Abstract
We present genetically identical twin patients who experienced late-onset migraine with visual and somatosensory auras and later developed hemiplegic migraines associated with severe cortical oedema and enhancement. Both positron emission tomography and electroencephalography showed an increase in activity contralateral to the hemiplegic side. Brain biopsy during the attack showed reactive astrogliosis and microgliosis. Mutations in CACNA1A, ATP1A2, SLC1A3 and NOTCH3 were ruled out by sequencing. This report shows the clinical and genetic evaluation of a severe form of familial hemiplegic migraine as well as the evolution of the imaging changes.
Introduction
Hemiplegic migraine is characterized by a reversible aura of motor weakness followed by moderate to severe migraine headache (1). Familial hemiplegic migraine 1 (FHM1) is caused by mutations in the voltage gated P/Q type calcium channel, CACNA1A (2). FHM2 is caused by mutations in ATP1A2, a sodium-potassium ATPase (3). Hemispheric cerebral oedema and cortical enhancement have been associated with hemiplegic migraine caused by mutations in CACNA1A (4), ATP1A2 (5) and SLC1A3 (6). FHM3 caused by mutations in SCN1A has not been associated with cortical oedema (7).
We report twin brothers with late-onset hemiplegic migraine, encephalopathy and lateralized cortical abnormalities. An extensive work-up for infectious, autoimmune and metabolic abnormalities performed at our institution for one of the twins was negative. Clinical, functional, radiological and pathological data acquired during two ongoing hemiplegic attacks in one of the twins are presented.
Subjects and methods
Subjects
The proband is a developmentally normal 50-year-old right-handed man who developed migraine with aura at age 40. The migraines started with bilateral visual blurring and left face/arm paraesthesias and incoordination. The auras either occurred in isolation or were followed by severe throbbing occipital headache within 15 min of onset. The episodes were fully reversible but would persist until he was able to sleep. At age 48, he presented with a typical episode of visual loss and occipital headache, but developed additional symptoms of emotional lability and left-sided hemisensory and motor dysfunction. On initial evaluation, he showed left–right confusion, a left homonymous hemianopia, left hemisensory loss and left pyramidal weakness. Magnetic resonance imaging (MRI) done with contrast showed right posterior cerebral gyral enhancement with oedema causing mild mass effect and sulcal effacement (Fig. 1A) and increased T2 signal in the subcortical white matter of right greater than left occipital lobes. Brain magnetic resonance angiography (MRA) showed dilated right middle cerebral and distal posterior cerebral arteries. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed markedly increased radiotracer activity in the right temporal, insular and occipital lobes, suggesting underlying inflammation (Fig. 2). Electroencephalography (EEG) revealed 3-Hz spike and wave abnormalities in the right hemisphere on a background of diffuse slowing. His cerebrospinal fluid (CSF) profile was normal except for an elevated protein of 136 mg/dl. Opening pressure was normal. CSF and serum lactate and pyruvate levels and their ratios were normal. Electrolytes, blood count, creatine kinase, antinuclear antibodies, anticardiolipin antibodies, rheumatoid factor, fluorescent treponemal antibody-absorption, thyroid-stimulating hormone and B12 were normal. A right temporal lobe and dural biopsy showed reactive lymphocytes and astrogliosis, but no changes consistent with vasculitis, infection or malignancy. Microbial studies including cytomegalovirus, varicella zoster virus and herpes simplex virus polymerase chain reactions, Gram stain, bacterial cultures, fungal stains and culture were negative. The patient was treated with antibiotics and recovered with a left homonymous hemianopia and mild left-sided weakness.
Magnetic resonance imaging (MRI) scans of the patients acquired before, during and after hemiplegic episodes. (A) MRIs of twin A during his first attack. (B) MRIs of twin A during his second attack. (C) MRIs of twin B prior to the onset of his hemiplegic episode. (D) MRIs of twin B during his hemiplegic episode. (A1) Axial FLAIR imaging showing cortical oedema and sulcal effacement of the right temporal and occipital lobes. (A2) T1 with gadolinium showing gyral enhancement of the right temporal and occipital lobes. (A3) Magnetic resonance angiography (MRA) showing dilation of the middle cerebral artery (MCA) and distal posterior cerebral artery (PCA) ipsilateral to the area of enhancement. (B1) FLAIR imaging showing oedema and sulcul effacement of the left hemisphere as well as white matter alterations and cortical atrophy in the previously affected right hemisphere. (B2) T1 with gadolinium showing new enhancement of the left posterior temporal and occipital lobes. (C) FLAIR imaging of twin B during an asymptomatic period, showing subcortical occipital lobe white matter changes. (D1) FLAIR imaging during the first attack of hemiplegia in twin B showing cortical oedema over the right temporal and occipital lobes. (D2) The same areas showing gyral enhancement. (D3) Normal diffusion weighted imaging. (D4) MRA showing dilation of the MCA and PCA ipsilateral to the affected hemisphere.
18-Fluoro-2-deoxyglucose (FDG)-positron emission tomographic images performed during twin A's first admission showing markedly increased radiotracer uptake in the cortex of the right temporal lobe, insula and right occipital lobe. Figures shown are coronal (A), sagittal (B) and serial axial images (C,D,E). The remaining brain showed normal FDG uptake.
