Different vulnerability of fast and slow cortical oscillations to suppressive effect of spreading depolarization: state-dependent features potentially relevant to pathogenesis of migraine aura.

BACKGROUND: Spreading depolarization (SD), underlying mechanism of migraine aura and potential activator of pain pathways, is known to elicit transient local silencing cortical activity. Sweeping across the cortex, the electrocorticographic depression is supposed to underlie spreading negative symptoms of migraine aura. Main information about the suppressive effect of SD on cortical oscillations was obtained in anesthetized animals while ictal recordings in conscious patients failed to detect EEG depression during migraine aura. Here, we investigate the suppressive effect of SD on spontaneous cortical activity in awake animals and examine whether the anesthesia modifies the SD effect. METHODS: Spectral and spatiotemporal characteristics of spontaneous cortical activity following a single unilateral SD elicited by amygdala pinprick were analyzed in awake freely behaving rats and after induction of urethane anesthesia. RESULTS: In wakefulness, SD transiently suppressed cortical oscillations in all frequency bands except delta. Slow delta activity did not decline its power during SD and even increased it afterwards; high-frequency gamma oscillations showed the strongest and longest depression under awake conditions. Unexpectedly, gamma power reduced not only during SD invasion the recording cortical sites but also when SD occupied distant subcortical/cortical areas. Contralateral cortex not invaded by SD also showed transient depression of gamma activity in awake animals. Introduction of general anesthesia modified the pattern of SD-induced depression: SD evoked the strongest cessation of slow delta activity, milder suppression of fast oscillations and no distant changes in gamma activity. CONCLUSION: Slow and fast cortical oscillations differ in their vulnerability to SD influence, especially in wakefulness. In the conscious brain, SD produces stronger and spatially broader depression of fast cortical oscillations than slow ones. The frequency-specific effects of SD on cortical activity of awake brain may underlie some previously unexplained clinical features of migraine aura.

A Case Report of Migraine With Aura Worsened After Starting Apixaban and Literature Review.

INTRODUCTION: Multiple medications have been related to triggering headache attacks or worsening headache frequency or severity in patients with migraine disease. However, the impact of direct oral anticoagulants on headache frequency and severity in patients with migraine disease is unclear. Current literature is scarce and controversial. CASE REPORT: A 45-year-old male with a history of migraine with aura for the last 20 years underwent percutaneous transcatheter closure of an atrial septal defect due to right ventricular enlargement and systolic dysfunction. The intervention was complicated by postprocedural atrial fibrillation, for which he was started on apixaban. Shortly after starting the apixaban, the patient experienced an increase in the frequency and severity of his migraine with aura episodes that were persistent until he discontinued this medication 7 months later. Following the discontinuation of apixaban, the patient's frequency and severity of migraine episodes returned to baseline almost immediately. CONCLUSION: Novel oral anticoagulants, including apixaban, may be associated with an increase in the frequency and severity of migraine attacks in patients with migraine disease. Larger observational studies are required to investigate further the impact of direct oral anticoagulants on migraine disease.

Symptomatic migraine: A systematic review to establish a clinically important diagnostic entity.

OBJECTIVE: To determine if a clinical presentation indistinguishable from migraine can occur due to an underlying condition or pathology, that is, "symptomatic migraine." BACKGROUND: It is currently not clear whether migraine truly can be caused by an underlying condition or pathology. Characterization of the etiology and clinical features of possible symptomatic migraine is of significant clinical importance and further may help elucidate the pathophysiology of migraine. METHODS: We devised operational diagnostic criteria for "symptomatic migraine" and "possible symptomatic migraine" requiring strong evidence for a causal relation between underlying cause and migraine symptoms adhering strictly to diagnostic criteria. PubMed was searched for case reports of symptomatic migraine from inception to March 2020. Only articles published in English or German were included. No restrictions were placed on study design. Relevant references in the articles were also included. Papers were systematically reviewed by two independent reviewers for detailed clinical features of migraine as well as the proposed underlying conditions and the effects of treatment of these conditions. RESULTS: Our search retrieved 1726 items. After screening, 109 papers comprising 504 cases were reviewed in detail. Eleven patients with migraine with aura (MWA) fulfilled our working criteria for symptomatic migraine, and 39 patients fulfilled our criteria for possible symptomatic migraine. The most common etiologies of symptomatic migraine were arteriovenous malformations, carotid stenosis, dissection or aneurysm, brain infarctions, meningioma, and various intra-axial tumors. CONCLUSIONS: Symptomatic MWA, indistinguishable from idiopathic MWA, may occur due to cortical lesions or microembolization. We found no clear evidence supporting the existence of symptomatic migraine without aura although we did identify possible cases. Our findings are limited by the available literature, and we suggest that prospective studies are needed.

