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

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral angiopathy (see image below). As the name implies, it is dominantly inherited. The condition was first described more than 30 years ago in a Swedish family[1] , although the acronym CADASIL did not emerge until the early 1990s[2] . Clinically, CADASIL is associated with progressive dementia, mood disorders, migraine, and recurrent subcortical cerebral infarctions.

FLAIR MRI of the brain showing hyperintensities involving the temporal poles in a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). (Reprinted with permission from Mayo Clin Proc, Meschia, 2005.)

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 life[9] , with a mean age at presentation of 46.1 years[6] . Symptomatic onset as early as age 8 years has been reported.[10]

CADASIL is characterized by the clinical tetrad of dementia, psychiatric disturbances, migraine, and recurrent strokes.[11] 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.[12] 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.[13]

A study of the effects of gender on the presentation of CADASIL found that migraine with aura is more frequent in women aged 51 years and younger and stroke is more frequent in men in the same age group. A higher degree of cognitive impairment and cerebral atrophy was found in men aged 50 years and older at the late stage of the disease.[14]

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.[15] Seizures[6] and intracerebral hemorrhage[16] have also been described. Recent reports also suggest involvement of the spinal cord.[17]

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

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

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

Genetic Testing

Genetic testing is commercially available to detect mutations in NOTCH3. A small amount of venous blood is needed for the test (10 mL of whole blood in Lavender top tube, refrigerated). More than 90% of patients with CADASIL have mutations (mostly missense) in the NOTCH3 gene.[18] Also, approximately 90% of mutations could be detected within a few exons (exons 2-6).[19] Thus, genetic testing should initially be focused on these exons. Currently available genetic testing has a sensitivity approaching 100%.

Genetic testing for CADASIL is indicated when clinical findings (migraines with early-onset strokes and dementia) and radiographic (MRI) findings raise a high index of suspicion. Diffuse white matter disease in a young patient who suffers from migraines and who has a family history of early stroke raises the suspicion of CADASIL. Genetic testing for asymptomatic family members of CADASIL patients is available. However, the affected family member must be tested first to assess the sensitivity of the test.

A newly developed screening tool, the CADASIL scale, was designed to select patients with a high probability of being affected who should undergo genetic testing. While the scale needs validation, it is a good first step and highlights the prominent features of the disease.[20]

Magnetic resonance imaging (MRI)

Hyperintensities on T2-weighted imaging or FLAIR are seen in the periventricular and deep white matter.[21] These white matter hyperintensities on MRI can be visualized in those aged 21 years and older.[22] MRI lesion volume correlates with the level of disability associated with CADASIL.[23] A characteristic finding on the MRI in patients with CADASIL is the presence of isolated T2 hyperintensities involving the temporal poles (see image below), a feature that can differentiate the condition from chronic microvascular ischemia due to hypertension. This finding is associated with a sensitivity and specificity of 95% and 80% respectively.[24]

FLAIR MRI of the brain showing hyperintensities involving the temporal poles in a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). (Reprinted with permission from Mayo Clin Proc, Meschia, 2005.)

Another relatively conspicuous MRI feature is involvement of the external capsules (see image below), which has a sensitivity of 93% and a specificity of 45%.[25] In association with age, volume of lacunar lesions is a strong and independent MRI predictor of cognitive and motor disability in CADASIL.[26] MRI studies in patients with CADASIL have also shown an age-related increased risk of intracerebral microbleeds.[27]

FLAIR MRI of the brain showing hyperintensities involving bilateral external capsules in a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). (Reprinted with permission from Mayo Clin Proc, Meschia, 2005.)

Skin biopsy

Pathologic evaluation of skin biopsy (see Histologic Findings) in patients with CADASIL has a sensitivity of 45% and specificity of 100%.[25] Preliminary data demonstrate that immunostaining skin biopsy specimens for NOTCH3 protein is highly sensitive (96%) and specific (100%) for the diagnosis of CADASIL.[28]

Pathologically, CADASIL is characterized by degeneration and thickening of the arterial walls (especially cerebral vasculature) with deposition in the media of a nonatheromatous, nonamyloidotic substance that is characteristically periodic acid-Schiff (PAS) positive. Under the electron microscope (EM), this substance appears as a granular osmiophilic material (GOM), pathognomonic for the disease.[29] Skin biopsy typically shows ultrastructural alterations of skin vessels similar to those of brain arteries.[30] Recent reports indicate that these morphologic abnormalities may also involve the kidney.[31]

No specific system of staging exists for CADASIL.

