Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world.

BACKGROUND: Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months. METHODS: European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as ≥50% and ≥75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response. RESULTS: Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models. CONCLUSIONS: This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success.

Neglect scoring modifications in the National Institutes of Health Stroke Scale improve right hemisphere stroke lesion volume prediction.

BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) does not equitably assess stroke severity in the two cerebral hemispheres. By attributing a maximum of two points for neglect and seven for language, it undervalues right hemisphere deficits. We aimed to investigate if NIHSS equally predicts right hemisphere lesion volumes in patients with and without neglect, and if a modification of the neglect scoring rules could increase its predictive capacity. METHODS: We analyzed a prospective cohort of acute right middle cerebral artery ischemic stroke patients. First, we calculated the correlation between NIHSS scores and lesion volume and analyzed the partial correlation of neglect. Then, we applied different modifications in the neglect scoring rules and investigated how they interfered with lesion volume predictive capacity. RESULTS: A total of 162 ischemic stroke patients were included, 108 with neglect and 54 without. The correlation between lesion volume and NIHSS was lower in patients with neglect (r = 0.540 vs. r = 0.219, p = 0.004) and neglect was a statistically significant covariate in the partial correlation analysis between NIHSS and lesion volume (p = 0.017). With the neglect score tripled and with the duplication or triplication of all neglect modalities, the correlation was significantly higher than with the standard NIHSS (p = 0.043, p = 0.005, p = 0.001, respectively). With these modifications, neglect was no longer a significant covariable in the partial correlation between lesion volume and NIHSS. CONCLUSION: A modification of NIHSS neglect scoring might improve the scale's capacity to predict lesion volume.

Working memory during spontaneous migraine attacks: an fMRI study.

OBJECTIVE: To investigate the neural correlates of working memory during a spontaneous migraine attack compared to the interictal phase, using functional magnetic resonance imaging (fMRI). BACKGROUND: Cognitive disturbances are commonly observed during migraine attacks, particularly in the headache phase. However, the neural basis of these changes remains unknown. METHODS: In a fMRI within-subject test-retest design study, eleven women (32 years of age, average) with episodic migraine were evaluated twice, first during a spontaneous migraine attack, and again in a pain-free period. Each session consisted in a cognitive assessment and fMRI while performing a working memory task (N-back). RESULTS: Cognitive test scores were lower during the ictal session than in the pain-free session. Regions typically associated with working memory were activated during the N-back task in both sessions. A voxel wise between session comparison showed significantly greater activation in the left frontal pole and orbitofrontal cortex during the attack relative to the interictal phase. CONCLUSION: Migraine patients exhibited greater activation of the left frontal pole and orbitofrontal cortex while executing a verbal working memory task during a spontaneous migraine attack when compared to the interictal state. Given the association of these regions with pain processing and inhibitory control, these findings suggest that patients recruit inhibitory areas to accomplish the cognitive task during migraine attacks, a neural signature of their cognitive difficulties.

Real-world effectiveness of fremanezumab for the preventive treatment of migraine: Interim analysis of the pan-European, prospective, observational, phase 4 PEARL study.

BACKGROUND: The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment. METHODS: Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported. RESULTS: Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported. CONCLUSION: PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111.

Prognosis of headache in children: a 25-year follow-up.

AIM: To describe the natural history, evaluate the long-term prognosis, and identify predictors of a favorable outcome of childhood migraines in a cohort of children who had been diagnosed with migraine 25 years before. METHODS: One hundred eighteen children with headache (ages 2 to 15), observed in a headache outpatient clinic of a University Hospital in 1994, by one of the authors, were revaluated in 2019/2020 by a standardized telephone interview specifying headache characteristics, treatment, precipitants, and family history. Headache diagnosis at follow-up was based on ID-Migraine and confirmed by a semistructured interview. RESULTS: Revaluation was achieved for 88 (75%) patients (43 with migraine), 47 women and age average 41.2 ± 3.2. Over the follow-up (average 25.5 years), 33% of the patients had experienced remission, 41% maintained the same diagnosis, and 26% evolved into a different headache. Sixty six percent reported an improvement. Only eight patients were attending regular consultations because of headache. Male sex came out as the only predictor of a favorable outcome. CONCLUSION: Most patients (66%) with pediatric headache continue to experience headache although reporting a significant improvement. Boys tended to remit more often than girls. This data suggests that age, genetics, and hormonal factors may play an important role in migraine phenotypic expression.