Hyperhomocysteinemia increases susceptibility to cortical spreading depression associated with photophobia, mechanical allodynia, and anxiety in rats.

Epidemiological data suggest that elevated homocysteine is associated with migraine with aura. However, how homocysteine contributes to migraine is still unclear. Here, we tested whether hyperhomocysteinemia (hHCY) promotes cortical spreading depression (CSD), a phenomenon underlying migraine with aura, and whether hHCY contributes to pain behavior. hHCY was induced by dietary methionine in female rats while the testing was performed on their 6-8week-old offspring. CSD and multiple unit activity (MUA) induced by KCl were recorded from the primary somatosensory cortex, S1, using multichannel electrodes. In hHCY rats, compared to control, we found: i) higher probability of CSD occurrence; ii) induction of CSD by lower concentrations of KCl; iii) faster horizontal propagation of CSD; iv) smaller CSD with longer duration; v) higher frequency of MUA at CSD onset along with slower reappearance. Rats with hHCY demonstrated high level of locomotor activity and grooming while spent less time in the central area of the open field, indicating anxiety. These animals showed light sensitivity and facial mechanical allodinia. Thus, hHCY acquired at birth promotes multiple features of migraine such as higher cortical excitability, mechanical allodynia, photophobia, and anxiety. Our results provide the first experimental explanation for the higher occurrence of migraine with aura in patients with hHCY.

The Efficacy of Percutaneous Patent Foramen Ovale Closure on Migraine: a Meta-Analysis of Randomized Controlled Trials and Observational Studies.

OBJECTIVES: Whether patent foramen ovale (PFO) closure is effective on migraine is controversial. This article was aimed at assessing the efficacy of PFO closure on migraine based on randomized controlled trials (RCTs) and observational studies. METHODS: We searched PubMed, Embase, and Cochrane databases up to October 2020 evaluating PFO closure versus control in patients with migraine, then conducted a meta-analysis of all RCTs and observational studies, respectively. The main outcomes were (1) respond rate: complete cessation of migraine; (2) reduction in the frequency of migraine attacks per month; and (3) reduction in migraine days per month. RESULTS: Seven studies (3 RCTs and 4 observational studies), containing 887 migraine patients, were identified. (1) The respond rate of PFO closure on migraine was significantly higher than control group both in RCT subgroup and observational studies subgroup (OR 3.86, 95% CI 1.35-11.04, P = 0.01 in RCTs; OR 8.28, 95% CI 2.31-29.67, P = 0.001 in observational studies). (2) Reduction in frequency of migraine attacks was higher in PFO closure group compared with control group in the RCT subgroup analysis (mean difference (MD) = 0.57, 95% CI 0.23-0.90, P = 0.0009). (3) Reduction in migraine days was also higher in PFO closure group compared with control group in the RCT subgroup analysis (MD = 1.33, 95% CI 0.35-2.31, P = 0.008). CONCLUSIONS: PFO closure might be suitable for migraine patients, especially for migraine with aura, by cessation of migraine headaches or reducing migraine attacks and migraine days.

[Migraine with typical aura without headache; first presentation at older age]. / Visuele verschijnselen bij migraine met typisch aura.

Transient visual phenomena in later life due to a visual aura in migraine are not uncommon and can also occur without headache. This migraine with aura is not always recognized as such. Since visual phenomena can also have a variety of other causes, they can present a diagnostic dilemma in both primary and secondary care. Visual aura phenomena have various and often complex manifestations and are usually observed binocularly. In case of transient visual phenomena, the patient's history is of utmost importance to determine whether there is a mono- or binocular cause of the complaints. Timely recognition of visual phenomena in the context of migraine can prevent unnecessary diagnostics and treatments.

Branch Retinal Vein Occlusion and Venous Abnormalities in CADASIL.

