Neuro-ophthalmology of Cerebral Autosomal Dominant Arteriography with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
CADASIL is a genetic disease that affects small arteries in the brain and presents in middle-aged adults with progressive cognitive decline, and mood disturbances that correlate to subcortical ischemic events. Ophthalmologic manifestations in CADASIL are variable, but often present with visual aura, diplopia, and oscillopsia, with typically retinal vascular changes on examination. Clinicians should be aware of the ophthalmic presentations of CADASIL especially in stroke in the young. Currently, there is no treatment for CADASIL and management centers on prevention of vascular risk factors as well as symptom treatment.
Cerebral Autosomal Dominant Arteriography with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic disorder that affecting primarily the small blood vessels of the brain.  It is characterized by migraine with aura, cognitive impairment / encephalopathy, transient ischemic attacks (TIAs), and recurrent strokes and can lead to disability, dementia, and early death.  Like other autosomal dominant inherited disorders, CADASIL is an adulthood onset microangiopathy that leads to a variety of presentation depending on the affected vessels. CADASIL can present or manifest with visual symptoms.
CADASIL is linked to mutations in the NOTCH3 gene found on a single locus chromosome 19q12.   NOTCH3 encodes a transmembrane receptor with an extracellular domain with 34 epidermal growth factor repeats (EGFR).  The extracellular domain contains cysteine residues which encompass the EGFR. NOTCH3 contains 33 exons, however, mutations implicated in CADASIL are typically found in exons 2-24 which encode the EGFR domains.  Notably, the mutations implicated in CADASIL are cysteine altering mutations in NOTCH3 and identification of this mutation is currently one of the primary diagnostic criteria for making this diagnosis.  The transmembrane expressed by NOTCH3 is found in smooth muscle cells of small arteries and its activation signals the development of these smooth muscle cells.  Mutations in NOTCH3 result in the accumulation of the extracellular domain of this transmembrane without the contaminant accumulation of the intracellular domain. This eventually leads to poor maturation, structural defects, and microscopic clusters around small arteries in the brain.  The NOTCH3 mutation may cause a gain of function of the transmembrane.  and gene assays in CADASIL can signal gene transcription at wild-type levels.  This extracellular domain still maintains a functional transmembrane and the pathology may result from the accumulation of these extracellular domain aggregates.
CADASIL has an autosomal dominant inheritance (one mutated gene will cause the pathology). Affected individuals have a 50% chance of passing on the mutated gene to their offspring. However, CADASIL can also occur from sporadic mutations, so an individual without family history of the disease can be affected. The overall prevalence of CADASIL has been estimated to be 4.15 cases in every 100,000. However, this is might be underestimated as the only study of prevalence was from a small study in Scotland, UK.  In addition, prevalence of sporadic mutations is difficult to calculate. The duration of symptomatic disease is estimated to be around 20 -25 years. 
CADASIL is a multi-infarct encephalopathy, and the pathology and symptomology are due to chronic ischemia / infarction to areas of the brain. Autopsies have shown evidence of stenosed cerebral arteries as well as functional defects due to fibrosis and degeneration of smooth muscle cells in the vasculature.  Moreover, these vessels also have been shown to lead to poor autoregulation and reactivity to varying blood flow demand.  Chronic ischemia leads to cellular apoptosis and cortical atrophy which correlate with CADASIL symptoms.
The presentation of CADASIL is highly variable, even within the same family. A family or personal history of stroke in the young should prompt consideration for CADASIL. A history of migraine with aura, early onset of subcortical ischemic infarcts, and cognitive impairment are other features that should alert clinicians to include CADASIL as part of the differential diagnosis.  Migraine with aura is observed in about one third of the patients with CADASIL and is often the first symptom.  Progressive cognitive impairment and epilepsy are also reported in CADASIL patients as they age.  Ophthalmological symptoms such as transient vision loss or positive visual phenomena and aura with or without migraine, are often the first symptoms that patients experience.  Diplopia and oscillopsia are also often part of the initial presenting symptoms.  Specific questioning for other vascular risk factors is also necessary for other differential diagnoses.
