Characteristics of acute ischemic stroke and unusual aura in patients with migraine with aura.

BACKGROUND: Sometimes migraine aura changes from attack to attack, raising the question of whether the change is heralding an ischemic stroke or an unusual aura. Differentiating unusual migraine aura from the onset of an acute ischemic stroke in patients with migraine with aura (MwA) can be challenging. OBJECTIVE: The aim of this cohort study was to assess clinical characteristics that help distinguish between MwA and minor stroke in patients with a previous history of MwA who presented with suspicion of stroke. METHODS: We interviewed patients with MwA and ischemic stroke (MwA + IS) and patients with MwA and unusual aura, but without ischemic stroke (MwA - IS) from a tertiary hospital using a structured questionnaire. We assessed how symptoms of ischemic stroke or unusual aura differed from usual, that is, the typical aura in each patient. Stroke or exclusion of stroke was verified by multimodal magnetic resonance imaging. RESULTS: Seventeen patients with MwA + IS and twelve patients with MwA - IS were included. New focal neurological symptoms (13/17 [76%] vs. 3/12 [25%]), change of the first symptom (10/17 [59%] vs. 1/12 [8%]), and absence of headache (6/15 [40%] vs. 2/10 [20%]) were more often reported during ischemic stroke. The physical examination was normal in 8/17 (47%) MwA + IS and in 6/12 (50%) MwA - IS patients. In 5/17 (29%) patients with MwA + IS, there were unequivocal physical signs suggestive of stroke such as persistent visual loss, ataxia, or paresis. CONCLUSION: There are clues from the history that might help identify stroke in patients with MwA with changed aura symptoms. These might be particularly useful in patients presenting without physical findings suggestive of stroke.

Alterations of the alpha rhythm in visual snow syndrome: a case-control study.

BACKGROUND: Visual snow syndrome is a disorder characterized by the combination of typical perceptual disturbances. The clinical picture suggests an impairment of visual filtering mechanisms and might involve primary and secondary visual brain areas, as well as higher-order attentional networks. On the level of cortical oscillations, the alpha rhythm is a prominent EEG pattern that is involved in the prioritisation of visual information. It can be regarded as a correlate of inhibitory modulation within the visual network. METHODS: Twenty-one patients with visual snow syndrome were compared to 21 controls matched for age, sex, and migraine. We analysed the resting-state alpha rhythm by identifying the individual alpha peak frequency using a Fast Fourier Transform and then calculating the power spectral density around the individual alpha peak (+/- 1 Hz). We anticipated a reduced power spectral density in the alpha band over the primary visual cortex in participants with visual snow syndrome. RESULTS: There were no significant differences in the power spectral density in the alpha band over the occipital electrodes (O1 and O2), leading to the rejection of our primary hypothesis. However, the power spectral density in the alpha band was significantly reduced over temporal and parietal electrodes. There was also a trend towards increased individual alpha peak frequency in the subgroup of participants without comorbid migraine. CONCLUSIONS: Our main finding was a decreased power spectral density in the alpha band over parietal and temporal brain regions corresponding to areas of the secondary visual cortex. These findings complement previous functional and structural imaging data at a electrophysiological level. They underscore the involvement of higher-order visual brain areas, and potentially reflect a disturbance in inhibitory top-down modulation. The alpha rhythm alterations might represent a novel target for specific neuromodulation. TRIAL REGISTRATION: we preregistered the study before preprocessing and data analysis on the platform osf.org (DOI: https://doi.org/10.17605/OSF.IO/XPQHF , date of registration: November 19th 2022).

The longitudinal influence of tDCS on occipital GABA and glutamate/glutamine levels in episodic migraineurs.