INTRODUCTION: Individuals with the inherited progressive microangiopathy Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts (CADASIL) most classically develop migraine with aura and recurrent subcortical ischemic infarcts with progressive cognitive decline, gait dysfunction, psychiatric disturbances culminating in early death. However, clinically important venous pathologies may not be anticipated by treating neurologists such as branch retinal vein occlusions (BRVOs). Herein we describe a case of CADASIL with a BRVO and a brief review of venous pathology in CADASIL. CASE REPORT: A 66-year-old man with CADASIL and clinical symptoms of chronic migraine with aura, episodic "CADASIL coma," recurrent subcortical ischemic infarcts and normal cognition presented with an asymptomatic superior BRVO. Retinal analysis by wide-field fluorescein angiography revealed dye extravasation and optical coherence tomography identified macular edema prompting a monthly regimen of intravitreal bevacizumab. Systemic investigations for provoking etiologies was unfruitful tentatively attributing the BRVO to his underlying CADASIL. CONCLUSIONS: Within CADASIL, the venous circulation undergoes similar pathologic changes as compared with the arterial circulation. The retinal veins of CADASIL exhibit increased venous compliance, vessel wall diameter and wall thickness which may represent a structurally causative factor for retinal venous disease. However, these findings are not isolated to the retina as lower extremity varicose veins have associated with a family pedigree of CADASIL. Although presently it is uncertain whether those with CADASIL should undergo routine retinal screening, neurologists, and ophthalmologists, need to be cognizant of the extra-arterial manifestations of CADASIL to provide comprehensive clinical care.

[Atypical aura caused by a stroke in a 42-year-old man with migraine with aura].

Ischaemic stroke in persons with migraine may present with aura-like symptoms. In this case report a 42-year-old man with migraine with aura presented with a change in usual aura including visual loss and disorientation. A brain MRI revealed ischaemic stroke in precuneus compatible with these symptoms. We discuss the pathophysiology, the causes and the secondary prophylaxis in persons with migraine with aura and stroke.

Migraine and Ischemic Stroke in Women. A Narrative Review.

OBJECTIVE/BACKGROUND: Migraine is associated with ischemic stroke. Women are 3-fold as likely as men to have migraine, and high estrogen states increase the risk of migraine with aura (MWA), venous thromboembolism (VTE), and of stroke. We review the epidemiological and mechanistic evidence of the migraine-stroke relationship and its risk factors, with a focus on women and conditions that exclusively or predominantly affect them.  METHODS: We performed a search of MEDLINE/PubMed database, then a narrative review of the epidemiological evidence of the migraine-stroke relationship as well as the evidence for arterial, thrombophilic, and cardiac mechanisms to explain this connection. We examine the implications of this evidence for the diagnostic evaluation and treatment of MWA. RESULTS: MWA is associated with multiple stroke risk factors, such as hypertension, hyperlipidemia, diabetes mellitus, cigarette smoking, atrial fibrillation, and patent foramen ovale. In women, MWA is also associated with biomarkers of endothelial activation, hormonal contraceptive use, pregnancy, and VTE. This suggests that a subset of auras may be secondary, that is, induced by ischemia related to microemboli or in situ thrombosis. MWA-associated ischemic stroke is more common in young (<45 years old) women with high frequency of migraine attacks, hormonal contraception use, and with pregnancy and preeclampsia. There is increasing evidence that cardioembolism, often in conjunction with thrombophilia, plays a prominent role in MWA-associated cerebral infarction. CONCLUSION: The commonality of factors associated with MWA and with MWA-associated stroke suggest that persons with secondary, ischemia-induced aura may be at elevated risk of stroke. Although further research is needed, we recommend consideration of a diagnostic evaluation of MWA that mirrors the evaluation of transient ischemic attack, given that prophylactic treatment targeting the ischemic origin of secondary aura may prevent migraine as well as stroke.

Case Report: New-Onset Retinal Migraine After Transseptal Catheterization.

BACKGROUND: While new-onset migraine headaches and binocular visual aura have been reported after transseptal catheterization (TSC), this case suggests that retinal aura may emerge also after this procedure. CASE DESCRIPTION: This 38-year-old male with paroxysmal atrial fibrillation had received TSC and cryoablation, and subsequently developed isolated monocular aura phenomena. The first episode happened a few hours after the intervention and was not accompanied by headache or other aura phenomena. The patient's history was negative for migraine. Brain magnetic resonance imaging demonstrated 2 lacunar diffusion restrictions in the left medial cerebral artery territory that were most likely catheterization related. Over the next 14 days, 3 additional, stereotyped episodes (duration = 20-30 minutes) with zigzag lines and flickering small bright dots in the central visual field of one eye (moving laterally) occurred. A central scotoma was noted during one episode. CONCLUSIONS: This is the first case with retinal aura phenomena meeting International Classification of Headache Disorders diagnostic criteria for retinal migraine, suggesting that this rare migraine variant can be triggered by TSC.

