CADASIL
Introduction
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary cerebral small vessel disease and one of the most common monogenic causes of stroke and vascular cognitive impairment in adults. It is characterized by recurrent subcortical ischemic events, migraine headaches (often with aura), mood disturbances, progressive cognitive decline, and characteristic white matter abnormalities shown on brain MRI. The disorder primarily affects small penetrating arteries and leads to intracerebral arteriopathy.
Genetics
CADASIL is caused by pathogenic variants in the NOTCH3 gene located on chromosome locus 19p13 and follows an autosomal dominant pattern of inheritance. The NOTCH3 gene encodes the NOTCH3 receptor, which is predominantly expressed in vascular smooth muscle cells. Most pathogenic variants are missense mutations that lead to an abnormal number of cysteine residues within the epidermal growth factor–like repeats (EGFr) of the receptor.
Genotype–phenotype correlations have been described to some extent, with variants affecting EGFr domains 1–6 generally associated with a more severe disease course and earlier clinical onset.
Pathophysiology
The structural alteration of the NOTCH3 receptor promotes abnormal accumulation of the extracellular domain of NOTCH3 within the vessel wall. This process is associated with the deposition of granular osmiophilic material (GOM) in small arteries.
Over time, progressive degeneration of vascular smooth muscle cells leads to thickening of small arterial walls, narrowing of the vascular lumen, and impairment of cerebral blood flow. These vascular changes underlie the recurrent subcortical ischemic events and progressive white matter damage characteristic of the disease.
Epidemiology
The prevalence of CADASIL is approximately 2–5 per 100,000 individuals, which is likely underdiagnosed. Pathogenic variants in the NOTCH3 gene are more common in the general population than the number of clinically recognized cases. CADASIL affects both men and women, and its symptoms most commonly begin between 30 and 50 years of age, although both early and late onset forms have been reported. A higher frequency of cysteine-altering NOTCH3 variants has been reported in certain populations, including parts of Europe and East Asia, but their penetrance and clinical expression vary considerably.
Clinical Manifestations
The clinical manifestations of CADASIL are highly variable, even among affected family members. Migraine headaches with aura are usually the first manifestation of CADASIL and typically present in early adulthood. Recurrent ischemic events are the main pathological features and include lacunar strokes and transient ischemic attacks (TIA), leading to stepwise acceleration of neurological deficits.
Cognitive impairment, which is common and often begins with executive dysfunction, decision-making problems, concentration/attention deficit, and slowed processing ability, reflects subcortical involvement.
Over time, this may progress to subcortical dementia and eventually global cognitive decline. In some cases, epileptic seizures can be manifested later as complicating symptom. The severity and character of the symptoms depend largely on the location and extent of the lacunar infarcts.
As these small subcortical strokes occur and accumulate over time in different brain regions, they result in wide range of neurological deficits, including motor, sensory, bulbar, cognitive, and behavioral impairments.
Psychiatric manifestations are frequent and include depression, anxiety, brain fog, apathy, and other mood disturbances. Additional neurological features may develop as the disease advances, such as gait disturbance, pseudobulbar palsy, and urinary incontinence in later stages. Brain MRI shows highly characteristic abnormalities, including symmetric white matter hyperintensities with a predilection for the anterior temporal poles and external capsules. Lacunar infarcts are commonly found in the basal ganglia, thalamus, and pons, and cerebral microbleeds are present in a subset of patients.
Risk Factors
CADASIL is a genetically determined disorder caused by pathogenic variants in the NOTCH3 gene. However, some risk factors may influence disease severity and progression. Hypertension, obesity, smoking, diabetes mellitus, hyperlipidemia, and a stressful lifestyle are considered important factors in the clinical course. These factors contribute to ischemic damage, increase the burden of small-vessel injury, and finally worsen neurological outcomes. Therefore, strict control and aggressive management of contributory vascular risk factors are strongly indicated.