This study investigated differences in the concentration of gamma-aminobutyric acid (GABA) and the combination of glutamine and glutamate (as GLX) in the early visual cortex of patients with episodic migraine and the influence of transcranial direct current stimulation (tDCS) on GABA and GLX. In this single-blind, sham-controlled trial, we randomly assigned patients with episodic migraine to receive daily anodal tDCS or sham stimulation. In addition, we included healthy controls. We acquired proton MR spectroscopy data of the visual cortex with 3 Tesla MRI at baseline and from migraine patients directly after the stimulation period and 4 months later. In 22 migraineurs and 25 controls, the GABA and the GLX concentrations did not differ at baseline between the groups. tDCS resulted in reduced concentrations of GABA but not GLX or the migraine frequency directly after the stimulation period, but not 4 months later. The changes in the levels of GABA in the early visual cortex of patients with episodic migraine in the interictal period suggest an effect of tDCS that allowed for subsequent changes in the migraine frequency. However, we might have missed relevant variations in the concentrations of these neurotransmitters during the follow-up period, as changes in migraine frequency appeared after the first MRI and disappeared before the second.

Changes of migraine aura with advancing age of patients.

AIM: Given the similar presentation of migraine aura and acute ischemic stroke, advancing patient age might change the characteristics of migraine with aura (MA) and be clinically important. Clinical data, however, are limited. Experimental studies indicate a decrease in the magnitude of cortical spreading depression (CSD), the pathophysiological correlate of migraine aura, with advancing age. Our study aimed to assess the influence of age on the clinical features of MA. METHODS: Three hundred and forty-three patients were interviewed using a structured questionnaire. The questions covered the headache characteristics and symptom types including the characteristics of the C-criterion, as defined by the International Classification of Headache Disorders 3rd Edition. The association of age with MA characteristics was assessed. RESULTS: The median age was 29 (IQR 28-52) and 235 of the 343 patients were women (69%). Individual symptoms of the C-criterion such as gradual aura spreading over longer than 5 min (P < 0.001), two or more aura symptoms occurring in succession (P = 0.005), duration of at least one MA symptom for longer than 60 min (P = 0.004), and associated headache (P = 0.01) were more frequent in younger patients. The number of symptoms including the C-characteristics decreased with increasing age (P < 0.001). Patients with sensory (P < 0.001), motor (P = 0.004) and speech disturbance (P = 0.02) were younger, and older patients with headache had less photophobia (P = 0.04) and phonophobia (P = 0.03). Sensitivity analyses yielded similar results. CONCLUSION: The frequency of typical characteristics of migraine aura and migraine headache including photophobia and phonophobia decreases with advancing patient age. This might have potentially difficult implications for the diagnosis of MA in the elderly.

Altered urinary tetrahydroisoquinoline derivatives in patients with Tourette syndrome: reflection of dopaminergic hyperactivity?

Tetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS.

Long-Term Effects of Self-Administered Transcranial Direct Current Stimulation in Episodic Migraine Prevention: Results of a Randomized Controlled Trial.

BACKGROUND: Migraine is a multifactorial neurovascular disorder, which affects about 12% of the general population. In episodic migraine, the visual cortex revealed abnormal processing, most likely due to decreased preactivation level. Transcranial direct current stimulation (tDCS) is able to modify cortical excitability and might result in an alleviation of migraine occurrence if used repetitively. OBJECTIVE: To test the hypothesis that self-administered anodal tDCS over the visual cortex significantly decreases the number of monthly migraine days in episodic migraine. MATERIALS AND METHODS: The study was single-blind, randomized, and sham-controlled. Inclusion criteria were age 18-80 years and an ICHD-3 diagnosis of episodic migraine. Exclusion criteria were pregnancy, presence of a neurodegenerative disorder, a contraindication against MRI examinations, and less than two migraine days during the 28-day baseline period. Patients in whom the baseline period suggested chronic migraine were excluded. After baseline, participants applied daily either verum (anodal-1 mA to 20 min) or sham tDCS (anodal-1 mA to 30 sec) at Oz (reference Cz electrode) for 28 days. Headache diaries were used to record the number of migraine days at baseline, during the stimulation period, and during four subsequent 28-day periods. RESULTS: Twenty-eight patients were included; two were excluded after the baseline period because less than two migraine days occurred; three were excluded because their headache diaries suggested the diagnosis of chronic migraine. Twenty-three datasets were taken for further analysis. Compared to sham tDCS (n = 12), verum tDCS (n = 11) resulted in a lower number of migraine days (p = 0.010) across all follow-up periods. We found no significant change in total headache days (p = 0.165), anxiety (p = 0.884), or depression scores (p = 0.535). No serious adverse events occurred; minor side effects were similar in both groups. CONCLUSIONS: This study provides Class II evidence that self-administered anodal tDCS over the visual cortex in episodic migraine results in a significantly lower number of monthly migraine days. However, it has neither an immediate nor a long-term effect.

