Forty percent of all stroke cases are idiopathic.1 Because stroke is the third leading cause of death in the United States1 and is also the leading cause of acquired physical or cognitive impairment in developed countries, researchers have long hoped to uncover the causes of idiopathic strokes.
Researchers noted that mental disorders have been attributed to cerebral vascular disease for more than 100 years.2 After exploring the relationship between cerebral vascular disease and mental disorders, researchers in 1977 first described a hereditary, multi-infarct dementia syndrome. Since then, numerous reports have described a new autosomal dominant disorder resulting in stroke and dementia - CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy).2
CADASIL is the first known genetic form of vascular dementia with an identified gene. More than 400 families from countries around the world have already been identified as carriers of the gene.2 CADASIL experts believe that the frequency of CADASIL is likely to be higher than previously thought. In fact, vascular dementias are the second most common type of dementia after Alzheimer's disease.3 Because CADASIL is believed to be largely undiagnosed the prevalence of the disease is not yet known.4
CADASIL is a hereditary cause of stroke, dementia, migraine with aura, and mood disorders. Symptoms of this disorder appear from the mid-twenties to around 45 years of age and affected individuals typically die by age 65.
Stroke: Stroke is the most common feature in patients presenting with this disorder. In one study of 102 patients, ischemic deficits were present in 87% of symptomatic patients, most of whom experienced recurrent ischemia, and all of the deceased patients had suffered from strokes.5,6 CADASIL is associated with a cerebral non-atherosclerotic, nonamyloid angiopathy and affects primarily the small arteries that innervate the white matter and the basal ganglia.1 Contrary to typical stroke symptomology, hypertension and other vascular risk factors are not usually present in individuals with CADASIL.2
Dementia: The second most common feature in CADASIL patients is the development of cognitive deficits. The dementia in these individuals progresses slowly, in addition to stepwise deterioration.5 The dementia causes frontal-like symptoms and memory impairment, and is usually associated with other problems, such as pseudobulbar palsy, gait disturbances, pyramidal signs, and sphincter incontinence.3 These symptoms all relate to vascular dementia. In addition, the dementia typically develops after a history of recurrent stroke.1 However, progressive dementia without any preceding stroke episodes associated with diffuse white matter hyperintensities is also a common presentation of CADASIL.
Migraine: Often one of the initial symptoms of CADASIL, migraine with aura occurs in approximately one-third of families with the disorder.2 In several studies, migraine with aura typically occurred earlier in patients' lives (a median age of 26) as compared to ischemic events (a median age of 45).3 Migraine occurs in CADASIL patients more often than in the general population. Some reports note that up to 40% of CADASIL cases have "migraine-like" headaches.3 However, these symptoms should suggest a diagnosis of CADASIL only when associated with diffuse white matter lesions on cerebral MRI.
Mood disorders: Mood and psychiatric disturbances, including severe depression, sometimes with alternating manic episodes, have been observed in patients with CADASIL. Studies of CADASIL patients note cases in which DSMIII-R criteria for major depression of melancholic type and manic episodes were met.3 When these were the initial symptoms of the disorder, they presented very similarly to the typical melancholic disorders. However, like migraine symptoms, mood disorders should suggest a diagnosis of CADASIL only when associated with diffuse white matter lesions on cerebral MRI.
| CADASIL Symptom | % of patients |
| Recurrent subcortical ischemic events | 84% |
| Dementia | More than 80% before death |
| Migraine with aura | 22% |
| Depression | 20% |
MRI total lesion volume closely correlates with disability on both T1- and proton density weighted images. A strong inverse correlation between total lesion volume and overall cognitive performance, as determined by the Mini-Mental Status Exam (MMSE), is observed in CADASIL patients.7 Typical MRI findings in these affected individuals include noticeable signal abnormalities with hyperintense lesions on T2-weighted images (SH) in the subcortical white matter and basal ganglia.3 Although MRI demonstrates findings of CADASIL in individuals in their 20s and penetrance of the disease on MRI appears to be complete by age 35, symptoms usually do not manifest until affected individuals are in their 50s or 60s.5,6
On MRI, white matter abnormalities (WMA), which usually appear two decades before onset of the disease, have been reported in migraine sufferers, particularly in migraine with aura.2,3 However, for young migraine patients without vascular risk factors or atypical symptoms, MRI is typically not necessary because of the straightforward clinical diagnosis. According to CADASIL studies, MRI should be considered in the following cases: affected individuals who have migraine attacks with aura when onset is in mid-adulthood; when aura is atypical (hemiplegic, basilar, or prolonged); and when there is a family history of stroke, dementia, or depression.3
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Figure 1. MRI in two CADASIL patients Dichgans, M. et al., Quantitative MRI in CADASIL. Neurology 1999; 52:1361-1367. |
CADASIL is an autosomal dominant disorder whose gene, Notch3, is located on chromosome 19. The symptoms of CADASIL are attributed to mutations in this gene. Physiologically, the Notch3 gene specifies cell fate in development.6 Allelic variants of Notch3 could also, although not yet demonstrated, be involved in other vascular conditions.
