Hemiplegic Migraine Research Articles

Efficacy of anti-calcitonin gene-related peptide monoclonal antibodies in hemiplegic migraine: a case report and review of literature

Hemiplegic migraine (HM) is a rare subtype of migraine with aura characterized by transient unilateral motor weakness during attacks. Although monoclonal antibodies (mABs) targeting the calcitonin gene-related peptide (CGRP) pathway have shown efficacy in migraine prevention, their role in HM remains largely unexplored, since these patients are generally excluded from randomized clinical trials aimed at developing migraine preventive drugs. We present a case of a middle-aged woman with chronic migraine and recurrent hemiplegic episodes treated with fremanezumab. After 11 months of monthly 225 mg subcutaneous fremanezumab injections, the patient experienced a substantial reduction in monthly headache days, aura episodes, and symptom severity, without safety concerns. This case adds to the emerging evidence supporting CGRP mABs as a potential therapeutic option for HM. Further research is needed to elucidate their precise mechanism and determine their efficacy in broader HM populations.

Apparent efficacy of NMDAR antagonist use as a targeted therapy for status epilepticus in an infant with ATP1A2-related developmental epileptic encephalopathy.

Apparent efficacy of NMDAR antagonist use as a targeted therapy for status epilepticus in an infant with ATP1A2-related developmental epileptic encephalopathy.

CACNA1A-related familial hemiplegic migraine presenting with prolonged impaired consciousness

CACNA1A-related familial hemiplegic migraine presenting with prolonged impaired consciousness

Differential Regulation of Nav1.1 and SCN1A Disease Mutant Sodium Current Properties by Fibroblast Growth Factor Homologous Factors.

Fibroblast growth factor homologous factors (FHFs) regulate the activity of several different voltage-gated sodium channels (Navs). However, more work is needed to determine how specific FHF isoforms and variants affect the properties of different Nav isoforms. In addition, it is not known if FHFs can differentially modulate the properties of Nav variants associated with disease. Here, we investigated the effects of FHF2A and FHF2B on Nav1.1 properties as well as on a familial hemiplegic migraine 3 (FHM3) causing mutation in this channel, F1774S. We found that FHF2A, but not 2B, induced prominent long-term inactivation (LTI) in the wild-type (WT) Nav1.1. Interestingly, FHF2A induced LTI in the F1774S FHM3 mutant channel to a greater extent than in the WT. Furthermore, persistent currents caused by the F1774S mutation were attenuated by the co-expression of FHF2A, leading to a possible rescue of the mutant channel phenotype. By contrast, the P1894L mutation, which is associated with epilepsy and mild intellectual disability, greatly attenuated the LTI induced by FHF2A. Overall, our data show for the first time that FHF2A might be a significant modulator of Nav1.1 that can differentially modulate the impact of Nav1.1 disease-associated mutations.

Abnormality of Voltage-Gated Sodium Channels in Disease Development of the Nervous System. A Review Article.

Sodium channels are necessary for electrical activity in modules of the nervous system. When such channels fail to work properly, it may cause different neurological diseases. This review will discuss how particular mutation in these channels leads to different diseases. Positive alterations can lead to such diseases as epilepsy, or any muscle disorder due to over activation of neurons. Conversely, loss-of-function mutations may cause heart diseases and problems regarding motor and mental activity since neurons are not functioning well because of lost machinery. The review would discuss over familiar channelopathies such as genetic epilepsies, the familial hemiplegic migraine, and Para myotonia congenital and relatively new interrelations with the complex ailments including Alzheimer's, Parkinson's and multiple sclerosis. Thus, knowledge of these mechanisms is important in designing specific therapeutic approaches. There is a rationale for altering the sodium channel activity in the treatment of these neurological disorders by drugs or indeed genetic methods. Thus, the review is undertaken to provide clear distinctions and discuss the issues related to sodium channel mutations for the potential development of individualized medicine. The review also gives information on the function and general distribution of voltage-gated sodium channels (VGSCs), how their activity is controlled, and what their structure is like. The purpose therefore is to draw understanding over the apparently multifaceted functions exerted by VGSCs in the nervous system relative to several diseases. This knowledge is imperative in the attempt to produce treatments for these disabling disorders.

Expanding the Genetic and Clinical Spectrum of SCN1A-Related Hemiplegic Migraine: Analysis of Mutations in Japanese.

