Normal glymphatic system function in patients with migraine: A pilot study.

OBJECTIVE: No studies have evaluated the glymphatic system function in patients with migraine. In this pilot study, we evaluated and compared the alterations in the glymphatic system function in patients with migraine with healthy controls using a diffusion tensor imaging (DTI) analysis along the perivascular space (DTI-ALPS) method. We also investigated the differences in the glymphatic system function table between patients with migraine with and without aura using the ALPS method. METHODS: This field study used a cross-sectional study design. We prospectively enrolled patients with migraine and healthy controls. All brain magnetic resonance imaging (MRI), including DTI, in participants, patients with migraine, and healthy controls were obtained using the same MRI scanner. We calculated and compared the ALPS index between patients with migraine and healthy controls, and between patients with migraine with and without aura. In addition, we investigated the association between the glymphatic system function and the clinical characteristics of migraine. RESULTS: We enrolled 92 patients with migraine and 80 healthy controls. There were no significant differences in the ALPS index between patients with migraine and healthy controls (1.655 ± 0.335 [patients with migraine] vs. 1.713 ± 0.297 [controls], difference = 0.058, 95% confidence interval [CI] of difference = -0.037 to 0.154, p = 0.233), and between patients with migraine with and without aura (1.690 ± 0.380 [with aura] vs. 1.645 ± 0.323 [without aura], difference = -0.044, 95% CI of difference = -0.213 to 0.124, p = 0.601). There was no significant correlation between the ALPS index and clinical characteristics of migraine, including age (r = -0.07, p = 0.507), age at onset (r = 0.07, p = 0.552), disease duration (r = -0.12, p = 0.306), attack frequency (r = -0.05, p = 0.668), and headache intensity (r = 0.00, p = 0.976). CONCLUSIONS: There was no glymphatic system dysfunction in patients with migraine. Moreover, there were no differences in the glymphatic system function between patients with migraine with and without aura. We also demonstrated the feasibility of the ALPS method, which can be used for research on various neurological diseases. Further studies are needed to confirm our findings.

Serial magnetic resonance imaging findings during severe attacks of familial hemiplegic migraine type 2: a case report.

BACKGROUND: Hemiplegic migraines represent a heterogeneous disorder with various presentations. Hemiplegic migraines are classified as sporadic or familial based on the presence of family history, but both subtypes have an underlying genetic etiology. Mutations in the ATP1A2 gene are responsible for Familial Hemiplegic type 2 (FHM2) or the sporadic hemiplegic migraine (SHM) counterpart if there is no family history of the disorder. Manifestations include migraine with aura and hemiparesis along with a variety of other symptoms likely dependent upon the specific mutation(s) present. CASE PRESENTATION: We report the case of an adult man who presented with headache, aphasia, and right-sided weakness. Workup for stroke and various infectious agents was unremarkable during the patient's extended hospital stay. We emphasize the changes in the Magnetic Resonance Imaging (MRI) over time and the delay from onset of symptoms to MRI changes in Isotropic Diffusion Map (commonly referred to as Diffusion Weighted Imaging (DWI)) as well as Apparent Diffusion Coefficient (ADC). CONCLUSIONS: We provide a brief review of imaging findings correlated with signs/symptoms and specific mutations in the ATP1A2 gene reported in the literature. Description of the various mutations and consequential presentations may assist neurologists in identifying cases of Hemiplegic Migraine, which may include transient changes in ADC and DWI imaging throughout the course of an attack.

Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway.

Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump α2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which α2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which α2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis. Functional neuroimaging reveals that conditional α2-Na/K ATPase knockout triggers spontaneous cortical spreading depression events that are associated with EEG low voltage activity events, which correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that α2-Na/K ATPase loss alters metabolic gene expression with consequent serine and glycine elevation in the brain. A serine- and glycine-free diet rescues the transient motor impairment in conditional α2-Na/K ATPase knockout mice. Together, our findings define a metabolic mechanism regulated by astrocytic α2-Na/K ATPase that triggers episodic motor paralysis in mice.

Retinal nerve fiber layer changes in migraine: A protocol for systematic review and meta-analysis.