Interrelated Pathogenesis? Neuronal Intranuclear Inclusion Disease Combining With Hemiplegic Migraine.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is considered a heterogeneous disease because of its highly variable clinical manifestations. To date, there are no reports of NIID patients presenting with hemiplegic migraine (HM)-like headache, or of HM and NIID co-occurring as comorbidity, and the connection between these 2 seemingly unrelated clinical conditions has yet to be established. METHOD: We present a patient with NIID who was previously diagnosed with HM. To determine the pathogenesis of HM in this NIID patient, we systematically reviewed published NIID and HM cases and cataloged them based on their clinical manifestations. RESULT: The clinical manifestations of NIID is highly various; however, there is no case reported to date that shows HM-like symptoms or cerebral edema. All documented symptomatic HM cases show vascular dysfunction to various degrees, but none of them has been shown to be correlated with NIID. CONCLUSION: Our patient is the first documented case in which HM and NIID occur simultaneously. Vascular dysfunctions that cause cerebral hypoperfusion and glucose hypometabolism, two of the dominant causes of symptomatic HM, may be associated with the accumulation of eosinophilic hyaline inclusions that cause NIID. However, the existence of inclusions may also alter neuronal behavior and indirectly cause cerebral hypoperfusion and glucose hypometabolism. Further research and observations are needed to examine the relationship between HM and NIID.

Migraine Aura: Pathophysiology, Mimics, and Treatment Options.

Recent insights into the clinical presentation and pathophysiology of migraine aura have paved the way for new treatments for this common but frequently debilitating condition. Marked efflux of cellular potassium and glutamate contributes to the cortical spreading depression that forms the electrophysiological basis of migraine aura phenomena. Secondary vascular perturbations also contribute to the various symptoms of a migraine attack. Calcitonin gene-related peptide (CGRP) plays a key role in many of these steps, and a growing class of CGRP-antagonists have emerged as a novel, efficacious preventative therapy. It is still not fully understood why a preponderance of migraine aura symptoms is visual, and this issue is an active area of research. In addition, the pathophysiological changes responsible for visual snow syndrome are under investigation. Before diagnosing a patient with migraine aura, it is important to consider the differential diagnosis of transient visual phenomena, with attention to clinical features that may suggest conditions such as retinal disorders, transient ischemic attack, or occipital epilepsy.

Right-to-Left Shunt and the Clinical Features of Migraine with Aura: Earlier but Not More.

BACKGROUND: The causal relationship between patent foramen ovale (PFO) and migraine with aura (MA) is controversial. We aimed at exploring whether attack clinical features relate to the presence of right-to-left shunt (RLS) in MA patients. METHODS: We retrospectively examined a cohort of consecutive patients diagnosed with MA in our headache center and undergoing transcranial doppler (TCD) for RLS detection. We collected from our clinical electronic dossiers, clinical features of MA attacks (type, frequency, duration of aura phenomenon, trigger factors, onset age), family history for MA, thrombophilia genotypes, and the response to preventive treatments. RLS was stratified for severity according to the results of the TCD examination. RESULTS: We found 111 patients. Binary logistic regression analysis showed that among features of MA attacks, only onset age was associated with the presence of RLS (p < 0.0001). Patients with RLS presented the first MA attack at a younger age (p < 0.0001). The greater RLS severity, the younger was onset age (p < 0.00001) and the presence of atrial septal aneurysms (ASA) was associated with a further decrease in onset age (ρ = -539, p < 0.00001). Family history for MA was associated with the presence of RLS (chi-square p = 0.022). Response to preventive treatments was not influenced by the type of treatment (antiplatelet compared with no antiplatelet drugs), comorbidity with migraine without aura, RLS presence, or by their double interactions (Logistic regression, consistently p > 0.05). CONCLUSION: Our findings support the hypothesis that although PFO does not influence MA attack frequency, it is not merely a bystander in MA physiopathology, as RLS, its severity, and the presence of ASA possibly make a difference in the disease history.

Familial hemiplegic migraine in a child with seizure disorder: clinical history is the key to diagnosis.

Headache is a common presenting complaint in the paediatric population, with often migraine being a clinical diagnosis. Hemiplegic migraine is characterised by aura, sudden onset weakness of one side of the body which usually recovers without any residual neurological deficit. We report a child with a history of seizure disorder, well controlled and off medication for 3 years, who presented with a headache, aura and transient hemiplegia. Similar history in the patient's mother suggests the diagnosis of familial hemiplegic migraine. We would like to emphasise the importance of detailed history as an important aid in the diagnosis of neurological disorders in children.

Relating Photophobia, Visual Aura, and Visual Triggers of Headache and Migraine.