Undergraduate neurology teaching: Comparison of an inpatient versus outpatient clinical setting.

BACKGROUND: Neurology is often perceived as a difficult discipline by medical students, yet it is an essential part of medical training. While the most common disorders of the nervous system can be observed in the outpatient setting, positive neurological signs are more likely to be found in neurology wards. We aimed to compare the impact of a neurology outpatient versus inpatient rotation setting on the grades obtained by medical students as a proxy measure of the learning outcomes. METHODS: We compared the results obtained by fourth year medical students in practical (OSCE) and multiple choice question (MCQ) exams in neurology, between students whose main (total of 24 h contact) teaching allocation was either the outpatient or inpatient setting, controlling for students' gender, teacher, academic year and student' previous achievement (measured by their scores on practical evaluation). RESULTS: A total of 1127 students were included, of whom 644 (57.14%) were allocated mainly to the neurology ward and 483 (42.86%) to the outpatient clinic. Students assigned to the ward obtained significantly higher grades in the OSCE and MCQ exams than those placed in the outpatient clinic. Teaching setting was an independent predictor of both classifications after adjustment. CONCLUSIONS: The teaching setting had a significant impact on the learning outcomes. This may be due to a higher likelihood of observing abnormal neurological signs or to more student-centered teaching on the ward. These results highlight the importance of a balanced distribution of students by different clinical settings.

Headache Gauge: a real-life calendar-based tool for headache monitoring.

BACKGROUND: This study aimed to validate a semi-quantitative composite score tool, "Headache Gauge" (HG), to monitor the treatment effect in primary headaches in everyday clinic practice, adjustable to any chosen timeframe. METHOD: A cohort validation study of HG was performed in primary headache patients, recovering their clinical data and patient-related outcome measures (PROMs) for headache (HIT-6, MIDAS, HURT), work impact (WPAIQ), quality-of-life (SF-12), and mood (STAI, ZUNG). HG score distribution, its relation to clinical variables, its internal consistency, and its convergent validity were determined. RESULTS: HG was plotted in 233 patients: 90.1% females, age average 37 years, 86% with migraine, 27% with chronic headaches, and 28% with medication overuse. HG ranged from 0.21 to 58.3 in this sample, higher in chronic headaches (HG 16) and medication overuse (HG 15). HG presented good concurrent validity, significantly correlating with HIT-6 (p < 0.0001), SF-12 (p = 0.001), WPAIQ (p < 0.0001), MIDAS (p < 0.0001), and HURT (p < 0.0001). Good sensitivity to change (p < 0.001) and moderate test-retest reliability (p = 0.001) were calculated after reassessment of 147 patients (63.1% of the initial sample). CONCLUSIONS: Headache Gauge is a clinical data-based outcome measure that conceptually translates the percentage of lost time to headache in any given timeframe. It relates to headache impact, therefore bearing the potential to be relevant in real-life clinical monitoring.

Cognitive aging in migraine sufferers is associated with more subjective complaints but similar age-related decline: a 5-year longitudinal study.

OBJECTIVES AND BACKGROUND: The effect of headache on cognitive performance is controversial, due to conflicting results obtained from studies in clinical or population settings. We aimed to understand if migraine and other headaches modify the rates of decline on different cognitive measures, during a 5-year interval. DESIGN AND METHOD: A cohort of community dwelling adults (> 50 years) with migraine (MH), non-migraine headaches (NMH) and controls without headache (WoH), was assessed by a comprehensive neuropsychological battery with tests of memory, language and executive functions, repeated 5 years apart. Change in performance between baseline and reevaluation was compared between groups, and controlled for age, gender, literacy and depressive symptoms. RESULTS: A total of 275 participants (78.5% WoH, 12.7% MH, 8.7% NMH) were reevaluated (average age 70.40 + 8.34 years, 64% females). Cognitive decline or dementia occurred in 11.4%, with a similar proportion among the three groups. Although MH participants had significantly more subjective cognitive complaints (p = 0.030, 95%CI:]-3.929,-0.014[), both MH and NMH subjects showed an age-associated decline identical to controls. Furthermore, migraine features (disease and attack duration, frequency and aura) were unrelated with cognitive performance. CONCLUSION: Migraine and non-migraine headache are not associated with increasing risk of dementia or cognitive decline at an older age although subjects with migraine have more cognitive complaints. Longer longitudinal studies are necessary to understand if this pattern persists for more than 5 years.

