Depression and Anxiety Symptoms in Headache Disorders: An Observational, Cross-Sectional Study.

BACKGROUND: Headache disorders have been associated with anxiety and depressive disorders. The aim of this study was to assess symptoms of anxiety and depression in a large sample of individuals with different headache disorders (HDs) in order to determine whether their frequency differs by headache type. METHODS: Consecutive individuals with headache attending a headache outpatient clinic were interviewed with the HAM-D and HAM-A, along with age, sex, and education matched non-headache individuals. RESULTS: Individuals numbering 2673 with headache (females 71.2%) and 464 non-headache individuals (females 70.9%) were interviewed (with participation rates of 98.3% and 91.0%, respectively). Migraine was diagnosed in 49.7%, tension-type headache in 38%, cluster headache 5.2%, and medication overuse (MO) in 21.8%. Participants with HD scored more in HAM-A (OR = 4.741, CI95%: 3.855-5.831, p < 0.001) and HAM-D scales (OR = 2.319, CI95%: 1.892-2.842, p < 0.001) than non-headache individuals. Participants with chronic HDs (≥15 days with headache for ≥3 consecutive months; 52.5%) scored higher for both HAM-A (OR = 1.944, CI95%: 1.640-2.303, p < 0.001) and HAM-D (OR = 1.625, CI95%: 1.359-1.944, p < 0.001) than those with episodic HDs (33.1%), as did participants with MO vs. participants without MO (OR = 3.418, CI95%: 2.655-4.399, p < 0.001 for HAM-A, OR = 3.043, CI95%: 2.322-3.986, p < 0.001 for HAM-D). Female and low-educated participants scored higher on both scales. CONCLUSION: Because symptoms of anxiety and depression are substantial in people with HD, the treating physicians should look out for such symptoms and manage them appropriately.

Evidence-based symptomatic treatment of migraine.

Symptomatic treatment of migraine includes patient education, mainly to avoid medication overuse and known trigger factors, as well as pharmaceutical and nonpharmaceutical interventions. Disease-specific and mechanism-based agents include ergotamine and dihydroergotamine targeting the adrenergic, dopaminergic, and serotoninergic systems followed by triptans, specific agonists for 5-HT1B/1D/1F receptors, the latest being more favorable in terms of safety and documentation of efficacy. Recently, antagonists of calcitonin gene-related peptide (gepants) and selective agonists of the 5-HT1F receptor (ditans) have been added, with promising efficacy and safety. Triptans stay as the first option treatment when attacks are moderate to severe, followed by nonspecific agents, including aspirin and paracetamol/acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs, ibuprofen and naproxen share the best documentation) for mild-to-moderate migraine attacks. Combinations with caffeine are effective as well, but barbiturates and opioids alone or in combinations should be avoided. Simple analgesics and NSAIDs attenuate cephalic pain via prostaglandin mediated mechanisms and may induce peptic, renal and hepatic adverse effects. Neuromodulation techniques include single-pulse transcranial magnetic stimulation (s-TMS), external trigeminal nerve stimulation (e-TNS), remote electrical neuromodulation (REN) and noninvasive vagus nerve stimulation (nVNS). All share good documentation and safety profile and are worthy of alternative treatment options along with physical therapy when medicines are contradicted or not well tolerated or unwanted by the patients.

Responder rates with eptinezumab over 24 weeks in patients with prior preventive migraine treatment failures: post hoc analysis of the DELIVER randomized clinical trial.

BACKGROUND AND PURPOSE: Eptinezumab reduced monthly migraine days more than placebo in the DELIVER study, a clinical trial with patients with difficult-to-treat migraine and prior preventive treatment failures. This post hoc analysis assesses the sustained response to eptinezumab at the population and patient level and evaluates the potential for response in initial non-responders. METHODS: Adults with chronic or episodic migraine and two to four prior preventive treatment failures were randomized to eptinezumab 100 mg, 300 mg or placebo every 12 weeks. Primary outcomes in this post hoc analysis are the proportion of patients with ≥30%, ≥50% or ≥75% reduction in monthly migraine days (i.e., migraine responder rates [MRRs]) during weeks 1-12 and weeks 13-24 and across 4-week intervals. Secondary outcomes are maintenance and shifts in MRRs from weeks 1-12 to weeks 13-24. RESULTS: Between weeks 1-12 and 13-24, ≥30% MRRs increased from 65.9% to 70.4% (100 mg) and from 71.0% to 74.5% (300 mg), versus 36.9% to 43.1% (placebo). The ≥50% and ≥75% MRRs were sustained or increased over the 24-week period. The largest increase in ≥30% MRRs occurred after the second infusion with eptinezumab. The percentage of initial non-responders (<30% MRRs during weeks 1-12) who experienced response (≥30% MRRs during weeks 13-24) to the second dose was 34.7% (100 mg) and 30.4% (300 mg) with eptinezumab versus 21.1% with placebo. CONCLUSION: Across MRR thresholds, most patients who responded to eptinezumab during weeks 1-12 maintained or improved response during weeks 13-24. More than one-third of initial non-responders became responders after their second infusion.

Nocebo-associated treatment discontinuation with subcutaneous anti-osteoporotic drugs. A systematic review and meta-analysis of placebo-arm dropouts in randomized-controlled trials.