OBJECTIVE: This study investigated a potential association between visual factors and symptoms related to migraine. It was predicted that photophobia and visual aura would be positively associated with interictal light sensitivity and visual headache triggers (flicker, glare, and eyestrain), and that these 2 visual symptoms would also be associated. BACKGROUND: Previous studies have found independent neurophysiological associations between several visual factors and symptoms related to headache disorders. Many of these connections appear to be associated with increased cortical hypersensitivity, a phenomenon that might be in part due to repeated avoidance and reduced tolerance to triggers. If true, and if associations between visual factors and symptoms can be established, this may have implications for an exposure-based treatment for migraine symptoms. METHODS: Four hundred and ninety-one participants (411 female, 80 male) were recruited through Griffith University (AUS), Headache Australia, Pain Australia, and through social media. Participants were grouped based on the presence of headache disorder symptoms and the presence or absence of photophobia and/or visual aura. A cross-sectional online survey design was utilized to gather information pertaining to interictal light sensitivity, visual triggers, and visual symptoms. RESULTS: With respect to interictal light sensitivity and photophobia, a significant difference (P < .001, eta squared [η2 ] = 0.084) was found between the 3 groups, where headache disorder participants with photophobia (group A1; mean [M] = 2.5, standard deviation [SD] = 0.97) reported significantly greater light sensitivity than participants with headache disorder and no photophobia (A2; M = 1.68, SD = 0.62) and control group participants (A3; M = 1.82, SD = 0.85). This pattern was repeated for participants reporting flicker as a headache trigger (P < .001, η2 = 0.061), with group A1 (M = 2.45, SD = 1.24) significantly higher than groups A2 (M = 1.68, SD = 0.83) and A3 (M = 1.68, SD = 0.89), and was also seen for glare as a headache trigger (P < .001, η2 = 0.092), with group A1 (M = 2.92, SD = 0.96) significantly higher than A2 (M = 2.31, SD = 0.89) and A3 (M = 2.09, SD = 0.93). This pattern of results was not replicated for headache disorder participants with and without visual aura. A significant association (P < .001) was found between photophobia and visual aura in headache disorder participants based on a chi-square test of independence, with 86/136 participants reporting either both or neither visual symptom. CONCLUSIONS: This study supports a link between certain visual phenomena in headache disorder populations, and supports future research into exposure-based treatments for migraine symptoms.

Orgasmic migraine aura: Report of two cases.

BACKGROUND: Paroxysmal neurological symptoms occurring with sex cause considerable anxiety and sometimes have a serious cause. Thunderclap headache is the most well-known and requires urgent investigation at first presentation for subarachnoid haemorrhage and other significant pathologies. After exclusion of underlying causes, many prove to be primary headache associated with sexual activity. Orgasmic migraine aura without headache is not currently recognised as a clinical entity. CASE REPORTS: We report two patients with acephalgic orgasmic neurological symptoms fulfilling the criteria for migraine aura. CONCLUSIONS: The incidence of acephalgic orgasmic migraine aura is unknown. It should be considered as part of the differential of paroxysmal sex-related neurological symptoms, and clinically differentiated from fixed deficits, reversible cerebral vasoconstriction syndrome and post-orgasmic illness syndrome.

The pathological spectrum behind migraine aura status: a case series.

BACKGROUND: The recently released International Classification of Headache Disorders-3rd edition (1) includes migraine aura status (MAS) among the complications of migraine (A1.4.5). It is defined as the recurrence of at least three auras over a period of 3 days, in a patient suffering from migraine fulfilling criteria for 1.2 Migraine with aura (MA) or one of its subtypes. CASE SERIES: We describe three cases of MAS secondary to an organic brain lesion: a migrainous infarction, an acute ischemic stroke secondary to a vertebral artery dissection, and an inflammatory demyelinating disease of the central nervous system. CONCLUSIONS: In front of a patient with a MAS, an organic lesion of the brain must be suspected, until a complete negative vascular and neuroradiological diagnostic workup has been performed. A spectrum of underlying pathologies (vascular or demyelinating diseases, epileptic or degenerative conditions) may cause a MAS-like clinical onset. The variability of aura symptoms may result in a real diagnostic challenge.

Migraine-like visual aura: Can it be an early-onset symptom of astrocytoma?

Photopsia, fortification spectra, and the slow propagation of a scintillating scotoma across the visual field are typical diagnostic features of the visual aura of migraine. In the vast majority of cases, the diagnosis can be made without the need for further investigations. Herein, we report three consecutive cases with an astrocytoma and discuss clinical features of migraine-like visual aura.