Cognition and Cognitive Impairment in Migraine.

BACKGROUND: Migraine is a complex neurological disorder that affects a significant percentage of the human species, from all geographic areas and cultures. Cognitive symptoms and dysfunctions are interim and disabling components of this disorder and may be related to the brain processes underlying the pathophysiology. Yet they are often undervalued by clinicians. In this review, we present the different types of cognitive dysfunctions associated with migraine and the mechanisms that are potentially causing them. FINDINGS: While reversible attack-related cognitive dysfunction seems extremely consistent and likely related to functional cortical and subcortical brain changes occurring during attacks, interictal cognitive dysfunction is less consistent and might become more relevant as attack frequency and disease complexity increase. Migraine traits do not seem a predisposition to long-term cognitive decline. Cognitive dysfunction is a frequent manifestation of migraine attacks and may be specific to this disorder; it is important to understand if it could be useful in migraine diagnosis. Attack-related cognitive dysfunction is clinically relevant and contributes to disability, so it should be perceived as a therapeutic target. While there is no evidence to support that migraine increases the risk of long-term or persistent cognitive dysfunction, the fact that it occurs during the attacks and may persist in subjects with frequent or complicated attacks should prompt the understanding of the mechanisms related to its pathophysiology for it may also clarify the processes underlying migraine.

Visual and visuomotor processing of hands and tools as a case study of cross talk between the dorsal and ventral streams.

A major principle of organization of the visual system is between a dorsal stream that processes visuomotor information and a ventral stream that supports object recognition. Most research has focused on dissociating processing across these two streams. Here we focus on how the two streams interact. We tested neurologically-intact and impaired participants in an object categorization task over two classes of objects that depend on processing within both streams-hands and tools. We measured how unconscious processing of images from one of these categories (e.g., tools) affects the recognition of images from the other category (i.e., hands). Our findings with neurologically-intact participants demonstrated that processing an image of a hand hampers the subsequent processing of an image of a tool, and vice versa. These results were not present in apraxic patients (N = 3). These findings suggest local and global inhibitory processes working in tandem to co-register information across the two streams.

Clinical description of attack-related cognitive symptoms in migraine: A systematic review.

Introduction Cognitive symptoms have been described during migraine attacks since the Roman era; while being neglected throughout the centuries, they are relevant contributors to migraine-related disability. Objective To determine whether cognitive symptoms are included in clinical series describing migraine attack phenomenology, and which symptoms occur in each attack phase. Method Systematic review of existing data on clinical descriptions of migraine attacks, focusing on cognitive symptomatology. Data were organized and analyzed qualitatively, due to methodological differences between studies. Results Twenty-four articles were reviewed, with a total sample of 7007 patients, including 82.9% females with an average age of 39.2 years. Twenty one (75%) studies analyzed one phase of the attack (eight prodromes, five auras, one between aura and pain, three headaches and three postdromes), the remaining studied more than one phase. Cognitive complaints were the most frequent symptom of the prodromic (30%) and headache (38%) phases, while fatigue (70%) dominated the resolution phase. Not enough data is available to estimate the frequency of cognitive symptoms during the aura. Discussion Cognitive symptoms are described in all phases of the migraine attack phenomenology in published clinical series of migraine. Their characteristics appear to be different in each attack phase, although methodological limitations prevent generalization of this finding.

Red Ear: Syndrome or Symptom?

Red ear syndrome (RES) is a rare disorder characterized by attacks of unilateral ear pain during which the ear becomes red. Episodes can occur spontaneously, or be triggered, in most cases, by rubbing or touching the ear. Both duration and frequency are variable. RES has been explained by a dysfunction of cervical spinal nerves (C3 root) and a dysregulation with disinhibition of brainstem trigemino-autonomic circuits, leading to sympathetic inhibition and parasympathetic hyperactivity producing vasodilation. We describe 6 new cases of RES with different characteristics. Although all presented the cardinal symptom of red ear, the headache patterns were suggestive of other primary headaches (migraine or cluster headache). Therapeutic response was obtained when directed to the associated primary headache phenotype, suggesting that RES may be a phenomena associated with different headaches, rather than a syndrome in itself.

Familial SUNCT in mother and son.