Tracking tDCS induced grey matter changes in episodic migraine: a randomized controlled trial.

BACKGROUND: Occipital transcranial direct current stimulation (tDCS) is an effective and safe treatment for migraine attack prevention. Structural brain alterations have been found in migraineurs in regions related to pain modulation and perception, including occipital areas. However, whether these structural alterations can be dynamically modulated through tDCS treatment is understudied. OBJECTIVE: To track longitudinally grey matter volume changes in occipital areas in episodic migraineurs during and up to five months after occipital tDCS treatment in a single-blind, and sham-controlled study. METHODS: 24 episodic migraineurs were randomized to either receive verum or sham occipital tDCS treatment for 28 days. To investigate dynamic grey matter volume changes patients underwent structural MRI at baseline (prior to treatment), 1.5 months and 5.5 months (after completion of treatment). 31 healthy controls were scanned with the same MRI protocol. Morphometry measures assessed rate of changes over time and between groups by means of tensor-based morphometry. RESULTS: Before treatment, migraineurs reported 5.6 monthly migraine days on average. A cross-sectional analysis revealed grey matter volume increases in the left lingual gyrus in migraineurs compared to controls. Four weeks of tDCS application led to a reduction of 1.9 migraine days/month and was paralleled by grey matter volume decreases in the left lingual gyrus in the treatment group; its extent overlapping with that seen at baseline. CONCLUSION: This study shows that migraineurs have increased grey matter volume in the lingual gyrus, which can be modified by tDCS. Tracking structural plasticity in migraineurs provides a potential neuroimaging biomarker for treatment monitoring. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03237754 . Registered 03 August 2017 - retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03237754 .

Structural brain network characteristics in patients with episodic and chronic migraine.

BACKGROUND: Migraine is a primary headache disorder that can be classified into an episodic (EM) and a chronic form (CM). Network analysis within the graph-theoretical framework based on connectivity patterns provides an approach to observe large-scale structural integrity. We test the hypothesis that migraineurs are characterized by a segregated network. METHODS: 19 healthy controls (HC), 17 EM patients and 12 CM patients were included. Cortical thickness and subcortical volumes were computed, and topology was analyzed using a graph theory analytical framework and network-based statistics. We further used support vector machines regression (SVR) to identify whether these network measures were able to predict clinical parameters. RESULTS: Network based statistics revealed significantly lower interregional connectivity strength between anatomical compartments including the fronto-temporal, parietal and visual areas in EM and CM when compared to HC. Higher assortativity was seen in both patients' group, with higher modularity for CM and higher transitivity for EM compared to HC. For subcortical networks, higher assortativity and transitivity were observed for both patients' group with higher modularity for CM. SVR revealed that network measures could robustly predict clinical parameters for migraineurs. CONCLUSION: We found global network disruption for EM and CM indicated by highly segregated network in migraine patients compared to HC. Higher modularity but lower clustering coefficient in CM is suggestive of more segregation in this group compared to EM. The presence of a segregated network could be a sign of maladaptive reorganization of headache related brain circuits, leading to migraine attacks or secondary alterations to pain.

Interictal Hyperperfusion in the Higher Visual Cortex in Patients With Episodic Migraine.

