Familial Hemiplegic Migraine and Recurrent Episodes of Psychosis: A Case Report

Familial hemiplegic migraine (FHM) is a rare autosomal dominant form of migraine with motor aura. We present a case report of a father and son with very similar attacks of hemiplegic migraine and recurrent episodes of accompanying psychoses. Previously, such episodes led to hospitalization and extended clinical examinations, which further worsened the psychoses. Since the episodes were recognized as related to the hemiplegic migraine, a treatment strategy combining sleep and sedation was initiated and progression onto psychosis was almost completely avoided in both father and son. Genetic analyses found no causal gene mutation in the three known FHM genes, suggesting that the phenotype is caused by a yet unidentified mutation.     

Partially Reversible Cortical Metabolic Dysfunction in Familial Hemiplegic Migraine With Prolonged Aura

We report a SPECT and PET voxel‐based analysis of cerebral blood flow and metabolic rate for glucose in a 23‐year‐old woman with familial hemiplegic migraine (FHM) caused by ATP1A2 gene mutation. In comparison with healthy subjects, a PET scan showed brain glucose hypometabolism, controlaterally to the hemiplegia, in the perisylvian area early in the attack (Day 1), without any SPECT perfusion abnormalities. Decrease in metabolic rate was only partially reversible at Day 78, concordant at this time with a remaining hemisensory loss. These findings provide further evidence for a primary cortical metabolic dysfunction in FHM.     

Familial Hemiplegic Migraine With Crossed Cerebellar Diaschisis and Unilateral Meningeal Enhancement

A 6-year-old boy with a family history of hemiplegic migraine had a hemiplegic migraine lasting for 6 days complicated by prolonged fever, lethargy, and two brief focal seizures. An acute single photon emission computerized tomogram (SPECT) demonstrated decreased blood flow in the symptomatic cerebral hemisphere as well as crossed cerebellar diaschisis not previously documented in migraine. Another unique finding was the MRI with enhancement of the meninges and pial vessels over the symptomatic cerebral hemisphere. These findings suggest cerebellar and extra-axial involvement as components of hemiplegic migraine.     

Sporadic Hemiplegic Migraine With Permanent Neurological Deficits

By definition, the neurologic impairments of hemiplegic migraine are reversible. However, a few cases of permanent neurologic deficits associated with hemiplegic migraine have been reported. Herein, we present the case of a patient with permanent impairments because of hemiplegic migraine despite normalization of associated brain magnetic resonance imaging abnormalities. Cases like these suggest the need to consider aggressive prophylactic therapy for patients with recurrent hemiplegic migraine attacks.     

Migraine and Epilepsy: Review of the Literature

Migraine and epilepsy are disorders that are common, paroxysmal, and chronic. In many ways they are clearly different diseases, yet there are some pathophysiological overlaps, and overlaps in clinical symptomatology, particularly with regard to visual and other sensory disturbances, pain, and alterations of consciousness. Epidemiological studies have revealed that the two diseases are comorbid in a number of individuals. Both are now recognized as originating from electrical disturbances in the brain, although their wider manifestations involve the recruitment of multiple pathogenic mechanisms. An initial excess of neuronal activity in migraine leads to cortical spreading depression and aura, with the subsequent recruitment of the trigeminal nucleus leading to central sensitization and pain. In epilepsy, neuronal overactivity leads to the recruitment of larger populations of neurons firing in a rhythmic manner that constitutes an epileptic seizure. Migraine aura and headaches may act as a trigger for epileptic seizures. Epilepsy is not infrequently accompanied by preictal, ictal, and postictal headaches that often have migrainous features. Genetic links are also apparent between the two disorders, and are particularly evident in the familial hemiplegic migraine syndromes where different mutations can produce either migraine, epilepsy, or both. Also, various medications are found to be effective for both migraine and epilepsy, again pointing to a commonality and overlap between the two disorders.     

Familial hemiplegic migraine, neuropsychiatric symptoms, and Erdheim-Chester disease

We report the occurrence of unilateral cerebral hemisphere edema with subsequent cortical laminar necrosis in the setting of familial hemiplegic migraine (FHM) and permanent neurologic sequelae after resolution of an attack in 1 patient. Contemporaneous with this severe attack of FHM, the patient was found to exhibit multiple systemic and neurological symptoms referable to Erdheim-Chester disease (a rare non-Langerhans cell histiocytosis) that was confirmed by bone biopsy. This case demonstrates the severity possible with a migrainous infarction associated with FHM. The co-occurrence of two such rare entities in 1 patient suggests a possible relationship.     