Diagnosis
The diagnosis of CADASIL is primarily based on clinical suspicion, neuroimaging findings, and confirmation by genetic testing. The disorder should be suspected in young or middle-aged adults who present with migraine with aura, recurrent lacunar strokes, progressive cognitive decline, and a positive family history of stroke or dementia.
Neuroimaging, particularly magnetic resonance imaging (MRI), plays a central role in the diagnostic evaluation. Characteristic findings include white-matter lesions (white -matter hyperintensity) involving the anterior temporal poles, which are highly suggestive of the disorder. Additional typical features include involvement of the external capsule and the presence of lacunes and cerebral microhemorrhages.
White matter changes associated with obesity, diabetes, or even insulin resistance may complicate the diagnostic evaluation. These metabolic conditions can produce MRI abnormalities that resemble small-vessel disease. As a result, they may obscure or mimic the characteristic white-matter findings of CADASIL, making neuroimaging interpretation more challenging.
Definitive diagnosis is established by genetic testing demonstrating a pathogenic variant in the NOTCH3 gene, which is considered the diagnostic gold standard.
Skin biopsy was used as an adjunct diagnostic method. Electron microscopy could reveal deposits of granular osmiophilic material (GOM) in the walls of small vessels. However, this method has largely been replaced by molecular genetic testing.
In patients with CADASIL, fundoscopic and retinal examination may provide both diagnostic and prognostic information, reflecting the systemic nature of the underlying arteriopathy. Retinal vascular narrowing is one of the most consistently described findings. It mirrors the small-artery wall thickening and luminal narrowing seen in cerebral vessels and likely represents similar pathological processes, including degeneration of vascular smooth muscle cells and progressive arteriopathy.
Retinal atrophy constitutes a second, distinct but interrelating feature. Chronic hypoperfusion resulting from retinal microangiopathy may lead to thinning of retinal layers, particularly in the inner retina. Importantly, vascular narrowing and retinal atrophy are not two distinct phenomena but two interconnected manifestations of the same underlying pathology. Their presence and extent may reflect cumulative ischemic injury and disease progression.
While retinal examination is not currently part of standard diagnostic criteria, it provides a non-invasive window into systemic small-vessel involvement and, in selected cases, may support diagnosis and indirectly provide more information about disease intensity and prognosis.
Treatment
There is currently no curative therapy for CADASIL, and management is supportive and relatively preventive. Stroke prevention is a central component and includes strict control of vascular events risk factors. Antiplatelet therapy is commonly used, although evidence is limited, and treatment decisions should be individual. Anticoagulation is generally avoided due to the risk of cerebral microbleeds, unless there is a clear and strong indication. Migraines are managed according to standard therapeutic principles. Conventional migraine treatments may be used, and triptans can be considered with caution. Excessive use of vasoconstrictive agents should be avoided.
Cognitive and psychiatric symptoms require appropriate therapeutic and supportive care. Antidepressants are commonly prescribed for mood disorders, and cognitive rehabilitation may help to maintain function. Broader supportive interventions are often necessary while the disease progresses.
Genetic counseling is essential because of the autosomal dominant inheritance pattern. Testing of at-risk family members should be offered with appropriate counseling and informed consent.
Prognosis
CADASIL is a progressive disorder with considerable variability in symptom severity and rate of progression. The median age at first stroke is usually around 45–50 years. Over time, many patients develop progressive cognitive decline leading to significant functional impairment. A high proportion of patients develop dementia by around the age of 60.
Life expectancy is generally lower than in the general population; nevertheless, many patients live into the seventh decade. The prognosis is influenced by several factors, including the specific genotype, the presence of risk factors, the frequency and location of stroke events, and individual variation in disease expression. The disease course is usually characterized by a gradual accumulation of neurological disability resulting from recurrent subcortical infarcts and progressive small-vessel dysfunction.
A number of lifestyle factors may deteriorate the prognosis. These include hypertension, obesity (high body mass index), excessive alcohol consumption, smoking, chronic stress, and a diet high in fat and sugar; all of them can aggravate vascular dysfunction and increase the risk of recurrent strokes.