Neither a cure nor a specific treatment exist for CADASIL. Treatment endeavors should be focused on management of headaches, mood and psychiatric disturbances, and rehabilitation following a brain ischemic injury.

There is no specific surgical procedure indicated for the treatment of CADASIL.

See the list below:

• Vascular neurology: To assist in diagnosis, patients who are suspected to have CADASIL should be seen and later observed by a vascular neurologist.

• Dermatology: Consultation should be placed to a dermatologist for skin biopsy in those patients in whom biopsy is desired (for example, patients in whom genetic testing is negative but confirmation of the disease would be helpful).

• Dermatopathology: The skin biopsy specimen should preferentially be investigated by a dermatopathologist.

• Psychiatry: The many forms of psychiatric manifestations of CADASIL may be managed more appropriately by a psychiatrist.

• Neuropsychology: A neuropsychologist can assist in gauging cognitive status or rate of deterioration.

• Physical therapy

• Occupational therapy

• Speech therapy

No specific diet is recommended for patients with CADASIL. However, because of the risk of developing dysphagia secondary to cerebral infarctions, some may eventually require percutaneous endoscopic gastrostomy (PEG) or jejunal feeding tube. Swallow evaluation should be performed after every ischemic episode or if the swallowing ability of the patient becomes questionable due to progressive pseudobulbar palsy.

Physical and cognitive disability is progressive and may be quite severe. In patients with CADASIL, it is important to frequently assess their ability in performing activities of daily living, ambulation, and self-care. A rehabilitation regimen should be prescribed when appropriate.

Aspirin and related medications are often used in an effort to prevent thrombotic occlusion of cerebral arteries. However, the benefit of antiplatelet agents for CADASIL has not been established.[5] Moreover, because of the potential presence of microhemorrhages, using these drugs in patients with CADASIL may increase their risk of intracerebral hemorrhage.[32] A study involving 168 patients with CADASIL showed that donepezil (Aricept) had no effect on the primary endpoint (the V-ADAS-cog score) in patients with CADASIL with cognitive impairment.[33] Two isolated case reports suggest the benefit of acetazolamide (ACZ) in migraine associated with CADASIL.[34, 35]

In fact, studies using transcranial Doppler and Tc-99m brain perfusion single-photon emission computed tomography (SPECT) scanning have reported increases in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) after the administration of ACZ.[36, 37] Further investigations evaluating the efficacy and benefit of this agent in CADASIL are needed.

The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) has not proven any benefit in patients with CADASIL.[4] 5HT1B/1D agonists (triptans) are not routinely used in CADASIL-associated migraine due to a presumed potential to increase the risk of stroke. Medications for migraine prophylaxis are reasonable, although no study has clearly demonstrated their efficacy in CADASIL-related migraine.

Patients with CADASIL should be followed routinely by a neurologist or a vascular neurologist to monitor their degree of disability and rate of progression. Management is primarily symptom-based and addressing rehabilitation needs is paramount. Routine psychiatric follow-up is also reasonable if the patient suffers from a complex mental disorder.

Inpatient care of patients with CADASIL depends on the reason for admission. Inpatient care of patients with CADASIL who present with a stroke is not entirely different than patients without CADASIL who have a stroke (see Acute Stroke Management). However, safety and efficacy of recombinant tissue plasminogen activator (rtPA) in patients with CADASIL who present with an acute cerebral infarction within the therapeutic window has not been systematically assessed.

See Medication.

Exact mortality rate in patients with CADASIL is unknown.

Age at onset for stroke is 45-50 years.

Mean age at death has been reported to be 61 years after a mean disease duration of approximately 23 years.[6]

Close to 80% of patients are completely dependent immediately before death.[7]

Genetic counseling

Because CADASIL has an autosomal dominant inheritance, patients and their families should be counseled on the nature of the disorder and the probability of developing or transmitting it.