CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is an autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy. It is a hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene on chromosome 19 (19q12) and is considered the most common hereditary cause of stroke known to date1).
The main clinical symptoms are migraine with aura, subcortical ischemic strokes, psychiatric symptoms, and cognitive impairment. In addition, the neuro-ophthalmological feature of this disease is that it presents various ophthalmic signs such as visual aura, diplopia, oscillopsia, and retinal vascular changes.
The prevalence has been reported as 4.15 per 100,000 in a Scottish study, but this may be an underestimate. Meanwhile, the carrier frequency of NOTCH3 pathogenic variants in the general population is 3.4 per 1000, with particularly high rates confirmed in Asians 2). Onset typically occurs in middle age, and the disease duration after symptom onset is approximately 20–25 years. It is inherited in an autosomal dominant pattern (50% transmission rate), but de novo mutations also occur. Men have a shorter life expectancy than women and tend to develop subcortical infarcts and cognitive decline earlier.
A Scottish study reported a prevalence of 4.15 per 100,000, but this may be an underestimate. The carrier frequency of NOTCH3 pathogenic variants in the general population is 3.4 per 1000 2), and many asymptomatic carriers are thought to exist. Asians have been shown to have particularly high carrier rates.
Ophthalmic Findings
Visual acuity, visual field, and pupillary light reflex: Usually remain normal.
Retinal vascular changes: Arteriolar narrowing, sheathing, arteriovenous nicking (AV nicking), and soft exudates may be observed. Often asymptomatic. Retinal vascular occlusion is rare.
Slit-lamp findings: Early lens opacities and ciliary body atrophy (due to involvement of ciliary arterioles) have been reported.
Optic nerve: Usually normal, but pallor and atrophy have also been reported.
Neuro-ophthalmic findings
Ocular motility abnormalities: Slowing of saccades, limitation of horizontal gaze, and internuclear ophthalmoplegia (INO) may be observed.
OCT-A findings: In the stroke history group, macular vessel density in the superficial retinal capillary plexus is significantly reduced, and inner retinal thickness is also decreased. Macular vessel density and inner retinal thickness are positively correlated with walking speed and negatively correlated with the number of lacunar infarcts 5).
Cognitive impairment: Executive function and processing speed are most prominently impaired, and the prevalence of VCI is reported to be 39.8–47.7% (mean age 51 years) 5).
Headache in CADASIL is classified as a secondary headache under ICHD-3 as “Headache attributed to CADASIL” (code 6.8.1) 3). Sensory, language, and motor auras are excessively expressed, with 59.3% showing atypical or complex auras. Additionally, since auras may overlap with TIA (transient ischemic attack), it is not appropriate to treat them as simple migraine.
CADASIL is caused by mutations in the NOTCH3 gene. NOTCH3 encodes a transmembrane receptor with 34 EGF-like repeats, and mutations are concentrated in exons 2–24 (EGFR domain). Cysteine-substituting mutations are predominant, leading to accumulation of the extracellular domain of the transmembrane protein. Over 280 pathogenic mutations have been reported 2).
The severity of the phenotype varies depending on the mutation site. Mutations in EGFr domains 1–6 are more severe and associated with lower survival than those in EGFr domains 7–34; some individuals with mutations in EGFr 7–34 have normal MRI findings and are asymptomatic at age 58 5). In mainland China, hotspots are concentrated in exons 3, 4, 11, 12, 13, and 14 6).
The main differential diagnoses are shown below.
| Disease name | Inheritance pattern | GOM deposits | Distinguishing features |
|---|---|---|---|
| CARASIL | Autosomal recessive | None | HTRA1 homozygous mutation, young onset, alopecia and low back pain |
| CADASIL-like disease (HTRA1 heterozygous mutation) | Autosomal dominant | None | Onset later than CADASIL8) |
| Fabry disease | X-linked | — | Alpha-galactosidase A deficiency |
CADASIL-like disease (HTRA1 heterozygous mutation) shows brain MRI findings similar to CADASIL, but the absence of GOM deposits is useful for differentiation on skin biopsy 8).
Brain MRI plays a central role in diagnosis. The main findings are as follows.