BACKGROUND: Migraine is a common neurological disease, which seriously affects the quality of life and daily activities of patients. Although migraine is a transient phenomenon of cerebral vasoconstriction, it is well documented that recurrent attacks of migraine may lead to abnormalities in retinal structure. Optical coherence tomography (OCT) is a sensitive method to detect subtle damage in retinal nerve fiber layer (RNFL). There have been many studies investigating the difference in RNFL thickness with optical coherence tomography (OCT) between migraine patients and healthy controls. However, the results were not consistent. Our purpose is to perform a meta-analysis to investigate RNFL alterations in migraine. METHODS: We will search PubMed, Embase, Web of science for studies assessing the differences in RNFL measured by OCT between patients with migraine and healthy controls. Case-control studies published in English will be included. Two reviewers will independently screen eligible articles, extract data, and assess quality. This meta-analysis will synthesize selected research data and compare the difference in RNFL thickness between patients with migraine and healthy controls. We will use Stata 15 in this meta-analysis. I statistics will be used to assess heterogeneity. If I ≤ 50%, the data are synthesized will use a fixed effect model. Otherwise, a random effect model will be performed. Publication bias will be determined by the Egger test. The methodological quality of all included studies will be evaluated by the Newcastle-Ottawa Scale (NOS). We will perform subgroup analysis, sensitivity analysis, and meta-regression analysis to test the robustness of the results. RESULTS: We will obtain quantitative results regarding the difference in RNFL thickness between migraine patients and healthy controls. The results will be published in a peer-reviewed journal. CONCLUSIONS: The results of this study provide a high-quality synthesis of existing evidence and provide a basis for assessing the effect of migraine on the thickness of RNFL. REGISTRATION NUMBER: INPLASY 202060033.

Findings in susceptibility weighted imaging in pediatric patients with migraine with aura.

BACKGROUND: Migraine with aura (MwA) in pediatric patients is clinically frequent. Clinically complex symptoms need to be differentiated to exclude mimicking conditions. PURPOSE: We hypothesize that MwA in children induces abnormalities readily visible in perfusion time to peak (TTP) maps as well as non-enhanced susceptibility weighted magnetic resonance imaging (SWI). MATERIALS AND METHODS: Between 2010 and 2018, we retrospectively evaluated symptoms and imaging of consecutive pediatric patients <18 years with MwA. We visually scored abnormalities on SWI and TTP maps in 12 regions of interest on both hemispheres on three axial slices, as normal, slightly, distinctly or severely abnormal. RESULTS: 99 patients (69.7% female), mean age 14.07 y (±2.8) were included. Focally increased deoxygenation (FID) in SWI was present in 61.6%. FID on SWI was dominant for the left hemisphere (60.7% vs. 31.1%, (p < .001)), and in 8.2% symmetric. Side of aura symptoms and contralateral hemispheric imaging alterations in patients with FID correlated significantly (p = .002.). 61 of 99 patients had perfusion MR and 59% of these patients showed focal increase of TTP. Age correlated significantly with FID in SWI (r = -.248, p = .013) and increase of TTP in perfusion (r = -.252, p = .05). Focal abnormalities correlated significantly between SWI and TTP maps. Brain regions most often abnormal were the temporal superior, occipital and fronto-parietal regions. CONCLUSIONS: This study provides confidence in recognizing FID, and linking FID in SWI to acute MwA in pediatric patients. FID phenomenon had a left hemispheric significant dominance, and can be found bilaterally.

Functional NHE1 expression is critical to blood brain barrier integrity and sumatriptan blood to brain uptake.

Disruption of blood-brain barrier integrity and dramatic failure of brain ion homeostasis including fluctuations of pH occurs during cortical spreading depression (CSD) events associated with several neurological disorders, including migraine with aura, traumatic brain injury and stroke. NHE1 is the primary regulator of pH in the central nervous system. The goal of the current study was to investigate the role of sodium-hydrogen exchanger type 1 (NHE1) in blood brain barrier (BBB) integrity during CSD events and the contributions of this antiporter on xenobiotic uptake. Using immortalized cell lines, pharmacologic inhibition and genetic knockdown of NHE1 mitigated the paracellular uptake of radiolabeled sucrose implicating functional NHE1 in BBB maintenance. In contrast, loss of functional NHE1 in endothelial cells facilitated uptake of the anti-migraine therapeutic, sumatriptan. In female rats, cortical KCl but not aCSF selectively reduced total expression of NHE1 in cortex and PAG but increased expression in trigeminal ganglia; no changes were seen in trigeminal nucleus caudalis. Thus, in vitro observations may have a significance in vivo to increase brain sumatriptan levels. Pharmacological inhibition of NHE1 prior to cortical manipulations enhanced the efficacy of sumatriptan at early time-points but induced facial sensitivity alone. Overall, our results suggest that dysregulation of NHE1 contributes to breaches in BBB integrity, drug penetrance, and the behavioral sensitivity to the antimigraine agent, sumatriptan.