Two years later, he awoke with severe occipital headache, nausea and right-sided hemianaesthesia. Over the course of the day, he developed aphasia and extreme lethargy. He presented to a local hospital where he was afebrile, but responded only to painful stimuli. On transfer to our institution 2 weeks later, he was awake but could not follow commands. He had a right homonymous hemianopia and moved all extremities weakly but symmetrically. An MRI with contrast showed gyral enhancement of the left temporal, parietal and occipital lobes with increased T2 signal in the same territories (Fig. 1B), but no diffusion restriction. There was increased T2 signal in the subcortical and deep white matter of the previously involved right hemisphere with development of atrophy and encephalomalacia. EEG showed triphasic waves in the left frontopolar regions but no clinical or electrographic seizures. He underwent a left temporal lobe and dural biopsy, which showed marked astrocytosis and microgliosis without evidence of vasculitis or viral inclusions. He was treated with acyclovir and ceftriaxone for presumed encephalitis, then acetazolamide and verapamil for migraine. After 1 month, he was occasionally alert and responsive to name but was aphasic. Four months later, he was able to do most of his self care but was unable to live alone.
His twin brother developed identical spells of decreased vision followed by hemianaesthesia and occipital headache at the age of 42 years, usually affecting the right face and arm. His migraines were fully reversible and were relieved only by sleep. MRI performed during an asymptomatic period showed isolated subcortical occipital white matter disease (Fig. 1C). His only other risk factor for ischaemic disease was hypertension. At the age of 52, he developed a particularly severe migraine headache that, over the course of a day, progressed to involve disorientation and dense left-sided hemianaesthesia and hemiplegia. He was admitted to another hospital where he was treated for presumed encephalitis. Infectious studies were negative. His MRI showed oedema and enhancement of right posterior temporal, insular and occipital cortices. Diffusion studies were negative and MRA showed ipsilateral dilation of the middle cerebral artery (Fig. 1D). He recovered over the course of 2 months to the point where he could eat with utensils.
Neither of the brothers' parents experienced migraine headaches, visual or somatosensory auras. They have a completely asymptomative sister. Both children of the second brother experience migraine headaches with visual and sensory auras; both have normal brain MRIs.
Methods
DNA was extracted from peripheral blood lymphocytes using standard methods. Genotyping was performed with polymorphic microsatellite markers on multiple chromosomes. All exons and flanking introns of CACNA1A, ATP1A2, SLC1A3 and NOTCH3 were sequenced as previously described (2, 3, 6, 8).
Results
Genotyping analysis revealed that the brothers are identical twins. Mutations in CACNA1A, ATP1A2, SLC1A3 and NOTCH3 were negative.
Discussion
We present the clinical, genetic and imaging evaluation of two brothers with late-onset hemiplegic migraine. The average age of onset of FHM has been reported to be 17 years (range 1–45 years) (9), and the age of onset of other migraines with aura to be 22 years (range 5–77 years) (10) in population-based Danish studies. The age of onset of FHM1 specifically has been reported as 11.7 years (range 1–51 years) (11). Sporadic case reports indicate that there are rare pedigrees with late-onset symptoms (12, 13).
Hemiplegic migraine attacks rarely lead to permanent deficits (4, 9, 13–15). Although the severe hemiplegic episodes in each brother led to permanent neurological deficits, they were preceded by migraine features which were otherwise qualitatively the same as prior migraines, indicating that these spells were different only in terms of severity and not the underlying inciting event. Indeed, the spells followed a posterior to anterior neuroanatomical progression, beginning with visual symptoms, sensory loss, cognitive abnormalities and then motor dysfunction. The underlying occipital lobe white matter disease seen in twin B, prior to the onset of hemiplegic spells, indicates that there was subclinical insult to the brain during the migraines when aura was limited to visual loss.
The pathological changes seen in the first twin's biopsy were consistent with active and prior inflammation, as evidenced by reactive lymphocytes and astrogliosis, and represent the only report of which we were aware of pathological data in migraineurs obtained during active symptoms. Previous reports were of samples taken at autopsy (16, 17). Diffusion imaging was consistent with cytotoxic oedema rather than primary ischaemia. MRI, MRA, FDG-PET and EEG all implicated a process of increased metabolic demand and cortical irritability. This increase in metabolic demand can lead to vasodilation of the blood vessels ipsilateral to the irritated cortex, breakdown of the blood–brain barrier, release of inflammatory mediators and worsen the cortical irritability. This vicious cycle may have been the reason why his symptoms were prolonged and the radiological changes persistent for so long (18). Our study, as well as several others, shows that the primary process involved in the prolongation of symptoms is one of increased, not decreased perfusion (19–21).
Similar symptoms exhibited in genetically identical twins support an underlying genetic cause. However, the mode of transmission is unclear. Long-term follow-up is required to determine whether the children of the second twin will develop similar symptoms. If so, this would support an autosomal dominant transmission. Although a late-onset form of migraine with aura has been described in a family with Leber's hereditary optic neuropathy (22), the age of onset of migraine in our patients would be very atypical for a mitochondrial disorder. Moreover, our patients exhibited no supporting features of a mitochondrial disorder such as myopathy, lactic acidosis or retinopathy.
We are aware of one other report of hemiplegic migraine and cerebral oedema not associated with CACNA1A or ATP1A2 mutations, although there have been other reports where mutation analysis was not done. A two-generation Native Indian family from Canada was reported with a late-onset autosomal dominantly transmitted disorder of recurrent episodes of hemiplegic migraine and encephalopathy. These individuals showed lateralized cerebral oedema and leptomeningeal enhancement during the attacks with development of laminar necrosis, cerebral atrophy and white matter changes (12). The late onset of hemiplegic spells in this family and the similarity in evolution of the radiological changes to our patient suggests that there is at least a fourth locus for this severe form of hemiplegic migraine.
Acknowledgements
This project was funded by NIH/NIDCD grant P50DC05224, NIH grant 5U54RR019482 and the Clinical Research Training Fellowship grant from the American Academy of Neurology.