarily consisting of migraines and premature onset of small vessel ischemic disease. It has a relatively characteristic appearance on magnetic resonance imaging. 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. This activity reviews the evaluation and management of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and highlights the role of interprofessional teams in caring for affected patients.

Objectives:

• Describe the epidemiologyof cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
• Summarize the clinical symptoms of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
• Identify the typical imaging findings of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
• Explain a well-coordinated interprofessional team approach to provide effective care to patients affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

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 an

• Acute disseminated encephalomyelitis
• Behcet disease
• HIV encephalopathy and AIDS dementia complex
• Lyme disease
• Multiple sclerosis
• Neurosarcoidosis
• Neurosyphilis

d 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]

Differential Diagnosis

• Acute disseminated encephalomyelitis

• Behcet disease

• HIV encephalopathy and AIDS dementia complex

• Lyme disease

• Multiple sclerosis

• Neurosarcoidosis

• Neurosyphilis

Enhancing Healthcare Team Outcomes

CADASIL is a rare genetic disorder with no cure. The condition is best managed by an interprofessional 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.

Review Questions

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References

1.

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. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996 Oct 24;383(6602):707-10. [PubMed: 8878478]

2.

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. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC Med. 2017 Feb 24;15(1):41. [PMC free article: PMC5324276] [PubMed: 28231783]

3.

Craggs LJ, Yamamoto Y, Deramecourt V, Kalaria RN. Microvascular pathology and morphometrics of sporadic and hereditary small vessel diseases of the brain. Brain Pathol. 2014 Sep;24(5):495-509. [PMC free article: PMC4228759] [PubMed: 25323665]

4.

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;43(11):2871-6. [PubMed: 22996955]

5.

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. 2005 Jul;62(7):1091-4. [PubMed: 16009764]

6.

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. 2004 Nov;127(Pt 11):2533-9. [PubMed: 15364702]

7.

Anamnart C, Songsaeng D, Chanprasert S. A large number of cerebral microbleeds in CADASIL patients presenting with recurrent seizures: a case report. BMC Neurol. 2019 May 30;19(1):106. [PMC free article: PMC6542033] [PubMed: 31146726]

8.

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. J Neurol. 2019 Jul;266(7):1782-1788. [PubMed: 31028544]

9.

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. J Headache Pain. 2019 Apr 17;20(1):36. [PMC free article: PMC6734224] [PubMed: 30995925]

10.

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. J Stroke Cerebrovasc Dis. 2019 Jun;28(6):1431-1439. [PubMed: 30956055]

Disclosure: Justin Cramer declares no relevant financial relationships with ineligible companies.

Disclosure: Matthew White declares no relevant financial relationships with ineligible companies.