Familial hemiplegic migraine (FHM) is characterized by repeated episodes of reversible localized neurological deficits, in addition to headache. The aura of HM includes visual, sensory, motor, and verbal symptoms. Hemiplegic migraine (HM) is classified into non-familial sporadic HM (SHM) and familial HM (FHM). Here, we analyzed the clinical symptoms and their relevance in four Japanese patients considered to have SCN1A mutations as a cause. Sequencing of SCN1A was performed using a whole exome sequence method in 48 blood samples from clinically suspected patients with FHM. Subsequently, algorithm analysis, allele frequency determination, and three-dimensional structure analysis of the recognized variants were performed, and the recognized variants were evaluated. We found five heterozygous missense mutations (p.A23E, p.V250L, p.T398M, p.R1575C, p.L1660I) in SCN1A, three of which had not been reported. These five mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural analysis. In all cases, the clinical symptoms included visual, sensory, motor, and verbal symptoms, which are forms of aura. Similarities were detected, such as the appearance of symptoms at a young age and other symptoms, such as hemiplegia after a headache attack. We report five missense mutations in SCN1A of Japanese cases.

A Longitudinal Exploration of CACNA1A-Related Hemiplegic Migraine in Children Using Electronic Medical Records.

Since the initial description of CACNA1A-related hemiplegic migraine (HM), the phenotypic spectrum has expanded from mild episodes in neurotypical individuals to potentially life-threatening events frequently seen in individuals with developmental and epileptic encephalopathies. However, the overall longitudinal course throughout childhood remains unknown. We analyzed HM and seizure history from electronic medical records in individuals with CACNA1A-related HM, delineating frequency and severity of events in monthly increments through a standardized approach. Combining these data with medication prescription information, we assessed the response of HM to different agents. Our cohort involved 15 individuals between 3 and 29 years (163 patient years) and included 11 unique and 2 recurrent variants (p.R1349Q and p.V1393M; both n = 2). The age of first confirmed HM ranged from 14 months to 13 years (average 3 years). 25% of all HM events were severe (lasting >3 days), and 73% of individuals had at least 1 severe occurrence. Spacing of HM events ranged from 1 month to 14 years, and changes in HM severity over time showed increases or decreases of >2 severity levels in 12 of 122 events. Eight individuals had epilepsy, but severity of epilepsy was only weakly correlated with frequency and severity of HM events. While levetiracetam (n = 6) and acetazolamide (n = 5) were the most frequently used medications, they did not show efficacy in HM prevention or severity reduction. However, verapamil (risk differences [RD] 0.10, CI 0.05-0.15) and valproate (RD 0.08, CI 0.04-0.12) were associated with a modest prevention of HM, but not reduction in severity. The longitudinal course of CACNA1A-related HM lacks recognizable patterns for timing and severity of HM events or strong correlation with seizure patterns. Our data underscore the unpredictability of CACNA1A-related HM, highlighting the need for close surveillance for reoccurring HM events even in individuals with symptom-free periods.

Combined effects of cannabidiol and Δ9-tetrahydrocannabinol alleviate migraine-like symptoms in mice.

The therapeutic use of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) to treat migraine has been understudied. Using three mouse models, we examined the impact of CBD and THC on migraine-relevant behaviors triggered by: 1) calcitonin gene-related peptide (CGRP), 2) sodium nitroprusside (SNP), and 3) cortical spreading depolarization (CSD). Both male and female CD1 mice were treated with CBD (100 mg/kg) or THC (1 mg/kg) alone or in combinations of CBD (1, 30 or 100 mg/kg) and THC (1 mg/kg) prior to injection of CGRP or SNP. The mice were assessed for light aversion (photophobia), squint (non-evoked pain), and periorbital tactile hypersensitivity, as well as possible adverse effects. In a separate set of experiments, CSD events were optogenetically induced in familial hemiplegic migraine 1 (FHM1) mutant and wildtype littermates (WT) mice (C57BL/6 background), followed by grimace and motor assessments with and without combinations of CBD (30 or 100 mg/kg) and THC (1 mg/kg). In CD1 mice, a 100:1 CBD:THC combination mitigated light aversion induced by CGRP and SNP in males and females. Rescue of CGRP- and SNP-induced squint was observed only in male mice with 100:1 CBD:THC. None of the treatments rescued periorbital tactile hypersensitivity in either sex. In FHM1 mutant and WT mice, the 100:1 CBD:THC ratio did not affect CSD characteristics but did reduce CSD-induced grimace features (i.e., head pain mimic). No adverse effects of any of the cannabinoid treatments were observed using cognitive, emotional, or motor tests. A 100:1 ratio of CBD:THC has a beneficial effect on some of the most bothersome migraine-related symptoms in three mouse models. Our findings support a potential therapeutic efficacy of combined CBD and THC treatments.