BACKGROUND: Migraine pathophysiology is complex and probably involves cortical and subcortical alterations. Structural and functional brain imaging studies indicate alterations in the higher order visual cortex in patients with migraine. Arterial spin labeling magnetic resonance imaging (ASL-MRI) is a non-invasive imaging method for assessing changes in cerebral blood flow (CBF) in vivo. OBJECTIVE: To examine if interictal CBF differs between patients with episodic migraine (EM) with or without aura and healthy controls (HC). METHODS: We assessed interictal CBF using 2D pseudo-continuous ASL-MRI on a 3 Tesla Philips scanner (University Hospital Zurich, Switzerland) in EM (N = 17, mean age 32.7 ± 9.9, 13 females) and HC (N = 19, mean age 31.0 ± 9.3, 11 females). RESULTS: Compared to HC, EM showed exclusively hyperperfusion in the right MT+ and Cohen's d effect size was 0.99 (HC mean CBF ± SD: 33.1 ± 5.9 mL/100 g/minutes; EM mean CBF: 40.9 ± 9.4 mL/100 g/minutes). EM with aura (N = 13, MwA) revealed hyperperfusion compared to HC in the right MT+ and superior temporal gyrus. For MT, Cohen's d effect size was 1.34 (HC mean CBF ± SD: 33.1 ± 5.9 mL/100 g/minutes; MwA mean CBF: 43.3 ± 8.6 mL/100 g/minutes). For the superior temporal gyrus, Cohen's d effect size was 1.28 (HC mean CBF ± SD: 40.1 ± 4.9 mL/100 g/minutes; MwA mean CBF: 47.4 ± 6.4 mL/100 g/minutes). In EM, anxiety was positively associated with CBF in the parietal operculum and angular gyrus. CONCLUSIONS: Our results suggest that extrastriate brain regions probably involved in cortical spreading depression are associated with CBF changes in the interictal state. We conclude that ASL-MRI is a sensitive method to identify local neuro-functional abnormalities in CBF in patients with EM in the interictal state.

Movement disorders in genetically confirmed mitochondrial disease and the putative role of the cerebellum.

BACKGROUND: Mitochondrial disease can present as a movement disorder. Data on this entity's epidemiology, genetics, and underlying pathophysiology, however, is scarce. OBJECTIVE: The objective of this study was to describe the clinical, genetic, and volumetric imaging data from patients with mitochondrial disease who presented with movement disorders. METHODS: In this retrospective analysis of all genetically confirmed mitochondrial disease cases from three centers (n = 50), the prevalence and clinical presentation of video-documented movement disorders was assessed. Voxel-based morphometry from high-resolution MRI was employed to compare cerebral and cerebellar gray matter volume between mitochondrial disease patients with and without movement disorders and healthy controls. RESULTS: Of the 50 (30%) patients with genetically confirmed mitochondrial disease, 15 presented with hypokinesia (parkinsonism 3/15), hyperkinesia (dystonia 5/15, myoclonus 3/15, chorea 2/15), and ataxia (3/15). In 3 patients, mitochondrial disease presented as adult-onset isolated dystonia. In comparison to healthy controls and mitochondrial disease patients without movement disorders, patients with hypo- and hyperkinetic movement disorders had significantly more cerebellar atrophy and an atrophy pattern predominantly involving cerebellar lobules VI and VII. CONCLUSION: This series provides clinical, genetic, volumetric imaging, and histologic data that indicate major involvement of the cerebellum in mitochondrial disease when it presents with hyper- and hypokinetic movement disorders. As a working hypothesis addressing the particular vulnerability of the cerebellum to energy deficiency, this adds substantially to the pathophysiological understanding of movement disorders in mitochondrial disease. Furthermore, it provides evidence that mitochondrial disease can present as adult-onset isolated dystonia. © 2017 International Parkinson and Movement Disorder Society.

Magnesium in Migraine Prophylaxis-Is There an Evidence-Based Rationale? A Systematic Review.