Astrocytes in Atp1a2-deficient heterozygous mice exhibit hyperactivity after induction of cortical spreading depression.

The ATP1A2 coding α2 subunit of Na,K-ATPase, which is predominantly located in astrocytes, is a causative gene of familial hemiplegic migraine type 2 (FHM2). FHM2 model mice (Atp1a2tmCKwk/+ ) are susceptible to cortical spreading depression (CSD), which is profoundly related to migraine aura and headache. However, astrocytic properties during CSD have not been examined in FHM2 model mice. Using Atp1a2tmCKwk/+ crossed with transgenic mice expressing G-CaMP7 in cortical neurons and astrocytes (Atp1a2+/- ), we analyzed the changes in Ca2+ concentrations during CSD. The propagation speed of Ca2+ waves and the percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/- were higher than those in wild-type mice. Increased percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/- may contribute to FHM2 pathophysiology.

Reversible Lesion of the Corpus Callosum in a Patient With Migraine With Aura: A Case Study.

OBJECTIVE: To describe a patient with migraine with aura (MWA) who was found to have a reversible lesion of the corpus callosum. BACKGROUND: Reversible lesions of the splenium of the corpus callosum are well-described clinical-radiographic phenomena, which have been associated with a wide array of disease states, including epilepsy, demyelinating disease, infection, and metabolic derangements. There have been few case reports in the literature to date of these lesions associated with migraine headache. DESIGN/METHODS: A case report. RESULTS: A 41 year-old female with a history of migraine with visual aura presented with headache associated with left-sided sensorimotor deficits. Routine laboratory tests were within normal limits. An electroencephlogram was also normal. Magnetic resonance imaging (MRI) of the brain with and without contrast revealed areas of restricted diffusion in the splenium and the genu of the corpus callosum. The patient's symptoms resolved after 2 days. A follow-up MRI 2 days after the onset of symptoms revealed resolution of the callosal lesions. The patient was diagnosed clinically with migraine with prolonged aura. CONCLUSION: MWA may be associated with reversible lesions of the corpus callosum.

Higher burden of rare frameshift indels in genes related to synaptic transmission separate familial hemiplegic migraine from common types of migraine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare form of migraine with aura that often has an autosomal dominant mode of inheritance. Rare mutations in the CACNA1A, ATP1A2 and SCN1A genes can all cause FHM revealing genetic heterogeneity in the disorder. Furthermore, only a small subset of the affected individuals has a causal mutation. We set out to investigate what differentiates patients with FHM with no mutation in any known FHM gene from patients with common types of migraine in both familial and sporadic cases. METHODS: 2558 male and female participants from a migraine cohort from the Danish Headache Center were included. 112 had FHM; 743 had familial migraine; and 1703 had sporadic migraine. Using a linear regression model, we analysed for over-representation of rare functional variants in FHM versus familial migraine and sporadic migraine. Post hoc analyses included pathway analysis and testing for tissue specificity. RESULTS: We found that patients with FHM have significantly more rare frameshift indels compared with patients with familial migraine and sporadic migraine. Pathway analysis revealed that the 'ligand-gated ion channel activity' and 'G protein-coupled receptor downstream signalling' pathways were significantly associated with mutated genes. We moreover found that the mutated genes showed tissue specificity towards nervous tissue and muscle tissue. CONCLUSION: We show that patients with FHM compared with patients with common types of migraine suffer from a higher load of rare frameshift indels in genes associated with synaptic signalling in the central nervous system and possibly in muscle tissue contributing to vascular dysfunction.

Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations.

The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2-/- mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.

Impact of right-to-left shunt and transcatheter closure on the clinical features of migraine.