BACKGROUND: Trigeminal autonomic cephalalgias comprise a heterogeneous group of lateralized headaches associated with ipsilateral autonomic symptoms. They are usually localized within the territory of one or more rami of the trigeminal nerve, but may be localized outside its cutaneous territory. Although these headaches are considered primary disorders, the evidence supporting their genetic nature is lacking, particularly concerning their neuralgic forms, with the exception of a familial case described partly based on a historical account. CASE REPORTS: We report on a mother and son with episodic, short-lasting, intense, paroxysmal headaches, with the same localization in the left retroauricular region, associated with prominent conjunctival injection and tearing, which are consistent with the diagnosis of SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing). DISCUSSION: These cases corroborate the existence of hereditary forms of this disorder, thus supporting its primary nature.

The impact of cognitive symptoms on migraine attack-related disability.

BACKGROUND: The socio-economic impact of migraine is mostly related to work loss either by absenteeism or decreased work performance. Migraine-associated cognitive dysfunction during an attack may contribute to these difficulties. OBJECTIVE: The objective of this article is to analyze the presence and relevance of cognitive symptoms during migraine attacks and to relate their intensity and symptom-related disability with other migraine-defining symptoms. METHODS: Consecutive migraine patients of a headache clinic completed diaries scoring each migraine symptom (including cognitive symptoms) intensity and symptom-related disability. RESULTS: Of 100 consecutive patients included in this study, 34 (all females, age average 31.8 ± 8.8 years) returned information on 229 attacks, on average 6.7 per participant. Every symptom's intensity was always rated slightly higher than the disability it caused. Pain was the symptom scored with the highest intensity and disability, followed by cognitive symptoms (difficulty in thinking and worsening with mental effort) and photo- and phonophobia. Scoring was independent of any of the clinical variables. Attack intensity and disability scores correlated with intensity and disability from pain and from worsening with mental effort. CONCLUSIONS: Attack-related cognitive symptoms are intense and disabling. Some attack-related cognitive symptoms correlate to intensity and disability subjectively attributed to the migraine attack. Cognitive performance should be addressed as a valuable secondary endpoint in trials of acute migraine treatment.

Education modifies the type of subjective memory complaints in older people.

OBJECTIVE: The aim of the study is to analyze the relationship between the level of education and the profile of subjective memory complaints (SMC). METHODS: Participants were healthy volunteers aged >50 years old, from a community-based sample. Educational attainment was self-reported, and participants were subsequently assembled in four groups, according to the highest grade achieved in school. Additionally, they were questioned about their own memory abilities using an SMC scale (total score 0-21) and assessed for the presence of depressive symptoms. RESULTS: A total of 841 participants aged 50-92 years old were included. The mean total score on the SMC scale was 5.3 ± 3.2, and 80.4% of the subjects reported at least one minor complaint about their memory. There was no correlation between total SMC score and higher educational level, even after accounting for the presence of depressive symptoms. However, regarding specific SMC, the use of notes to avoid forgetting was more frequent in higher levels of education, whereas the opposite trend was observed for complaints of transient confusion. CONCLUSION: Educational attainment possibly modulates the frequency and type of SMC in normal aging. Because these complaints are a major symptom for the diagnosis of cognitive decline, it seems relevant to consider the level of education when interpreting subjective reports on memory.

A novel approach to investigate recursion and iteration in visual hierarchical processing.

We describe a new method to explore recursive cognition in the visual domain. We define recursion as the ability to represent multiple hierarchical levels using the same rule, entailing the ability to generate new levels beyond those previously encountered. With this definition recursion can be distinguished from general hierarchical embedding. To investigate this recursion/hierarchy distinction in the visual domain, we developed two novel methods: The Visual Recursion Task (VRT), in which an inferred rule is used to represent new hierarchical levels, and the Embedded Iteration Task (EIT), in which additional elements are added to an existing hierarchical level. We found that adult humans can represent recursion in the visuo-spatial domain, and that this ability is distinct from both general intelligence and the ability to represent iterative processes embedded within hierarchical structures. Compared with embedded iteration, visual recursion correlated positively with other recursive planning tasks (Tower of Hanoi), but not with specific visuo-spatial resources (spatial short-term memory and working memory). We conclude that humans are able to use recursive representations to process complex visuo-spatial hierarchies and that our visual recursion task taps into specific cognitive resources. This method opens exciting opportunities to explore the relationship between visual recursion and language.