Exploring the association between familial hemiplegic migraine genes (CACNA1A, ATP1A2 and SCN1A) with migraine and epilepsy: A UK Biobank exome-wide association study.

Familial hemiplegic migraine (FHM) types 1-3 are associated with protein-altering genetic variants in CACNA1A, ATP1A2 and SCN1A, respectively. These genes have also been linked to epilepsy. Previous studies primarily focused on phenotypes, examining genetic variants in individuals with characteristic FHM symptoms. This study aimed to investigate the association of FHM genetic variation with migraine and epilepsy, utilizing a genotype-first approach. Whole-exome sequence data from 454,706 individuals from the UK Biobank were examined for self-reported and inpatient-diagnosed migraine and epilepsy. Carriers were compared with non-carriers in a burden analysis using logistic regression while accounting for age, biological sex and UK Biobank assessment center. A machine learning-based approach was employed to predict whether variants resulted in gain-of-function (GoF), loss-of-function (LoF) or neutral effects. Heterozygous carriers of GoF CACNA1A variants, LoF ATP1A2 variants or neutral SCN1A variants were at increased risk of migraine. Homozygous carriers of neutral SCN1A variants were also associated with migraine but these carriers showed a reduced disease risk of epilepsy. Heterozygous genotypes in all three FHM genes were associated with migraine but not epilepsy in this genotype-focused study. Homozygous SCN1A genotypes also showed increased disease risk of migraine, yet these carriers were protected against epilepsy.

Association between CACNA1A and ATP1A2 Variants are Responsible for Severe Neurodevelopmental Disorder.

ATP1A2 and CACNA1A genes encode proteins forming transmembrane channels, Na+/K+/ATPase transporter, and voltage-gated calcium channels, respectively. Pathogenic variants in these genes are associated with hemiplegic migraines, movement disorders, and developmental and epileptic encephalopathy.We report a child presenting epileptic encephalopathy with cognitive and behavioral troubles. He carries a likely pathogenic variant in the ATP1A2 gene, inherited from his mother who presents hemiplegic migraines, and a variant of uncertain significance in the CACNA1A gene, inherited from his asymptomatic father and also found in his brother, who presents a milder neurodevelopmental disorder (NDD). No other significant copy number or single nucleotide variations were identified after an in-depth genetic study including whole exome sequencing, array comparative genomic hybridization, and screening for Fragile X and Prader-Willi/Angelman syndromes.We illustrate the synergetic impact of ATP1A2 and CACNA1A genes in NDDs.

It’s all in the History - Hemiplegic Migraine versus Stroke due to Arterial Dissection: A Case Report

It’s all in the History - Hemiplegic Migraine versus Stroke due to Arterial Dissection: A Case Report

A case of hemiplegic migraine with regional cerebral hypoperfusion and focal cortical diffusion restriction by MRI.

A case of hemiplegic migraine with regional cerebral hypoperfusion and focal cortical diffusion restriction by MRI.

Clinical characterization of a novel ATP1A2 p.Gly615Glu mutation in nine family members with familial hemiplegic migraine.

Familial hemiplegic migraine type 2 results from pathogenic variants in the ATP1A2 gene, which encodes for a catalytic subunit of sodium/potassium ATPase. This extremely rare autosomal dominant disorder manifests with a spectrum of symptoms, most commonly pure hemiplegic phenotype, epilepsy, and/or intellectual disability. In this study, we detail the clinical features and genetic analysis of nine patients from a large family spanning four generations, with all carrying a previously unreported likely pathogenic variant, p.Gly615Glu, in ATP1A2, compatible with a diagnosis of familial hemiplegic migraine type 2, fully penetrant with variable expressivity. This newly identified likely pathogenic variant primarily presented with psychiatric disturbances and a non-hemiplegic phenotype. Only one patient presented hemiplegic attacks, while seven were diagnosed with migraine with aura, including visual, sensory, and speech/language aura, and one with migraine without aura. The identification of the genes responsible for the more common forms of migraine, both with and without aura, remains a significant challenge in migraine genetics and is critical for advancing personalized medicine.