There are no specific physical exam findings that are specific to CADASIL, however, a comprehensive neurological exam usually reveals motor and/or sensory deficits. In the ophthalmological examination, visual acuity, field, and pupillary reflexes are usually normal.   However, a slit lamp examination may show early lens opacification as well as ciliary body atrophy.  These findings relate to the involvement of ciliary body arterioles in CADASIL.  Retinal vascular changes (often asymptomatic) may occur in CADASIL (e.g., arteriolar narrowing sheathing, and arteriovenous nicking)    may be due to long term reactive vascular smooth muscle alterations. Cotton wool patches have also been described in CADASIL.  However, retinal vessels occlusion is rarely observed in these patients.  The optic nerve is usually normal, but some studies have reported optic nerve pallor and atrophy.  Eye movement abnormalities may be present on examination, reflecting involvement of the brainstem, and can include slow saccades, horizontal gaze restriction, internuclear ophthalmoplegia. 
The diagnostic workup for patients with CADASIL is challenging because most of its symptoms are common in other pathologies. Neuroimaging with cerebral MRI often demonstrates subcortical infarcts, leukoencephalopathy, and exhibits white matter hyperintensities, and may show cortical infarcts.  The work up should also include workup of the differential diagnoses for CADASIL, including a nutritional screen (vitamin B12 and vitamin E especially), assessment of standard cerebrovascular risk factors (diabetes, hypertension, hypercholesterolemia, risk of cardiogenic emboli). Ultimately, genetic testing for the NOTCH3 mutation is the gold standard for diagnosis. Pescini et al created an ad hoc screening scale tool to be utilized to determine when it is appropriate to consider genetic testing for suspected CADASIL patients, shown in the table below.  This was shown in a small population of patients to be highly sensitive and specific. 
Table 1: CADASIL Scale suggested by Pescini et al. A score of > 15 is consider suggestive of the diagnosis .
|Migraine with aura||3|
|TIA or stroke||1|
|TIA / stroke onset < 50 years||2|
|Cognitive decline / dementia||3|
|Leukoencephalopathy extended to temporal pole||1|
|Leukoencephalopathy extending to external capsule||5|
|Family history* in at least 1 generation||1|
|Family history* in at least 2 generations||2|
Many diagnostic criteria have been proposed, typically simplified into clinical, pathologic, and genetic criteria.  One such criteria is listed below and suggests a CADASIL diagnosis is likely when a patient meets all of:
- Presence of white matter lesions by MRI/CT involving the anterior temporal pole
- Exclusion of leukodystrophies
- Evidence of NOTCH3 mutations and/or meeting the pathological criteria (granular osmiophilic material detected by electron microscopy). 
Probable CADASIL is based on clinical / radiological criteria:
- Age < 55 years old at time of first symptoms / abnormal MRI
- At least two of:
- Subcortical dementia, long tract signs, pseudobulbar palsy
- Stroke like episodes with focal neurological deficits
- Mood disorder
- Autosomal dominant inheritance
- Presence of white matter lesions by MRI/CT involving the anterior temporal pole
- Exclusion of leukodystrophies
- Sporadic cerebral small vessel disease (SVD): It is characterized by infarcts that lead to cognitive impairment, functional, and memory loss in the elderly patients.
- Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): CARASIL presents similar to CADASIL with subcortical infarcts, and functional loss but is autosomal recessive (i.e., two copies of the defective gene are required to cause the disease).
- Fabry disease: In the late stages, Fabry disease presents with corneal clouding, lens opacification, cerebrovascular lesions such as transient ischemic attack, and stroke.
- Multiple infarct dementia: It is the second most common cause of dementia in the elderly. Like CADASIL, it also presents with cognitive decline and memory loss
Currently there is no proven treatment for CADASIL. Rather, management is based on individualized treatment of symptoms.  Ischemic infarcts are prevented by managing vascular risk factors such as hypertension, hypercholesterolemia as well as utilization of antiplatelets. Donepezil has shown to improve executive function in CADASIL pts. 
Males with CADASIL have a shorter life expectancy than females.  In addition, males also experience earlier onset of subcortical infarcts and cognitive decline.  CADASIL patients face poor long-term prognosis, and most patients have severe and progressive, non-reversible neurologic deficits. 
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