Objectives: In this study, we aimed to explore the influence of right-to-left shunt (RLS) presence on the clinical features of migraine and to follow-up on the post-operative curative effect of transcatheter patent foramen ovale (PFO) closure on migraine features.Methods: A total of 103 migraine patients were divided into a mild volume RLS group, moderate volume RLS group, large volume RLS group and non-RLS group in accordance with contrast enhancement transcranial Doppler (c-TCD) findings. The Visual Analogue Scale (VAS) score, migraine frequency, migraine duration, migraine disability assessment (MIDAS) and headache impact test-6 (HIT-6) scores were compared amongst the different groups. A total of 39 patients with moderate or large RLS received transcatheter PFO closure and those patients were followed up by the same criteria.Results: The attack frequency, HIT-6 and MIDAS scores amongst the migraine patients with moderate or large RLS were significantly higher than those in patients from the mild RLS group and non-RLS group (p < .05). The transcatheter closure was successful in all patients (n = 39), and no post-operative complications were observed during the hospitalisation and follow-up period. The differences in VAS, HIT-6 and MIDAS scores as well as the headache duration were statistically significant amongst patients before and after PFO closure (p < .05).Conclusions: Moderate to large RLS significantly influenced the clinical features of migraine, and transcatheter PFO closure could significantly relieve headache symptoms in migraine patients with PFO.

Recent Insights in Migraine With Aura: A Narrative Review of Advanced Neuroimaging.

INTRODUCTION: Migraine is a complex neurological disorder characterized by severe headaches associated with a plethora of sensory hypersensitivity and neurovegetative symptoms. In about one-third of the cases, a set of fully reversible focal neurological symptoms, the aura, accompanies the headache. In the last decades, advanced neuroimaging investigations allowed identification of structural, microstructural, and functional abnormalities characterizing the brain of patients with migraine with aura (MwA). However, mechanisms underlying the aura phenomena are still a matter of debate. AIMS: This article reviews the most significant findings from advanced neuroimaging studies in patients with MwA both to provide a unifying physiopathological model of the aura phenomena and to clarify the potential impact of advanced neuroimaging investigation in the clinical field. METHODS: A comprehensive review of PubMed citations was conducted by entering the key words "magnetic resonance imaging" combined with "migraine" AND "aura." Other key words included "grey matter" OR "white matter," "structural" OR "functional." The only restriction was to English-language publications. The abstracts of all articles published between 1997 and 2018 meeting these criteria were reviewed, and the full texts were examined for relevance to the topic. CONCLUSION: Although several advanced neuroimaging studies have been conducted to investigate the neural correlates of aura phenomena, they have failed in identifying underlying pathophysiological mechanisms in their entirety. Nevertheless, functional and structural neuroimaging findings concerning the extrastriate visual cortex are characterized by a high level of reproducibility, so much so that they could be applied, in a not so far future, as diagnostic, prognostic, or therapeutic biomarkers for MwA.

Retinal vascular density evaluation of migraine patients with and without aura and association with white matter hyperintensities.

Underlying pathophysiological mechanism of migraine is not all clear; however, recent reports suggested that neurovascular system is involved. We aimed to evaluate the retinal vessel densities of migraine patients with and without aura and the associations with white matter hyperintensities (WMH), using optical coherence tomography angiography (OCTA). We recruited 28 migraine with aura (MWA) patients, 26 migraine without aura (MWO) and age and sex-matched 34 healthy controls in our study. All participants were evaluated with optical coherence tomography (OCT) and OCTA for optic nerve parameters and retinal vessel densities with RTVue XR AVANTI. On macular OCTA, superficial and deeper retinal foveal vessel density (VD) were significantly lesser in MWA and MWO than controls. On optic nerve OCTA, whole optic disc, peripapillary, superior hemisphere, superior layer and temporal layer VD were significantly lesser in MWA and MWO. In group of MWA with the WMH, deeper foveal VD and superior hemisphere VD, average RNFL, superior hemisphere and superior layer were significantly lesser and also foveal avascular zone was significantly larger than the group of without WMH. Alterations of VD in patients with migraine are showed in our study. In addition, in group of MWA these alterations have associations with WMH. Supporting these findings with further reports can be useful to understand the pathophysiology of this disease.

Volume alterations of brainstem subregions in migraine with aura.