Cyclic nocturnal awakening: a warning sign of a cluster bout.

INTRODUCTION: Cluster headache is an excruciating unilateral headache with autonomic symptoms whose periodic nocturnal activity, which interrupts sleep, has been attributed to a hypothalamic generator. CASE REPORT: We describe a patient with a longstanding episodic cluster headache who experienced, on two occasions, a period of nocturnal awakenings without pain or autonomic symptoms, lasting one week before the onset of a cluster bout. Awakenings occurred twice/night at the same hours of impending cluster attacks and had no apparent trigger, being unusual for this patient who had no previous sleep disturbances. Neurological examination and brain imaging were normal. DISCUSSION: This case documents two new aspects of cluster headache. It suggests that repeated nocturnal awakenings can be a warning sign of an impending cluster period, a finding that may have therapeutic implications, and also that hypothalamic activation may begin several days before trigemino-autonomic symptoms, thus behaving as a true bout generator.

Cognitive dysfunction during migraine attacks: a study on migraine without aura.

BACKGROUND: Cognitive difficulties contribute to patients' disability during migraine attacks and have been overlooked in migraine research. Neuropsychological studies performed during attacks have produced inconsistent findings due to design differences and limitations. OBJECTIVE: Our objective is to document changes in cognitive performance of migraine patients during migraine attacks with a comprehensive battery of cognitive/behavioral tests, while controlling for potential confounders. METHOD: A prospective two-period, randomized, cross-over study compared within-subject neuropsychological evaluation in two conditions-during a naturally occurring untreated migraine attack and a headache-free period. RESULTS: Thirty-nine patients with episodic migraine (37 females, average 38 years old) were included and 24 completed the study. Participants performed worse during the attack in the majority of cognitive tests, compared to the headache-free status, and significantly so in word reading speed (p = 0.013), verbal learning (p = 0.01), short-term verbal recall with (p = 0.01) and without (p = 0.013) semantic cueing and delayed recall with (p = 0.003) and without (p = 0.05) semantic cues. Differences found were unrelated to age, gender, literacy, condition order, interval between evaluations, anxiety, pain intensity or duration of the attack. DISCUSSION: Cognitive performance decreases during migraine attacks, especially in reading and processing speed, verbal memory and learning, supporting patients' subjective complaints. These findings suggest the existence of a reversible brain dysfunction during attacks of migraine without aura, which can relate specifically to migraine or be a consequence of acute pain processing by the brain.

Do Acoustic Characteristics of Dysarthria in People With Parkinson's Disease Differ Across Languages?

PURPOSE: Cross-language studies suggest more similarities than differences in how dysarthria affects the speech of people with Parkinson's disease (PwPD) who speak different languages. In this study, we aimed to identify the relative contribution of acoustic variables to distinguish PwPD from controls who spoke varieties of two Romance languages, French and Portuguese. METHOD: This bi-national, cross-sectional, and case-controlled study included 129 PwPD and 124 healthy controls who spoke French or Portuguese. All participants underwent the same clinical examinations, voice/speech recordings, and self-assessment questionnaires. PwPD were evaluated off and on optimal medication. Inferential analyses included Disease (controls vs. PwPD) and Language (French vs. Portuguese) as factors, and random decision forest algorithms identified relevant acoustic variables able to distinguish participants: (a) by language (French vs. Portuguese) and (b) by clinical status (PwPD on and off medication vs. controls). RESULTS: French-speaking and Portuguese-speaking individuals were distinguished from each other with over 90% accuracy by five acoustic variables (the mean fundamental frequency and the shimmer of the sustained vowel /a/ production, the oral diadochokinesis performance index, the relative sound level pressure and the relative sound pressure level standard deviation of the text reading). A distinct set of parameters discriminated between controls and PwPD: for men, maximum phonation time and the oral diadochokinesis speech proportion were the most significant variables; for women, variables calculated from the oral diadochokinesis were the most discriminative. CONCLUSIONS: Acoustic variables related to phonation and voice quality distinguished between speakers of the two languages. Variables related to pneumophonic coordination and articulation rate were the more effective in distinguishing PwPD from controls. Thus, our research findings support that respiration and diadochokinesis tasks appear to be the most appropriate to pinpoint signs of dysarthria, which are largely homogeneous and language-universal. In contrast, identifying language-specific variables with the speech tasks and acoustic variables studied was less conclusive.