OBJECTIVE: The primary objective was to systematically evaluate the existing evidence base on magnesium in migraine prophylaxis. METHODS: The search for clinical trials published from 1990 to 2016 was separately conducted by AvL and FR using standard search terms as well as MeSh terms on PubMed and EMBASE. Randomized, double-blind, placebo-controlled trials investigating prophylactic magnesium administration in migraineurs aged 18-65 were considered eligible. In a mutual effort, the studies found were sorted and analyzed under consideration of the guidelines for controlled trials for drugs in migraine by the International Headache Society and using predefined eligibility criteria. The resulting clinical trials were jointly analyzed by FR and AvL applying the evidence classification scheme by the American Academy of Neurology and the Cochrane bias tool to assess the evidence-base. In accordance with the guidelines for controlled trials, the number of migraine days and number of migraine attacks were chosen as primary efficacy parameters. The present review was not registered. RESULTS: Out of 204 search results, five clinical trials fulfilling the selection procedure were found. One out of two Class I evidence trials showed a significant reduction of the number of migraine attacks compared with placebo, while two out of three Class III trials evinced a statistically significant reduction of the primary efficacy parameters compared with placebo. CONCLUSION: This systematic review provides Grade C (possibly effective) evidence for prevention of migraine with magnesium. Prophylactic treatment of migraine by means of high levels of magnesium dicitrate (600 mg) seems to be a safe and cost efficient strategy in clinical use.

Pain modulation is affected differently in medication-overuse headache and chronic myofascial pain - A multimodal MRI study.

Background Neuroimaging studies revealed structural and functional changes in medication-overuse headache (MOH), but it remains unclear whether similar changes could be observed in other chronic pain disorders. Methods In this cross-sectional study, we investigated functional connectivity (FC) with resting-state functional magnetic resonance imaging (fMRI) and white matter integrity using diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) and mean diffusivity (MD) in patients with MOH ( N = 12) relative to two control groups: patients with chronic myofascial pain (MYO; N = 11) and healthy controls (CN; N = 16). Results In a data-driven approach we found hypoconnectivity in the fronto-parietal attention network in both pain groups relative to CN (i.e. MOH < CN and MYO < CN). In contrast, hyperconnectivity in the saliency network (SN) was detected only in MOH, which correlated with FA in the insula. In a seed-based analysis we investigated FC between the periaqueductal grey (PAG) and all other brain regions. In addition to overlapping hyperconnectivity seen in patient groups (relative to CN), MOH had a distinct connectivity pattern with lower FC to parieto-occipital regions and higher FC to orbitofrontal regions compared to controls. FA and MD abnormalities were mostly observed in MOH, involving the insula. Conclusions Hyperconnectivity within the SN along with associated white matter changes therein suggest a particular role of this network in MOH. In addition, abnormal connectivity between the PAG and other pain modulatory (frontal) regions in MOH are consistent with dysfunctional central pain control.

Cortical Alterations in Medication-Overuse Headache.

OBJECTIVE: Using surface-based morphometry we aimed to provide a detailed examination of cortical alterations in medication-overuse headache (MOH), by disentangling between altered cortical thickness and gyrification (folding). BACKGROUND: In MOH, pain modulation is probably dysfunctional at the cortical and subcortical level, resulting in a disequilibrium between pain inhibition and facilitation. Both increased and decreased cortical volumes have been reported in individuals with MOH. There is however no detailed examination to date that distinguishes between altered cortical thickness and gyrification. Such distinction would help to identify the nature and timing of neurodevelopmental mechanisms at play in affected individuals. METHODS: We investigated cortical thickness and gyrification in 29 patients with MOH according to International Headache Society criteria and 29 age- and gender-matched controls, using high-resolution structural MRIs of the brain analyzed with FreeSurfer. This is a secondary analysis of data from a previously published voxel-based morphometry study. RESULTS: In patients with MOH compared to controls, reduced cortical thickness was observed in the left prefrontal cortex. We also observed higher local gyrification in one cluster extending from the fusiform cortex to adjacent medial temporal regions, and in another cluster in the right occipital pole. Higher gyrification in the right occipital pole predicted poor response after detoxification. CONCLUSIONS: Corroborating previous volumetric results, our study adds information on the putative neurobiological mechanisms involved in MOH, suggesting neurodevelopmental changes in MOH.