Hemiplegic Migraine with Hemibody Dysautonomia: First Presentation of Hemiplegic Migraine with CT Perfusion and Electrographic Abnormalities Triggered by Influenza B Infection

Hemiplegic Migraine with Hemibody Dysautonomia: First Presentation of Hemiplegic Migraine with CT Perfusion and Electrographic Abnormalities Triggered by Influenza B Infection

Targeting Na,K-ATPase-Src signaling to normalize cerebral blood flow in a murine model of familial hemiplegic migraine

Familial hemiplegic migraine type 2 (FHM2) is linked to Na,K-ATPase α2 isoform mutations, including that of G301R. Mice heterozygous for this mutation ( α 2 + / G3 0 1R ) show cerebrovascular hypercontractility associated with amplified Src kinase signaling, and exaggerated neurovascular coupling. This study hypothesized that targeting Na,K-ATPase-dependent Src phosphorylation with pNaKtide would normalize cerebral perfusion and neurovascular coupling in α 2 + / G3 0 1R mice. The effect of pNaKtide on cerebral blood flow and neurovascular coupling was assessed using laser speckle contrast imaging in awake, head-fixed mice with cranial windows in a longitudinal study design. At baseline, compared to wild type, α 2 + / G3 0 1R mice exhibited increased middle cerebral artery tone; with whisker stimulation leading to an exaggerated increase in sensory cortex blood flow. No difference between genotypes in telemetrically assessed blood pressure occurred. The exaggerated neurovascular coupling in α 2 + / G3 0 1R mice was associated with increased Kir2.1 channel expression in cerebrovascular endothelium. Two weeks pNaKtide treatment normalized cerebral artery tone, endothelial Kir2.1 expression, and neurovascular coupling in α 2 + / G3 0 1R mice. Inhibition of the Na,K-ATPase-dependent Src kinase signaling with pNaKtide prevented excessive vasoconstriction and disturbances in neurovascular coupling in α 2 + / G3 0 1R mice. pNaKtide had only minor hypotensive effect similar in both genotypes. These results demonstrate a novel treatment target to normalize cerebral perfusion in FHM2.

A structural analysis of the splice-specific functional impact of the pathogenic familial hemiplegic migraine type 1 S218L mutation on Cav2.1 P/Q-type channel gating

P/Q-type (Cav2.1) calcium channels mediate Ca2+ influx essential for neuronal excitability and synaptic transmission. The CACNA1A gene, encoding the Cav2.1 pore forming subunit, is highly expressed throughout the mammalian central nervous system. Alternative splicing of Cav2.1 pre-mRNA generates diverse channel isoforms with distinct biophysical properties and drug affinities, which are differentially expressed in nerve tissues. Splicing variants can also affect channel function under pathological conditions although their phenotypic implication concerning inherited neurological disorders linked to CACNA1A mutations remains unknown. Here, we quantified the expression of Cav2.1 exon 24 (e24) spliced transcripts in human nervous system samples, finding different levels of expression within discrete regions. The corresponding Cav2.1 variants, differing by the presence (+) or absence (Δ) of Ser-Ser-Thr-Arg residues (SSTR) in the domain III S3-S4 linker, were functionally characterized using patch clamp recordings. Further, the + /ΔSSTR isoforms were used to demonstrate the differential impact of the Familial Hemiplegic Migraine Type 1 (FHM-1) S218L mutation, located in the domain I S4-S5 linker, on the molecular structure and electrophysiological properties of Cav2.1 isoforms. S218L has a prominent effect on the voltage-dependence of activation of +SSTR channels when compared to ΔSSTR, indicating a differential effect of the mutation depending on splice-variant context. Structural modeling based upon Cav2.1 cryo-EM data provided further insight reflecting independent contributions of amino acids in distant regions of the channel on gating properties. Our modelling indicates that by increasing hydrophobicity the Leu218 mutation contributes to stabilizing a structural conformation in which the domain I S4-S5 linker is oriented alongside the inner plasma membrane, similar to that occurring when S4 is translocated upon activation.The SSTR insertion appears to exert an influence in the local electric field of domain III due to an change in the distribution of positively charged regions surrounding the voltage sensing domain, which we hypothesize impacts its movement during the transition to the open state. In summary, we reveal molecular changes correlated with distinct functional effects provoked by S218L FHM-1 mutation in hCav2.1 splice isoforms whose differential expression could impact the manifestation of the neurological disorder.

Treatment of thoracic outlet syndrome to relieve chronic migraine.