Hemiplegic migraine aura begins with cerebral hypoperfusion: imaging in the acute phase

Imaging studies of spontaneous migraine aura have proved challenging because of the episodic and unpredictable nature of migraine attacks. Two patients with signs of acute ischemic stroke were evaluated for thrombolysis and turned out to suffer from familial hemiplegic migraine. It was possible to record the early phase of the hemiplegic aura with computed tomography with perfusion sequences and magnetic resonance imaging. We found cerebral hypoperfusion in the relevant cortical areas within the first hour after onset of aura symptoms. This report supports the concept that migraine aura across the migraine spectrum is caused by similar mechanisms. In a setting with efficient cooperation between headache and stroke neurologists, thrombolysis centers provide the set-up and opportunity to record aura symptoms at an early phase. Furthermore, in the time of ready access to acute systemic thrombolysis treatment, these cases underscore the importance of an accurate headache history, especially in younger patients.     

Familial hemiplegic migraine in pediatric patients: A genetic,clinical, and follow-up study

Objective

The aim of this study was to describe a cohort of pediatric patients with genetically confirmed familial hemiplegic migraine (FHM). The knowledge of genotype–phenotype correlations may suggest prognostic factors associated with severe phenotypes.

Background

Hemiplegic migraine is a rare disease and data concerning the pediatric population are even more rare as they are often extrapolated from mixed cohorts.

Methods

We selected patients who met International Classification of Headache Disorders, third edition criteria for FHM, who had a molecular diagnosis, and whose first attack occurred under the age of 18 years.

Results

We enrolled nine patients (seven males and two females) first referred to our three centers. Three of the nine (33%) patients had calcium voltage-gated channel subunit alpha1 A (CACNA1A) mutations, five (55%) had ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) mutations, and one had both genetic mutations. The patients experienced at least one aura feature other than hemiplegia during the first attack. The mean (SD) duration of HM attacks in the sample was 11.3 (17.1) h; 3.8 (6.1) h in the ATP1A2 group, and 24.3 (23.5) h in the CACNA1A group. The mean (SD, range) duration of follow-up was 7.4 (2.2, 3–10) years. During the first year from the disorder's onset, only four patients had additional attacks. Over the course of follow-up, the attack frequency overall was 0.4 attacks/year without a difference between the two groups (CACNA1A and ATP1A2).

Conclusion

The study data show that most of our patients with early-onset FHM experienced infrequent and non-severe attacks, which improved over time. Furthermore, the clinical course revealed neither the appearance of novel neurological disorders or a deterioration of basic neurological or cognitive functioning.     

Migraine with prolonged aphasic aura associated with a CACNA1A mutation: A case report and narrative review

Objective

To demonstrate that a known CACNA1A variant is associated with a phenotype of prolonged aphasic aura without hemiparesis.

Background

The usual differential diagnosis of prolonged aphasia without hemiparesis includes vascular disease, seizure, metabolic derangements, and migraine. Genetic mutations in the CACNA1A gene can lead to a myriad of phenotypes, including familial hemiplegic migraine (FHM) type 1, an autosomal dominant disorder characterized by an aura of unilateral, sometimes prolonged weakness. Though aphasia is a common feature of migraine aura, with or without hemiparesis, aphasia without hemiparesis has not been reported with CACNA1A mutations.

Methods

We report the case of a 51-year-old male who presented with a history of recurrent episodes of aphasia without hemiparesis lasting days to weeks. His headache was left sided and was heralded by what his family described as “confusion.” On examination, he had global aphasia without other focal findings. Family history revealed several relatives with a history of severe headaches with neurologic deficits including aphasia and/or weakness. Imaging revealed T2 hyperintensities in the left parietal/temporal/occipital regions on MRI scan with corresponding hyperperfusion on SPECT. Genetic testing revealed a missense mutation in the CACNA1A gene.

Conclusions

This case expands the phenotypic spectrum of the CACNA1A mutation and FHM to include prolonged aphasic aura without hemiparesis. Our patient's SPECT imaging demonstrated hyperperfusion in areas correlating with aura symptoms which can occur in prolonged aura.     

Is familial hemiplegic migraine a hereditary form of basilar migraine?

We studied aura symptoms in 83 patients from 6 unrelated families suffering from familial hemiplegic migraine. Fifty-five of the patients reported symptoms that allowed us to categorize them as basilar migraine (BM) patients, in accordance with the International Headache Society (IHS) criteria. In a control group of 33 patients suffering from migraine with aura and 33 patients suffering from migraine without aura, 9 patients complained of vertigo, and only one patient of diplopia during one of her attacks. None of these control patients fulfilled the IHS criteria for BM We suggest that familial hemiplegic migraine and BM may share certain pathophysiologic mechanisms, which may consist of a (genetically determined) disturbance of basilar artery blood flow.     

