Abstract
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be present with negative family history and, especially in younger patients, with normal brain magnetic resonance. For this reason, those CADASIL patients that present only with migraine may be misdiagnosed. In the case of migraine with motor aura, sporadic hemiplegic migraine (SHM) is one of the possible misdiagnoses.
Case results: We present a case of a patient who, in the first years of her disease, met the clinical criteria for SHM. A diagnosis of CADASIL was considered only when her sister presented with headache and an unknown leukoencephalopathy.
Conclusions: This case illustrates the need for a careful review of the clinical and family history during the follow-up of primary headaches.
Introduction
Migraine is a prominent part of the phenotype of complex Mendelian vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1). CADASIL is a small-vessel disease of the brain that is phenotypically characterised by migraine with aura (MA), subcortical ischemic events, mood disturbances, apathy, cognitive impairment and MRI white-matter abnormalities. The onset of symptomatic disease in patients with CADASIL occurs in adulthood. MA is the third cardinal symptom of CADASIL, present in up to 40% of patients; frequently it is the first event, presenting 10 years ahead of the other clinical manifestations (2). The age of onset of MRI white-matter abnormalities is variable, but by the age of 35 years all patients or asymptomatic mutation carriers have developed MRI lesions (3). Since its first description, some clinical heterogeneity between and within families has been recognised. Hemiplegic migraine attacks fulfilling the criteria for familial hemiplegic migraine (FHM) according to the International Classification of Headache Disorders II (ICHD II) (4) have already been reported (5). The occurrence of hemiplegic attacks in a young patient without familiar history of typical CADASIL symptoms and normal MRI can contribute to the misdiagnosis of sporadic hemiplegic migraine (SHM). We present a clinical case whose migraine characteristics changed over time, such that classification changed from migraine with typical aura to SHM and, finally, CADASIL.
Case report
A 29-year-old female illiterate farm worker presented in 1993 to the neurology outpatient clinic with a 4-year history of paroxysmal alternating hemicranial and throbbing headache, which was moderately intense, with photophobia and phonophobia, aggravated by routine physical activity. No neurological focal symptoms were associated. She reported four episodes each month, with durations ranging between 4 and 12 hours. Her GP had diagnosed migraine without aura and started flunarizine 10 mg/day, which reduced the number of attacks to one per month. She had a history of euthyroid goitre, for which she was taking levotiroxin. The patient was also using an oral contraceptive; there were no other known vascular risk factors. She belonged to a very low-income family, where most of the members worked in agriculture. There was no known family history of migraine, stroke, dementia or psychiatric disorders. Her parents were both alive. The mother was 54 years old and reported daily tension-type headaches. She had two sisters and five brothers (ages between 32 and 15). Her GP sent her to a neurology clinic because she reported three episodes of transient numbness in her left face, arm and leg, lasting between 1 hour and 1 day, without headache. The patient also reported the sensation that an object would drop out of her hand and that she had been paralysed. She was not able to detail the sequence of the symptoms. The interictal neurological examination was normal. Computed tomography, blood analyses, electrocardiography, echocardiography, electroencephalography and cervical duplex ultrasonography were also normal.
Between 1993 and 1996, the patient was kept on flunarizine, and the transitory symptoms did not recur. In 1996 (32 years old), during the follow-up appointment, she reported an episode of transient aphasia, lasting less than 1 hour, without accompanying headache.
In 1998, at the age of 34 years old, she reported three transient episodes of right hemiparesis and numbness, without visual aura, followed by severe headache with migraine characteristics. In one of the episodes, the neurological deficits lasted 3 hours. The other two episodes were shorter and associated with less severe headache intensity. At that time, the MRI was normal (T1, T2, FLAIR, DWI). SHM was suspected.
The patient was followed until 2005, when she was 41 years old. During this period, some episodes were considered as likely to be hemiplegic migraine attacks, although she was never observed during one of them.
In 2006, her older sister (45 years old) was also sent by her GP with new daily persistent headaches and a CT scan disclosing ischemic leukoencephalopathy, in the absence of vascular risk factors. Her sister was worried because the mother had died at 64 years old of unclassified stroke. This information was omitted by the first patient. A brain MRI of the second patient showed T2 white-matter hyperintensities, mainly periventricular with temporal predominance, but also in basal ganglia, with no correspondence in T1 and no gadolinium enhancement. CADASIL was suspected, and a genetic test performed, revealing a mutation in chromosome 19 in exon 11 (p.R558C). The first patient performed a new MRI, at age 44, which showed similar changes to those observed in her sister. Genetic testing was also positive with the same mutation. The rest of the family was referred to us. At the moment, one brother and one sister had symptoms and were also positive for the same mutation.
Discussion
A few patients with migraine have motor weakness during the aura, qualifying them for hemiplegic migraine. Those that have at least one affected first- or second-degree relative are classified as FHM and those with no family history as SHM (6). Before the genes of FHM were known, it was thought that CADASIL and FHM were allelic diseases, but this was later proved to be an inaccurate hypothesis (7). Although they are separate genetic and pathological entities, it is still recognised that they share clinical characteristics – both have migraine with aura as a prominent part of the phenotype (8).
In this patient, at the first observation, her headache syndrome fulfilled criteria for migraine without aura. Subsequent transient neurological symptoms were thought to be part of the migraine spectrum, possibly representing typical aura without headache, after excluding vascular or epileptic aetiology. Nine years after the start of symptoms, she had her first episode suggesting SHM. However, first-degree relatives were not systematically observed. It was only after the observation of one sister with a typical MRI lesion that the final diagnosis was made.
The risk of diagnosing a CADASIL as SHM in young patients, especially among those under 30 years of age and with normal brain MRI, is not well appreciated. In our patient, until she was 34 years of age, we found the coexistence of hemiplegic migraine, the absence of other neurological syndromes and normal MRI. The clinical suspicion of CADASIL is probably appropriate in all sporadic cases of hemiplegic migraine and normal MRI, regardless of the patient’s age (including those aged 30 years or older). Furthermore, the diagnosis of SHM should not be established solely based on the proband interviews. We recommend clinical observation of all the family suspects and also all first-degree relatives, even when described as healthy.
Based upon this case report, when diagnosing SHM physicians should be mindful to consider alternative possibilities and long-term clinical and MRI follow-up appears appropriate to exclude the subsequent appearance of clinical and/or radiographic features suggestive of CADASIL.