Prior case reports have suggested that treating thoracic outlet syndrome (TOS) may relieve intractable migraine headaches, but there has been no case series large enough to show when underlying TOS should be suspected as a contributor to migraine burden. This observational followed by questionnaire study was performed in an outpatient neurology practice to identify clinical features of patients with migraine in which TOS contributed to migraine burden. We report the clinical features of 50 consecutive patients (48 women, 2 men, age = 43.9+/12.7 years) who were treated for chronic migraine and TOS (20 migraine with aura, 28 migraine without aura, two hemiplegic migraines). Headaches had become chronic within 1 year of onset in 21 patients (42%) with characteristics as follows (percentages are based on known data): greater severity ipsilateral to TOS limb pain (38/50=76%), presence of limb swelling (32/48=67%), and worsened by recumbency (32/38=84%). Thirty-two patients eventually needed surgery, which included percutaneous transluminal venoplasty, 1st rib removal, scalenectomy, pectoralis minor tenotomy, and/or vein patching. The mean improvement of headaches on the treated side was 72 ± 26.7%; 12 patients experienced complete resolution of headaches after treatment of TOS (follow-up 7.2 ± 5.2 months). Questionnaire responders reported significant reductions in headache days (18.3 ± 8.6 to 11.1 ± 10.8 days/month, p < 0.0016), severity (7.8+/2.5 to 5.4 ± 2.9, p < 0.00079), and need for emergency care (3.6 ± 4.0 to 0.71 ± 1.3 visits/year, p < 0.0029). Chronic migraines can be important manifestations of TOS. Early transition to a chronic state, lateralized limb pain, and headaches worsened by recumbency are clues to the contribution of TOS pathology. Addressing the TOS contribution to migraine can significantly reduce migraine headache burden.

MIGRAINE

Background Migraine is a prevalent neurological disorder characterized by chronic headaches, significantly impacting the global population. This comprehensive review aims to advance the understanding of migraine pathogenesis and treatment, focusing on molecular markers and novel therapeutic strategies. Material Molecular markers such as calcitonin gene-related peptide (CGRP) and their role in migraine development. Traditional medical treatments and emerging therapeutic strategies, including neuromodulation, are analyzed for their effectiveness and limitations. Clinical studies and imaging techniques are leveraged to identify key mechanisms and triggers in migraine pathology. Approximately 95% of people experience a headache at some point, with migraines being a significant contributor. Migraine is recognized by the World Health Organization as one of the top ten causes of disability globally, particularly affecting women. CGRP is identified as a crucial factor in migraine development. Inhibitors targeting CGRP have shown significant effectiveness in managing migraines. Other molecular markers, including proinflammatory cytokines and neurotransmitters, are discussed for their roles in pain transmission and migraine pathophysiology. Traditional treatments, such as triptans and NSAIDs, are evaluated alongside new therapies, including CGRP inhibitors and neuromodulation techniques. Neuromodulation, involving devices like external trigeminal nerve stimulators, shows promise in migraine management. Genetic markers associated with familial hemiplegic migraine (FHM) and common migraine forms are reviewed. Recent genome-wide association studies (GWAS) have identified several genetic variants linked to migraine susceptibility. Conclusion This presentation enhances the understanding of migraine pathogenesis and introduces novel therapeutic possibilities. By focusing on molecular markers like CGRP and exploring advanced treatment options, the study aims to improve migraine management and patient care. The findings underscore the need for continued research and innovation in migraine treatments to reduce the global burden of this debilitating condition.

De novo SCN1A missense variant in a patient with Parkinson's disease.

Variants in a gene encoding sodium voltage-gated channel alpha subunit 1 (SCN1A) are known to cause a broad clinical spectrum of epilepsy and associated features, including Dravet syndrome (MIM 607208), non-Dravet developmental and epileptic encephalopathy (MIM 619317), familial febrile seizures (MIM 604403), familial hemiplegic migraine (MIM 609634), and generalized epilepsy with febrile seizures (MIM 604403). In this study, we examined a patient with Parkinson's disease (PD) without any clinical manifestations of epilepsy and associated features. Genomic nucleic acid was extracted, and a complete coding sequence of the human genome (whole-exome sequencing) was sequenced. Moreover, Sanger sequencing of variants of interest was performed to validate the exome-discovered variants. We identified a heterozygous pathogenic missense mutation (c.1498C>T; p.Arg500Trp) in the SCN1A gene in the patient using the whole-exome sequencing approach. The onset of PD features in our patient occurred at the age of 30 years. Biochemical investigations were carried out to rule out any secondary cause of the disease, including Wilson's disease or another metabolic disorder. MRI of the brain and spinal images were unremarkable. Moreover, a dramatic response to carbidopa-levodopa treatment was also observed in the patient. Our results suggest that the pathogenic variant in SCN1A may lead to PD features without epilepsy.

Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2

Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2