Postoperative hemicrania continua-like headache - a case series.

BACKGROUND: Hemicrania continua (HC) is a rare chronic headache disorder, typically accompanied by cranial autonomic features and responding to therapeutic doses of indomethacin. The pathophysiology of hemicrania continua is not fully understood. FINDINGS: We report a series of three patients who developed a continuous hemicranial headache after cranial surgery. Each case presented a similar phenotype of continuous half-sided headache, cranial autonomic symptoms with exacerbations (2/3), and a response to indomethacin. CONCLUSION: The biology of hemicrania continua may be activated post-craniotomy just as can be seen with other primary headache disorders.

Decrease of gray matter volume in the midbrain is associated with treatment response in medication-overuse headache: possible influence of orbitofrontal cortex.

Patients with chronic daily headache and overuse of analgesics, triptans, or other acute headache compounds, are considered to suffer from medication-overuse headache (MOH). This implies that medication overuse is the cause of headache chronification. It remains a key question why only two-thirds of patients with chronic migraine-like headache and overuse of pain medication improve after detoxification, whereas the remainder continue to have chronic headache. In the present longitudinal MRI study, we used voxel-based morphometry to investigate gray matter changes related to medication withdrawal in a group of humans with MOH. As a main result, we found that only patients with significant clinical improvement showed a significant decrease of previously increased gray matter in the midbrain including periaqueductal gray matter and nucleus cuneiformis, whereas patients without improvement did not. Patients without treatment response had less gray matter in the orbitofrontal cortex. Another striking result is the correlation of treatment response with the amount of orbitofrontal gray matter. Thus, we demonstrate adaptive gray matter changes within the pain modulatory system in patients with MOH who responded to detoxification, probably reflecting neuronal plasticity. Decreased gray matter in the orbitofrontal cortex at baseline may be predictive of poor response to treatment.

Signatures of migraine aura in high-density-EEG.

OBJECTIVE: Cortical spreading depolarization is highly conserved among the species. It is easily detectable in direct cortical surface recordings and has been recorded in the cortex of humans with severe neurological disease. It is considered the pathophysiological correlate of human migraine aura, but direct electrophysiological evidence is still missing. As signatures of cortical spreading depolarization have been recognized in scalp EEG, we investigated typical spontaneous migraine aura, using full band high-density EEG (HD-EEG). METHODS: In this prospective study, patients with migraine with aura were investigated during spontaneous migraine aura and interictally. Time compressed HD-EEG were analyzed for the presence of cortical spreading depolarization characterized by (a) slow potential changes below 0.05 Hz, (b) suppression of faster activity from 0.5 Hz - 45 Hz (c) spreading of these changes to neighboring regions during the aura phase. Further, topographical changes in alpha-power spectral density (8-14 Hz) during aura were analyzed. RESULTS: In total, 26 HD-EEGs were recorded in patients with migraine with aura, thereof 10 HD-EEGs during aura. Eight HD-EEGs were recorded in the same subject. During aura, no slow potentials were recorded, but alpha-power was significantly decreased in parieto-occipito-temporal location on the hemisphere contralateral to visual aura, lasting into the headache phase. Interictal alpha-power in patients with migraine with aura did not differ significantly from age- and sex-matched healthy controls. CONCLUSIONS: Unequivocal signatures of spreading depolarization were not recorded with EEG on the intact scalp in migraine. The decrease in alpha-power contralateral to predominant visual symptoms is consistent with focal depression of spontaneous brain activity as a consequence of cortical spreading depolarization but is not specific thereof. SIGNIFICANCE: Cortical spreading depolarization is relevant in migraine, other paroxysmal neurological disorders and neurointensive care.