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Migraine affects approximately 12% of the U.S. population and has many clinical manifestations.5 The majority of migraines can be classified as migraine without aura (common) or migraine with aura (classic). Aura affects up to 31% of migraineurs and is defined as transient focal neurological symptoms (usually visual) that precede a headache.6 According to the International Headache Society (IHS), aura gradually develops over 5 to 20 minutes and lasts less than one hour, warning of an impending headache.7 Migraine with aura is commonly found in association with inherited diseases such as CADASIL.8
CADASIL is an uncommon, but underdiagnosed, inherited small vessel disease caused by mutations in the Notch3 gene characterized by small artery strokes and vascular dementia.2,9 Migraine with aura is a remarkably common early manifestation of CADASIL, reported in 38% to 60% of affected individuals.1,10,11 In CADASIL patients, migraine with aura is often the first symptom and is expressed at a mean age of 25 years.1,2 CADASIL is further characterized by white matter abnormalities on a brain MRI (during the second through fourth decade), ischemic attacks (in the fifth decade), subcortical dementia (in the sixth decade) and other neurological features including pseudobulbar palsy, gait disturbance, and pyramidal signs.2,12 While disease presentation in CADASIL patients is highly variable, all patients, regardless of symptoms, have white matter abnormalities on MRI by age 35. These MRI typically show diffuse T2 hyperintensities of the cerebral white matter with hyperintensity of the temporal pole but no other temporal lobe involvement.2 Subtle hyperintensities have even been seen in individuals in their early twenties.1,10
A diagnosis of CADASIL is typically made in the fifth decade of life when an individual presents with recurrent strokes or cognitive decline.1 An initial presentation of migraine, in the absence of other neurological deficits and vascular risk factors, generally does not prompt a physician to consider CADASIL.4 However, due to the low frequency of confluent white matter abnormalities (WMAs) among migraineurs, the presence of prominent WMAs in patients experiencing migraine suggests that migraine with aura may be a result of another etiology, such as CADASIL.9,13 Despite this connection, the mechanisms underlying the association of migraine and CADASIL remain unclear.3,14
Studies confirm that migraine with aura and white matter abnormalities are early indications of CADASIL. For example:
- Dichgans et al. (1998): delineated the phenotypic manifestations of CADASIL in 102 cases. Migraine with aura was the third most frequent feature of CADASIL patients (38%), revealing a younger than previously reported age of onset, 26 years.11
- Lesnik Oberstein et al. (2003): studied eight families with individuals younger than 35 years with Notch3 mutations and revealed that disease expression was limited to migraine with aura and, less frequently, to stroke. All subjects showed WMAs on MRI.1
- Ceroni et al. (2000): described a family where prolonged atypical aura was the major clinical feature of CADASIL. Subjects had few neurological signs, no evidence of stroke, and only one incidence of dementia in a 75 year-old family member.5
- Mellies et al. (1998): studied a German CADASIL family whose symptoms were limited to migraine with aura followed by insidiously progressive dementia. The family never experienced TIAs, stroke or neurological deficits.15
- Schon et al. (2003): identified patients originally diagnosed with acute encephalitis and revealed that CADASIL was the cause of their migraine with aura, other neurological deficits and WMAs.16
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| Figure 1. 30 year old woman with multiple prolonged episodes of migraine with aura. MRI shows one large confluent area of high signal and multiple small areas of high signal. | Figure 2. 34 year old woman with many episodes of migraine with aura and a strong family history of migraine. MRI shows multiple lacunar infarcts. | |
| *Figures are the property of Stephen Salloway, MD, MS, Associate Professor of Clinical Neurosciences and Psychiatry, Brown Medical School, Director of Neurology and The Memory Disorders Program, Butler Hospital and are provided as a courtesy of Athena Diagnostics. |
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CADASIL can be difficult to diagnose due to the variable symptom presentation and is now thought to be more common than originally projected.17 The hereditary nature of CADASIL is not always apparent in family histories because of its non-specific clinical presentation and incomplete penetrance until 50-60 years of age.18,19 Migraine presents in CADASIL patients at approximately 25 years of age, the same age at which a migraineur would begin having symptoms, making it difficult to distinguish CADASIL from classic migraine in the absence of other neurological deficits. The difficulty of identifying symptoms as manifestations of CADASIL often leads to the misdiagnosis of the disease.
A CADASIL patient presenting with a family history of migraine can be misdiagnosed with familial hemiplegic migraine (FHM).17 FHM is inherited in an autosomal dominant manner and is preceded by hemiparesis.8 However, unlike CADASIL patients, these individuals do not develop additional symptoms.4 The majority of mutations resulting in FHM have been mapped to 19p13, involving a gene locus close to Notch3, while additional mutations on chromosome 1 have also been linked to FHM.8
CADASIL is often confused with demeylinating disease due to the extensive white matter abnormalities revealed on MRI. Such disorders include multiple sclerosis, Binswanger's disease and acute encephalopathic illness.16-18 As a result of the psychiatric symptoms experienced by some CADASIL patients, CADASIL can also present as depression or bipolar disorder.17 Individuals experiencing strokes at a young age may have been diagnosed with a mitochondrial disorder such as mitochondrial encephalomyopathy, lactic acidosis and stroke-like symptoms (MELAS) rather than CADASIL.5 Additionally, the differential diagnosis of CADASIL includes: HIV, amyloidosis, neurosyphilis, vasculitis, adult-onset leukodystrophies and other familial diseases associated with stroke.20
CADASIL is caused by mutations in the Notch3 gene on chromosome 19 that specifies cell fate during development.3 The mutation is autosomal dominant with 100% penetrance. All CADASIL mutations are located within epidermal growth factor-like repeat domains, which are encoded for by the first 23 exons of the Notch3 gene.3,21 CADASIL is pathologically characterized by systemic destruction of vascular smooth muscle cells (VSMC) and arterial deposits of granular osmiophilic material (GOM), which can be detected by electron microscopic investigation of a skin biopsy.3 However, due to the high false-negative rates of skin biopsy, sequencing of all 23 exons on the Notch3 gene is the most reliable procedure for detecting CADASIL in symptomatic individuals.11,21 Molecular diagnosis can help avoid inappropriate treatment and can also lead to genetic counseling for patients and family members.
Currently, treatment for CADASIL is symptom specific. Though no studies with antiplatelet agents to prevent stroke in CADASIL have been conducted, aspirin is frequently used to treat CADASIL patients because of its low complication rate. Anticoagulants and thrombolytic agents are not recommended.17,22 Cholinergic therapies, known to be effective in treating Alzheimer's disease, may also be beneficial for CADASIL patients.23 Continued molecular identification of individuals with Notch3 mutations will facilitate ongoing research investigating treatment options for CADASIL.
Migraine with aura affects 38% to 60% of CADASIL patients and can be the first sign of the disease, preceding the more common symptoms of ischemic attacks and cognitive dementia.1,10,11 Because migraine with aura is a common disorder, it may not prompt a MRI scan without the presence of additional neurological features.4 However, studies have shown that CADASIL should be considered in patients experiencing prolonged atypical aura and familial headache whose MRIs reveal white matter hyperintensities.4,9,15 A familiarity with the clinical signs of CADASIL, in conjunction with a MRI scan, will assist in the diagnosis of CADASIL in currently undiagnosed individuals.