Pescini screening scale: A score of 15 or more indicates consideration of NOTCH3 genetic testing 1). The main scoring items are shown below.
| Item | Score |
|---|---|
| Migraine with aura | 3 points |
| External capsule WMH | 5 points |
| Cognitive decline/dementia | 3 points |
| Leukoencephalopathy | 3 points |
| Family history in 2 or more generations | 2 points |
| Subcortical infarction | 2 points |
| Onset before age 50 | 2 points |
Neurofilament light chain (NfL) is significantly elevated in CADASIL patients and is being studied as a promising blood biomarker2). OCT-A can noninvasively assess retinal vascular density and has shown potential as a surrogate marker for CADASIL severity5).
NOTCH3 genetic testing is the gold standard for diagnosis. The Pescini scale is useful for screening; a score of 15 or more prompts consideration of genetic testing1). If genetic testing is inconclusive, detection of GOM via skin biopsy can also support the diagnosis.
Currently, there is no curative treatment for CADASIL. Treatment focuses on vascular risk factor management, secondary prevention, and symptomatic therapy.
Vascular Management
Control of vascular risk factors: Management of hypertension, hypercholesterolemia, diabetes, and obesity is a top priority. Smoking cessation, weight management, exercise, and blood glucose control are also important2).
Antiplatelet therapy: Aspirin or clopidogrel is used. Although efficacy has not been clearly proven, many neurologists use it for secondary prevention1,2).
Statins: Used for lipid management2).
Symptom Management
Cognitive impairment: Acetylcholinesterase inhibitors such as donepezil are used. However, an RCT involving 168 patients did not show significant improvement in vascular dementia 2).
Epilepsy: Antiepileptic drugs such as sodium valproate (starting at 500 mg/day) and oxcarbazepine are used 4).
Migraine: Symptomatic treatment is the mainstay. Since the “aura” of CADASIL requires differentiation from TIA, the choice of migraine medication should be made carefully 3).
The use of IV-tPA (alteplase 0.9 mg/kg) for acute ischemic stroke is controversial.
No curative treatment currently exists. Management of vascular risk factors (hypertension, hypercholesterolemia, smoking, etc.) and symptomatic treatment are the mainstays of therapy 1,2). Acetylcholinesterase inhibitors are used for cognitive impairment, and antiepileptic drugs for epilepsy, but none are curative.
Brain lesions in CADASIL are a multi-infarct encephalopathy resulting from chronic ischemia and accumulation of infarcts.
NOTCH3 mutation → accumulation of extracellular domain (ECD) → impaired maturation and structural defects of smooth muscle cells → formation of GOM (granular osmiophilic material). GOM is mainly composed of NOTCH3 ECD and deposits near smooth muscle cells 1). The vessel wall undergoes arterial stenosis, smooth muscle fibrosis, and degeneration, leading to reduced cerebrovascular reactivity (autoregulation).
Wall thickening is not necessarily associated with luminal narrowing; impaired cerebrovascular reactivity is considered the main cause of ischemia and brain lesions 1). Chronic ischemia induces cell apoptosis, progressing to cortical atrophy and dementia. In gain-of-function mutations, wild-type levels of gene transcription may be maintained.
Aghetti et al. (2024) reported borderzone infarctions after COVID-19 infection in three CADASIL patients (total of 10 cases including 7 previously reported)7). SARS-CoV-2 induces endothelial cell damage via ACE2 and microthrombus formation through release of vWF and fibrinogen, leading to impaired vascular tone control. This acts synergistically with the chronic microvascular damage of CADASIL, and multiple infarctions without hypotension can occur even in mild COVID-19.
p.R90C mutant mice show increased susceptibility to cortical spreading depolarization (CSD). However, since CSD is also observed in cerebral ischemia, it is not specific to migraine, and the “aura” in CADASIL cannot be said to have the same mechanism as pure migraine3). It has also been reported that there is no difference in CGRP levels between CADASIL patients with and without migraine3).
Gene therapy aimed at eliminating or silencing NOTCH3 ECD is being studied experimentally1). It has not yet reached clinical application.
Gene therapy targeting the elimination of NOTCH3 ECD is being studied at the experimental stage1). Additionally, multiple approaches such as neuroprotection using hematopoietic growth factors and early diagnosis/prognosis prediction using NfL are being investigated2). Although there is currently no standard treatment, research is progressing toward personalized medicine based on mutation location and the establishment of non-invasive monitoring methods.