BACKGROUND: The brainstem plays a significant role in migraine pathogenesis, but a relationship between volume alterations of brainstem subregions and migraine aura characteristics has not been sufficiently investigated. The aim of this study is to compare the volume of the brainstem, and its subregions, between patients with a migraine with aura (MwA) and healthy controls (HC), and also to correlate characteristics of MwA and the volume of the brainstem subregions. METHODS: Forty-two MwA and 42 HCs, balanced by sex and age, were selected for this study. Total brainstem volume changes as well as volume changes in the pons, medulla, midbrain and the superior cerebellar peduncles were investigated in MwA relative to HCs. In addition, the relationships between brainstem subregions and aura characteristics (aura duration, the frequency of the aura, occurrence of somatosensory and dysphasic aura, duration of a headache, intensity of headache pain and disease duration) were explored in MwA. RESULTS: MwA patients had a larger brainstem volume relative to HCs (25,941.35 ±â€¯2559.2 mm3 vs. 25,179.32 ±â€¯2019.1 mm3; p = .008), as well as the midbrain and pons (6155.98 ±â€¯565.7 mm3 vs. 5964.22 ±â€¯457.0 mm3, p = .002; 15,105.13 ±â€¯1765.5 mm3 vs. 14,539.89 ±â€¯1408.4 mm3, p = .007, respectively). Total brainstem volume, as well as volumes of brainstem subregions, were not significantly correlated to the MwA characteristics. CONCLUSION: The results of this study reveal that a migraine with aura is associated with a larger volume of the brainstem with a particular involvement of the midbrain and pons.

Neuronal injuries evidenced by transient cortical magnetic resonance enhancement in hemiplegic migraine: A case report.

BACKGROUND: Magnetic resonance imaging abnormalities in hemiplegic migraine have been described previously but were limited to a cortical thickening and biphasic alternation of hypoperfusion and hyperperfusion. Our report reveals possible blood-brain barrier disruption during migraine. CASE: We present the first demonstrated case of regressive diffuse hemispheric cortical enhancement in sporadic hemiplegic migraine, with histological correlation revealing neuronal lesions similar to ischemic lesions. This is probably due to the severity of the attack as indicated by the left hemiplegia and transient altered consciousness in our 43-year-old male patient. CONCLUSION: Cortical contrast enhancement on 3D T1 images may suggest migraine severity and be predictive of neuronal loss.

Proposal for a Migraine Aura Complexity Score.

OBJECTIVES: Currently, there is no scoring system for assessing the complexity of migraine aura. Our goal was to develop a Migraine Aura Complexity Score that synthesizes the quantity and quality of aura symptoms and to test its applicability in neuroimaging studies. METHODS: Patients with migraine aura were interviewed in order to obtain characteristics of migraine aura. Explorative and confirmatory analyses were used to develop the Migraine Aura Complexity Score. Median values were derived from 10 consecutive migraine auras in each patient. The Migraine Aura Complexity Score was correlated with an average cortical thickness of different brain areas in studied patients. The Surface-based Morphometric Analysis approach was used to estimate cortical thickness. RESULTS: This study included 23 (16 females and seven males) migraineurs with aura. Confirmatory factor analysis suggested the second-order model with three-factor measurement for grading migraine aura. The first factor is linked to higher cortical dysfunction during migraine aura, while the second is associated with the degree of involvement of primary visual and somatosensory cortices; the third linked symptoms of somatosensory aura and hand and head involvement. Positive correlation of Migraine Aura Complexity Score and averaged cortical thickness were found in the left and right hemispheres overall (r = 0.568, p = 0.007; r = 0.617, p = 0.003) and in some of their regions. CONCLUSIONS: This study demonstrates that the Migraine Aura Complexity Score could be a valuable tool for assessing migraine aura. The score could be used in neuroradiological studies in order to achieve a stratification of patients with migraine aura.

Increased susceptibility to cortical spreading depression and epileptiform activity in a mouse model for FHM2.

Migraine is a highly prevalent, debilitating, episodic headache disorder affecting roughly 15% of the population. Familial hemiplegic migraine type 2 (FHM2) is a rare subtype of migraine caused by mutations in the ATP1A2 gene, encoding the α2 isoform of the Na+/K+-ATPase, predominantly expressed in astrocytes. Differential comorbidities such as epilepsy and psychiatric disorders manifest in patients. Using a mouse model harboring the G301R disease-mutation in the α2 isoform, we set to unravel whether α2+/G301R mice show an increased susceptibility for epilepsy and cortical spreading depression (CSD). We performed in vivo experiments involving cortical application of KCl in awake head-restrained male and female mice of different age groups (adult and aged). Interestingly, α2+/G301R mice indeed showed an increased susceptibility to both CSD and epileptiform activity, closely replicating symptoms in FHM2 patients harboring the G301R and other FHM2-causing mutations. Additionally, this epileptiform activity was superimposed on CSDs. The age-related alteration towards CSD indicates the influence of female sex hormones on migraine pathophysiology. Therefore, the FHM2, α2+/G301R mouse model can be utilized to broaden our understanding of generalized epilepsy and comorbidity hereof in migraine, and may be utilized toward future selection of possible treatment options for migraine.