In addition to the clinical workup for CADASIL, genetic testing for this mutation can be used in familial or sporadic ischemic disorders of undetermined cause to assist in confirming a diagnosis.1 With up to 99% specificity, Athena's CADASIL DNA Sequencing Test will detect approximately 85% of the mutations resulting in the phenotype of the disease. CADASIL experts recommend that people under 65 with the following characteristics6 should be tested:
- Depression, memory loss, behavior change, migraine, and/or stroke-like symptoms, such as recurrent stroke at a young age (<29 years old) when associated with prominent white matter disease/diffuse white matter hyperintensities on MRI
- Lack of significant vascular risk factors
- Family history of migraine, "young" recurrent stroke, depression, cognitive impairment, or white matter changes
It is important to note that because there is no treatment for CADASIL, a similar counseling protocol to Huntington's disease should be followed for presymptomatic patients (View protocol).6 It is understood that presymptomatic genetic testing for CADASIL can have potential benefit and clinical utility. Often under appreciated, however, are the types of possible adverse outcomes and, the severity and duration of the problems. The American Academy of Neurology has published recommendations and practice guidelines to inform clinicians of issues surrounding the presymptomatic testing of individuals for disorders such as CADASIL with the goal of optimizing benefits and minimizing adverse outcomes. Therefore, in accordance with the experts, Athena Diagnostics recommends that all asymptomatic individuals who want to be tested for CADASIL receive both pre-test and post-test genetic counseling.
The differential diagnosis of CADASIL is important because similar diseases may be treatable. Depending on MRI findings, several disorders are included in the differential diagnosis of CADASIL. Disorders that should be distinguished from CADASIL both clinically and radiologically6,8 are:
- Demyelinating disorders such as multiple sclerosis (MS) and acute disseminating encephalomyelitis
- Hypertensive arteriosclerotic encephalopathy (Binswanger's disease)
- Amyloid angiopathy
- Progressive multifocal leukoencephalopathy, chronic MS
- Mitochondrial disorders (i.e., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS])
- Amyloidoses
- Cerebral angeitis
- Vascular or apparently nonvascular dementia, such as Alzheimer's disease1
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Figure 2: MRI T2-weighted images Chabriat, H. et al., Clinical spectrum of CADASIL: a study of 7 families. The Lancet 1995; 346:934-938. |
A diagnosis of CADASIL cannot be made without an MRI. In addition to the clinical signs and symptoms of the patient, and the essential MRI, the diagnosis can be confirmed by genetic testing. CADASIL experts stress the importance of an accurate diagnosis:
The diagnosis should be considered not only in patients with recurrent small subcortical infarcts leading to dementia, but also in patients with transient ischemic attacks, migraine with aura, or severe mood disturbances, whenever MRI reveals prominent signal abnormalities in the subcortical white matter and basal ganglia. Clinical and MRI investigations of family members are then crucial for the diagnosis, which can be confirmed by genetic analysis.3
The establishment of a unique genetic etiology can impact patient management, prognosis, and family counseling. Recognizing the attributes of CADASIL can help distinguish this largely underdiagnosed disorder from similar conditions associated with aging and hypertension. Insights gained from the study of the CADASIL gene can increase our understanding of the mechanism of this disorder, as well as that of stroke and vascular dementia in general.1