Familial hemiplegic migraine presenting as recurrent encephalopathy in a Native Indian family

BACKGROUND: Familial hemiplegic migraine (FHM) is an autosomal dominant disorder, which can result from mutations in the CACNA1A (FHM1) and ATP1A2 (FHM2) genes. Typically, FHM presents with an aura of hemiplegia accompanied by a moderate-to-severe headache. FHM can be associated with other neurological findings including coma and seizures. METHODS: We describe the clinical and genetic features of a two-generation, seven-member Native Indian family with recurrent encephalopathy and FHM. RESULTS: Two of the three affected family members presented initially with encephalopathy, the third family member presented with classic episodes of migraine and hemiparesis. The CACNA1A gene locus was excluded in this family by haplotype analysis and no mutations were identified in the coding region of the ATP1A2 gene by direct sequencing. CONCLUSIONS: This emphasizes the genetic and clinical heterogeneity in familial hemiplagic migraine FHM and highlights the need to consider the diagnosis of FHM in cases of recurrent encephalopathy.     

Delayed Onset Dystonia Following Hemiplegic Migraine

SYNOPSIS
A 22-year-old woman developed complete left hemiplegia and sensory loss during an attack of migraine. She recovered almost totally but two months later incoordination and twisting of the left limb was noticeable. Examination showed tremor of the left arm and dystonia of the hand and foot secondary to a small infarction of the right posterolateral thalamic nuclei. Late onset dystonia may be another sequela of complicated migraine.     

Spreading Depolarization May Link Migraine and Stroke

Migraine increases the risk of stroke, particularly in young and otherwise healthy adults. Being the most frequent neurological condition, migraine prevalence is on a par with that of other common stroke risk factors, such as diabetes or hypertension. Several patterns of association have emerged: (1) migraine and stroke share a common association (eg, vasculopathies, patent foramen ovale, or pulmonary A‐V malformations); (2) injury to the arterial wall such as acute arterial dissections can present as migraine aura attacks or stroke; (3) strokes rarely develop during a migraine attack, as described for “migrainous stroke.” Increasing experimental evidence suggests that cerebral hyperexcitability and enhanced susceptibility to spreading depolarization, the electrophysiologic event underlying migraine, may serve as a mechanism underlying the migraine‐stroke association. Mice carrying human vascular or neuronal migraine mutations exhibit an enhanced susceptibility to spreading depolarization while being particularly vulnerable to cerebral ischemia. The severe stroke phenotype in migraine mutant mice can be prevented by suppressing spreading depolarization. If confirmed in the clinical setting, inhibiting spreading depolarization might protect migraineurs at stroke risk as well as decrease attacks of migraine.     

Investigation of neuromuscular transmission in some rare types of migraine

The aim of this study was to delineate any dysfunction of neuromuscular transmission (NMT) by single-fibre electromyography (SFEMG) in some rare types of migraine. Recent studies have shown subclinical dysfunction of NMT in migraine with aura and cluster headache by using SFEMG, whereas another recent study has shown NMT to be normal in familial hemiplegic migraine (FHM) with CACNA1A mutations. Thirty patients with rare primary headache syndromes [18 with sporadic hemiplegic migraine (SHM), six with FHM and six with basilar-type migraine (BM)] and 15 healthy control subjects without any headache complaints underwent nerve conduction studies, EMG and SFEMG during voluntary contraction of the extensor digitorum communis muscle. Ten to 20 different potential pairs were recorded and individual jitter values calculated. The results obtained from patient groups were compared with those from the normal subjects. Of 600 individual jitter values of the patients, 27 (4.5%) were abnormally high, whereas only 3/205 (1.5%) jitter values from normal subjects were abnormal. Abnormal NMT was found in 4/30 (13.3%) patients (three SHM and one BM), but in none of the control subjects. Only in SHM patients was the number of individual abnormal jitter values slightly but significantly different from normal controls. The present study demonstrates that subclinical NMT abnormality is slightly present in only SHM and BM patients, but not in FHM patients.     

Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders

Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, CACNA1A, ATP1A2, and SCN1A can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarization thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include KCKN18, PRRT2, and CSNK1D, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the TREX1 and COL4A1 also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome‐wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common migraine. Further studies are required to fully understand these findings and translate them into treatment options for migraine patients.     

Migraine Genetics: Part II

Migraine clusters in families and is considered to be a strongly heritable disorder. Hemiplegic migraine is a rare subtype of migraine with aura that may occur as a familial or a sporadic condition. Three genes have been identified studying families with familial hemiplegic migraine (FHM). The first FHM gene that was identified is CACNA1A. A second gene, FHM2, has been mapped to chromosome 1 q 21‐23. The defect is a new mutation in the α2 subunit of the Na/K pump (ATP1A2). A third gene (FHM3) has been linked to chromosome 2q24. It is due to a missense mutation in gene SCN1A (Gln1489Lys), which encodes an α1 subunit of a neuronal voltage‐gated Na+ channel. Genome‐wide association studies have identified many non‐coding variants associated with common diseases and traits, like migraine. These variants are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites. A role has been suggested for the two‐pore domain potassium channel, TWIK‐related spinal cord potassium channel. TWIK‐related spinal cord potassium channel is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine.