Investigating the causal association between systemic lupus erythematosus and migraine using Mendelian randomization analysis.

OBJECTIVE: To assess whether systemic lupus erythematosus (SLE) may be genetically causally associated with migraine, including the two primary subtypes: migraine with aura (MWA) and migraine without aura (MWoA). BACKGROUND: The association between SLE and migraine has been investigated extensively. Previous studies have shown a higher prevalence of migraine in patients with SLE, although the exact relationship remains unclear. This study investigated the potential causal association between SLE and migraine using the powerful analytical tool of Mendelian randomization (MR). METHODS: We performed two-sample MR analysis of publicly available summary statistic datasets using inverse variance-weighted (IVW), weighted median, and MR-Egger methods based on an SLE genome-wide association study (GWAS; 5201 cases; 9066 controls; the exposure frequency is 36.5%) as an exposure and migraine GWAS (15,905 cases; 264,662 controls) in individuals with European ancestry as outcomes, focusing on the two migraine subtypes MWA (6780 cases; 264,662 controls) and MWoA (5787 cases; 264,662 controls). Thepleiotropy and heterogeneity were performed. RESULTS: We selected 42 single-nucleotide polymorphisms from SLE GWAS as instrumental variables (IVs) for SLE on migraine, and 41 SNP IVs for SLE on MWA or MWoA. The IVW (odds ratio [OR] = 1.01, 95% confidence interval [CI] = [0.99, 1.03], p = 0.271), weighted median (OR = 1.00, 95% CI = [0.97, 1.03], p = 0.914), and MR-Egger (OR = 1.04, 95% CI = [0.99, 1.09], p = 0.153) methods showed no causal effect of SLE on migraine. A causal effect of SLE was observed on MWA (IVW: OR = 1.05, 95% CI = [1.02, 1.08], p = 0.001; weighted median: OR = 1.05, 95% CI = [1.01, 1.10], p = 0.018; MR-Egger: OR = 1.07, 95% CI = [1.01, 1.14], p = 0.035 and pIVW < 0.017 [Bonferroni correction]) but not MWoA (IVW: OR = 0.99, 95% CI = [0.96, 1.02], p = 0.331; weighted median: OR = 0.98, 95% CI = [0.94, 1.03], p = 0.496; MR-Egger: OR = 1.02, 95% CI = [0.95, 1.09], p = 0.652). The results showed no significant pleiotropy or heterogeneity. CONCLUSION: Our MR analysis demonstrated the complex relationship between SLE and migraine, suggesting a potential effect of SLE on the risk of MWA but not MWoA. These findings can aid in the development of improved subtype-specific management of migraine in patients with SLE.

Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and Emerging Approaches.

Migraine is a severe, debilitating neurovascular disorder. Hemiplegic migraine (HM) is a rare and debilitating neurological condition with a strong genetic basis. Sequencing technologies have improved the diagnosis and our understanding of the molecular pathophysiology of HM. Linkage analysis and sequencing studies in HM families have identified pathogenic variants in ion channels and related genes, including CACNA1A, ATP1A2, and SCN1A, that cause HM. However, approximately 75% of HM patients are negative for these mutations, indicating there are other genes involved in disease causation. In this review, we explored our current understanding of the genetics of HM. The evidence presented herein summarises the current knowledge of the genetics of HM, which can be expanded further to explain the remaining heritability of this debilitating condition. Innovative bioinformatics and computational strategies to cover the entire genetic spectrum of HM are also discussed in this review.

The right amygdala and migraine: Analyzing volume reduction and its relationship with symptom severity.

This study aimed to explore the relationship between gray matter volume changes and various clinical parameters in patients with migraine, focusing on symptom severity, quality of life, and states of depression and anxiety. Using a case-control design, we examined 33 patients with migraine, with or without aura, and 27 age-matched healthy subjects. We used magnetic resonance imaging to assess the volumes of 140 bilateral brain regions. Clinical evaluations included the Migraine Disability Assessment, the Migraine Specific Quality of Life Questionnaire, the Center for Epidemiologic Studies Depression scale, Spielberger's State and Trait Anxiety scales, and the Japanese version of the Montreal Cognitive Assessment. We compared the scores of these measures between migraine patients and healthy controls to examine the interplay between brain structure and clinical symptoms. Significant volumetric differences were observed in the pallidum and amygdala between migraine patients and healthy individuals. The reduction in the right amygdala volume correlated significantly with migraine severity as measured by the Migraine Disability Assessment. Path analysis revealed a model where Migraine Disability Assessment scores were influenced by Migraine Specific Quality of Life Questionnaire outcomes, which were further affected by depression, anxiety, and a low right pallidum volume. Our findings suggest that the chronicity and severity of migraine headaches specifically affect the right amygdala. Our path model suggests a complex relationship whereby migraine disability is strongly influenced by quality of life, which is, in turn, affected by psychological states, such as anxiety and depression.

Calcitonin gene-related peptide: a possible biomarker in migraine patients with patent foramen ovale.

BACKGROUND: Serum CGRP has been found to increase during migraine attack. However, whether CGRP can identify MA with PFO subtypes in MA remains unknown. This study aimed to investigate the differential expression of calcitonin gene-related peptide (CGRP) between migraine (MA) patients with and without patent foramen ovale (PFO), and to evaluate the predictive value of CGRP for MA with PFO. METHODS: A total of 153 patients with MA, 51 patients with PFO and 102 patients without. Venous blood was drawn and HIT-6 score was calculated during the onset of MA, and blood routine, inflammatory indexes and serum CGRP were detected. The differences in serum markers and HIT-6 scores were compared between the two groups, and the risk factors of MA with PFO were determined by univariate and multivariate logistics regression. Furthermore, the correlation between CGRP level with right-to-left shunt (RLS) grades and headache impact test-6 (HIT-6) score in MA patients with PFO were assessed. Independent risk factors were screened out by multivariate Logistic regression analysis. We used the receiver operating characteristic (ROC) curve to analyze the diagnostic value of these risk factors in MA complicated with PFO. RESULTS: The serum CGRP level and HIT-6 scores in the MA with PFO group were significantly higher than those in the MA group (P < 0.001). Multivariate regression analysis showed that CGRP was an independent risk factor for MA with PFO (OR = 1.698, 95% CI = 1.325-2.179, P < 0.001). CGRP values ​​increased with the increase of RLS grade(Spearmen rho = 0.703, P < 0.001). Furthermore, a positive correlation between CGRP and HIT-6 scores was found (Spearmen rho = 0.227; P = 0.016). ROC curve showed that the optimal cut-off value for diagnosing MA with PFO was 79 pg/mL, the area under the curve (AUC) for predicting MA with PFO was 0.845, with 72.55% sensitivity and 78.43% specificity. CONCLUSIONS: MA patients with PFO have higher serum CGRP level. elevated CGRP concentration was associated with higher RLS grade and increased HIT-6 score. Higher serum CGRP level has certain clinical value in predicting PFO in MA patients. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine (Ethics batch number: 20,201,215,005).

Familial hemiplegic migraine in Indian children-a tertiary center experience.

Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1-18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks.

Brainstem depolarization-induced lethal apnea associated with gain-of-function SCN1AL263V is prevented by sodium channel blockade.

Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1AL263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an Scn1aL263V knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization. The L263V mutation caused gain of NaV1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1aL263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1AL263V can cause life-threatening apneic events, which in a mouse model were caused by profound brainstem depolarization. In addition to being potentially relevant to sudden infant death syndrome pathophysiology, these data indicate that sodium channel blockers may be considered therapeutic for apneic events in patients with these and other gain-of-function SCN1A mutations.

Investigations of the migraine-provoking effect of levcromakalim in patients with migraine with aura.

BACKGROUND/HYPOTHESIS: Experimental provocation studies have yielded important insights in migraine pathophysiology. Levcromakalim has been previously shown to induce migraine-like attacks with and without aura. In this study, we aim to further explore the migraine aura-inducing potential of levcromakalim. METHODS: In a double-blind, randomized, placebo-controlled cross-over study, 27 adult participants with migraine with aura received intravenous infusions of levcromakalim and saline. Headache, aura and associated symptoms were evaluated for 24 hours following administration of the study drug. The primary endpoint was occurrence of migraine-like attacks with or without aura in the 24-hour observation period. RESULTS: Thirteen participants developed migraine-like attacks on the active day only (P = 0.0098), and four participants developed aura on the active day only (P = 0.68). The median time to onset of migraine-like headache was three hours, and the median time to onset of aura was 27.5 minutes. CONCLUSION/INTERPRETATION: Our findings affirm the potent migraine-inducing effect of levcromakalim. We observed a lower induction-rate of migraine aura than previously reported. Further studies are warranted to identify predictors of migraine aura following levcromakalim. CLINICALTRIALS.GOV IDENTIFIER: NCT04905654.

Síndrome de nieve visual y su relación con la migraña / Visual snow syndrome and its relationship with migraine

Introducción El síndrome de nieve visual (SNV) es un trastorno del sistema nervioso central que implica la visión de forma constante de pequeños puntos blancos y negros en la totalidad del campo visual. Desarrollo El SNV puede presentarse desde la infancia hasta la tercera edad, siendo más frecuente en jóvenes y sin diferencia entre géneros. En sus criterios diagnósticos se incluye la presencia de nieve visual, pero también otros fenómenos visuales como palinopsia, fotofobia, nictalopía y otros fenómenos visuales persistentes. La fisiopatología del SNV es desconocida, pero se postulan como mecanismos la hiperexcitabilidad del córtex visual y una disfunción en el procesamiento visual de orden superior. La prevalencia de migraña en los pacientes con SNV es alta en comparación con la población general y cuando se presentan conjuntamente los síntomas son más severos. No se dispone de un tratamiento eficaz, pero el fármaco con mejores resultados es la lamotrigina, recomendándose únicamente en casos seleccionados con alta limitación funcional. Conclusiones El síndrome de nieve visual es una entidad poco conocida e infradiagnosticada, pero el creciente número de investigaciones durante los últimos años ha permitido definir unos criterios diagnósticos y acercarnos a su fisiopatología. Es una entidad íntimamente relacionada con la migraña, con solapamiento de síntomas y probablemente mecanismos fisiopatológicos comunes. (AU)

Introduction Visual snow syndrome (VSS) is a central nervous system disorder that consists of the constant perception of small black and white dots throughout the entire visual field. Development VSS can present from infancy to old age, with greater prevalence in the young population, and shows no difference between sexes. The diagnostic criteria include the presence of visual snow and such other visual phenomena as palinopsia, photophobia, nyctalopia, and other persistent visual phenomena. The pathophysiology of VSS is unknown, but hyperexcitability of the visual cortex and a dysfunction in higher-order visual processing are postulated as potential mechanisms. The prevalence of migraine among patients with VSS is high, compared to the general population, and symptoms are more severe in patients presenting both conditions. No effective treatment is available, but the drug with the best results is lamotrigine, which is recommended only in selected cases with severe functional limitation. Conclusions VSS is a little-known and underdiagnosed entity, but the increasing number of studies in recent years has made it possible to establish diagnostic criteria and begin studying its pathophysiology. This entity is closely related to migraine, with overlapping symptoms and probably shared pathophysiological mechanisms. (AU)

Visual migraine aura iconography: A multicentre, cross-sectional study of individuals with migraine with aura.

INTRODUCTION: Visual disturbances are the most common symptoms of migraine aura. These symptoms can be described systematically by subdividing them into elementary visual symptoms. Since visual symptoms of migraine aura are not easy to describe verbally, we developed a collection of images illustrating previously reported elementary visual symptoms. OBJECTIVES: To test a standardised visual migraine aura iconography in a large population of migraine with aura patients and to improve it based on the participants' feedback. METHODS: We created a set of images representing 25 elementary visual symptoms and a web-based survey where participants could report whether they recognised these images as part of their visual aura. Elementary visual symptoms could also be recognised via a corresponding text description or described in a free text by participants. Individuals with migraine aura recruited from four tertiary headache centres (in Switzerland, Denmark, Norway and Italy) were invited to complete the survey. RESULTS: Two hundred and fifteen participants completed the study (78.9% women, median age 36). They recognised a total of 1645 elementary visual symptoms from our predefined list. Of those, 1291 (78.4%) where recognised via standardised iconography images. A new type of elementary visual symptom was reported by one participant. CONCLUSION: Most elementary visual symptoms experienced by participants were recognised via the standardised iconography. This tool can be useful for clinical as well as research purposes.

Astrocytic Na+, K+ ATPases in physiology and pathophysiology.

The Na+, K+ ATPases play a fundamental role in the homeostatic functions of astrocytes. After a brief historic prologue and discussion of the subunit composition and localization of the astrocytic Na+, K+ ATPases, the review focuses on the role of the astrocytic Na+, K+ pumps in extracellular K+ and glutamate homeostasis, intracellular Na+ and Ca2+ homeostasis and signaling, regulation of synaptic transmission and neurometabolic coupling between astrocytes and neurons. Loss-of-function mutations in the gene encoding the astrocytic α2 Na+, K+ ATPase cause a rare monogenic form of migraine with aura (familial hemiplegic migraine type 2). On the other hand, the α2 Na+, K+ ATPase is upregulated in spinal cord and brain samples from amyotrophic lateral sclerosis and Alzheimer disease patients, respectively. In the last part, the review focuses on i) the migraine relevant phenotypes shown by familial hemiplegic migraine type 2 knock-in mice with 50 % reduced expression of the astrocytic α2 Na+, K+ ATPase and the insights into the pathophysiology of migraine obtained from these genetic mouse models, and ii) the evidence that upregulation of the astrocytic α2 Na+, K+ ATPase in mouse models of amyotrophic lateral sclerosis and Alzheimer disease promotes neuroinflammation and contributes to progressive neurodegeneration.

Migraine with brainstem aura.

Migraine with brainstem aura has been long described but remains poorly understood. Previously known as "basilar" or "basilar artery" migraine, it is an uncommon subtype of migraine with aura, one seen primarily in children, adolescents, and younger adults. The condition is characterized by migraine headache accompanied by several neurological symptoms conventionally assigned to dysfunction of brainstem structures. Initially felt to be vascular in origin, partly due to prevailing concepts of migraine pathophysiology at the time, most now believe the aura symptoms of migraine with brainstem aura are secondary to neural circuitry dysfunction. The differential diagnosis is reasonably broad, and most patients warrant investigation to exclude conditions bearing high degrees of morbidity and mortality. Neuroimaging, specifically brain MRI without contrast, is recommended for migraine with brainstem aura. Depending on the clinical presentation certain cases may require consideration of contrasted or vascular imaging, EEG, or lumbar puncture with cerebrospinal fluid analysis. Migraine prophylaxis should involve lifestyle adjustments and preventive medical therapies shown to be effective in clinical trials of migraine, following evidence-based guidelines. The acute pharmacological management of attacks of migraine with brainstem aura remains a matter of controversy. The prognosis is generally favorable. Future refinements in the diagnostic criteria might possibly enhance diagnostic specificity and improved clinical research.

Hemiplegic migraine.

Hemiplegic migraine (HM) is a rare subtype of migraine with aura in which the aura phase includes transient motor weakness. Diagnosis is based on the International Classification of Headache Disorders criteria (ICHD-3). The most important diagnostic tools remain a patient interview, neurological examination during attacks, and exclusion of other disorders, such as epilepsy, stroke, encephalitis and secondary headache syndromes. Hemiplegic migraine can occur either familial or sporadic. Three genes, CACNA1A, ATP1A2, and SCN1A have been identified. Taken together, mutations in these three genes predict increased neurotransmitter and potassium ion levels at the synaptic cleft, which facilitates cortical spreading depolarization, the phenomenon underlying the migraine aura. The presence of several symptoms, including extensive weakness and brainstem manifestations increase the likelihood of finding a monogenic cause. While the diagnosis can be confirmed by genetic testing, it cannot be excluded if one of the known (F)HM genes is not implicated. Most patients with hemiplegic migraine without a mutation in CACNA1A, ATP1A2, or SCN1A display a mild phenotype that is more akin to that of common (nonhemiplegic) migraine. Additional diagnostics such as brain imaging, cerebrospinal fluid analysis or an electroencephalography are mainly performed to exclude other causes of focal neurologic symptoms associated with hemiparesis and headache. Due to the rarity of the disorder, current treatment recommendations are based on small, unblinded studies and empirical data.

Migrainous infarction.

Migrainous infarction is defined as a migraine attack occurring as migraine with aura, typical of the patient's previous attacks, except that one or more aura symptoms persist for >60min, and neuroimaging demonstrates ischemic infarct in the relevant area. To better understand migrainous infarction, one must disentangle the complex interactions between migraine and stroke. In this chapter, we first discuss the migraine-stroke association in sections including "Increased Risks of Stroke and Subclinical Infarcts in Patients With Migraine," "Migrainous Headache Cooccurring or Triggered by Ischemic Stroke," "Stroke Progression in Patients With Migraine," and "Clinic Conditions Associated With Higher Risks of Both Migraine and Stroke." As an extreme example of migraine-stroke association, the annual incidence of migrainous infarction was reported to be 0.80/100,000/year, with the incidence in females nearly twofold that of male patients. Patients diagnosed with migrainous infarction are typically younger (average age 29-39 in case series), have fewer traditional vascular risk factors, and have more favorable prognosis compared to strokes from traditional risk factors. Thorough evaluation is recommended to rule out other etiologies of stroke. Patients diagnosed with migrainous infarction should receive antiplatelet therapy and migraine preventive therapy to avoid future events. Vasoactive medications, including triptans and ergots, should be avoided.

Retinal migraine.

Retinal migraine is usually characterized by attacks of fully reversible monocular visual loss associated with migraine headache. Retinal migraine is most common in women of child-bearing age who have a history of migraine with aura. In the typical attack, monocular visual features consist of partial or complete visual loss lasting less than 1h. Although the current diagnostic criteria for retinal migraine require fully reversible visual loss, our findings suggest that irreversible visual loss is part of the retinal migraine spectrum. Nearly half of reported cases with recurrent transient monocular visual loss subsequently experienced permanent monocular visual loss.

Persistent aura, visual snow, and other visual symptoms.

In neurology practice, it is common to encounter a variety of visual complaints. Historically, in the absence of known ocular pathology, epilepsy, or insult to the central nervous system, positive symptoms were assumed to be migrainous in origin. This assumption was sometimes made even in the absence of a history of migraine. In the past decade, there has been considerable effort to better delineate and study nonmigrainous visual phenomena, with the most extensive focus on a newly defined syndrome, visual snow syndrome (VSS). The heightened awareness of visual snow as a symptom and syndrome has greatly enhanced the understanding of this visual phenomenon; however, in the last few years, there has been an almost pendulous swing in clinic, with patients now being given the diagnosis of VSS for any dots or flickering they may have in their vision. To avoid clinical misdiagnosis, it is critical that we expand our understanding not just of VSS but also of underlying pathologies that may present similarly. This chapter will review classical migraine aura, persistent migraine aura, visual snow and a number of positive and negative visual complaints that are on the differential when seeing patients with suspected aura or visual snow. This is followed by an in-depth discussion on the current understanding of the presenting symptoms, pathophysiology, evaluation and management of VSS. We also outline secondary causes of visual snow.

Clinical features of migraine with aura: a REFORM study.

BACKGROUND: About one-third of persons with migraine experience transient neurologic symptoms, referred to as aura. Despite its widespread prevalence, comprehensive clinical descriptions of migraine with aura remain sparse. Therefore, we aimed to provide an in-depth phenotypic analysis of aura symptoms and characteristics in a cross-sectional study of a large sample of adults diagnosed with migraine with aura. METHODS: Data were extracted from the baseline characteristics of participants in the Registry for Migraine (REFORM) study - a single-center, prospective, longitudinal cohort study. Participants were adults diagnosed with migraine aura, reporting ≥ 4 monthly migraine days in the preceding 3 months. Trained personnel conducted in-person semi-structured interviews, capturing details on the nature, duration, localization, and progression of individual aura symptoms. RESULTS: Of the 227 enrolled participants with migraine with aura, the mean age was 41.1 years, with a predominant female representation (n = 205 [90.3%]). Visual aura was present in 215 (94.7%) participants, somatosensory aura in 81 (35.7%), and speech and/or language aura in 31 (13.7%). A single type of aura was observed in 148 (65.2%) participants, whilst 79 (34.8%) reported multiple aura types. Most participants (n = 220 [96.9%]) described their aura symptoms as positive or gradually spreading. Headache in relation to aura was noted by 218 (96.0%) participants, with 177 (80.8%) stating that the onset of aura symptoms preceded the onset of headache. CONCLUSIONS: This study offers a detailed clinical depiction of persons with migraine with aura, who were predominantly enrolled from a tertiary care unit. The findings highlight potential gaps in the available literature on migraine with aura and should bolster clinicians' acumen in diagnosing migraine with aura in clinical settings.