OBJECTIVE: Nocebo is a concept of therapeutics referring to unpleasant symptoms attributed by a patient to a drug, due to negative anticipation. Patients receiving oral anti-osteoporotic drugs in randomized controlled trials (RCT) can experience adverse events leading to dropout, implying that nocebo contributes to treatment discontinuation for these drugs. In this study we aim to investigate the nocebo effect of subcutaneous anti-osteoporotic drugs with a higher compliance rate than orally administered drugs. STUDY DESIGN: We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for double-blind trials investigating subcutaneous anti-osteoporotic drugs for osteoporosis (namely, denosumab, teriparatide, abaloparatide and romosozumab) published up to May 2023. MAIN OUTCOME MEASURE: Dropouts due to reported adverse events in the placebo arms ("nocebo dropouts"). RESULTS: Data from 17 trials were extracted. Among 10,529 placebo-treated patients the pooled nocebo-dropout percentage was 3 % for denosumab (average: 0.03; 95 % CI: 0.01-0.05), 1 % for romosozumab (average: 0.01; 95 % CI: 0.00-0.03) and 6 % for teriparatide and abaloparatide (average: 0.06; 95 % CI: 0.05-0.07). Nocebo-dropouts were significantly higher in men than women (6 % vs. 3 %, respectively, p = 0.012), in older (mean age >68 years) than in younger patients (5 % vs. 1 %, respectively, p = 0.017) and in those with more severe osteoporosis (based on the percentage of participants with prior fragility-related fractures in the study cohort) compared with patients with no prior fracture history (4 % vs. 1 %, respectively, p = 0.046). CONCLUSION: Nocebo responses may contribute to treatment discontinuation with subcutaneous anti-osteoporotic drugs in clinical practice. Higher nocebo-related dropout rates in the higher-risk RCT population (older patients, males, those with prior fractures) show that nocebo mechanisms have the potential to hinder therapeutic efforts to specific populations who would benefit most. Prospero registration number CRD42020212843.

Numbers needed to treat or harm and likelihood of being helped versus harmed for fremanezumab in patients who had prior inadequate response to two to four classes of migraine preventive medications: A post hoc analysis.

OBJECTIVE: This study aimed to determine the number needed to treat (NNT), number needed to harm (NNH), and likelihood of being helped or harmed (LHH) in a post hoc analysis of the phase 3b FOCUS trial. BACKGROUND: Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy, tolerability, and safety in adults with episodic migraine (EM) or chronic migraine (CM), with documented previous inadequate response to two to four classes of migraine preventive medications. METHODS: In the 12-week double-blind period of the FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. NNT was based on responder analysis, defined as ≥50% reduction in monthly average number of migraine days at 12 weeks. NNH was based on discontinuations due to adverse events (AEs). RESULTS: Among patients with CM (n = 509), response rates and discontinuation rates were 27% (45/169) and 0 for quarterly fremanezumab, 29% (50/173) and 2% (3/173) for monthly fremanezumab, and 8% (13/167) and <1% (1/167) for placebo, respectively. These results translated to NNTs of 5.3 and 4.7, NNHs of 1000 and 88, and LHHs of 188 and 19 for quarterly and monthly fremanezumab, respectively. Among patients with EM (n = 328), response rates were 47% (50/107) for quarterly fremanezumab, 43% (47/110) for monthly fremanezumab, and 10% (11/111) for placebo. Discontinuation rates were <1% (n = 1) in all three groups. These results translated to NNTs of 2.7 and 3.0, NNHs of 1000 and 1000, and LHHs of 368 and 328 for quarterly and monthly fremanezumab, respectively. CONCLUSIONS: The NNT, NNH, and LHH for quarterly and monthly fremanezumab compare favorably with those for traditional oral preventive medications, including topiramate, valproate, and propranolol.

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.

Headache Attributed to Reversible Cerebral Vasoconstriction Syndrome (RCVS).

Reversible cerebral vasoconstriction syndrome (RCVS) is a condition with variable outcomes presenting a new onset thunderclap headache accompanied by focal neurological symptoms or seizures. It can be idiopathic or arise secondarily to a variety of trigger factors. The condition is increasingly recognized in clinical practice, but many facets remain poorly understood. This article aims to clarify the headache characteristics in RCVS, the temporal association of angiographic findings, the potential association of the condition with SARS-CoV-2 infection, and the clinical presentation of RCVS in children and is based on a systematic PRISMA search for published analytical or large descriptive observational studies. Data from 60 studies that fulfilled specific criteria were reviewed. Most people with RCVS exhibit a typical thunderclap, explosive, or pulsatile/throbbing headache, or a similar acute and severe headache that takes longer than 1 min to peak. Atypical presentations or absence of headaches are also reported and may be an underrecognized phenotype. In many cases, headaches may persist after resolution of RCVS. Focal deficits or seizures are attributed to associated complications including transient ischemic attacks, posterior reversible encephalopathy syndrome, ischemic stroke, cerebral edema, and intracranial hemorrhage. The peak of vasoconstriction occurs usually within two weeks after clinical onset, possibly following a pattern of centripetal propagation, and tends to resolve completely within 3 months, well after symptoms have subsided. There are a few reports of RCVS occurring in relation to SARS-CoV-2 infection, but potential underlying pathophysiologic mechanisms and etiological associations have not been confirmed. RCVS occurs in children most often in the context of an underlying disease. Overall, the available data in the literature are scattered, and large-scale prospective studies and international collaborations are needed to further characterize the clinical presentation of RCVS.

The 5-HT1F receptor as the target of ditans in migraine - from bench to bedside.

Migraine is a leading cause of disability in more than one billion people worldwide, yet it remains universally underappreciated, even by individuals with the condition. Among other shortcomings, current treatments (often repurposed agents) have limited efficacy and potential adverse effects, leading to low treatment adherence. After the introduction of agents that target the calcitonin gene-related peptide pathway, another new drug class, the ditans - a group of selective serotonin 5-HT1F receptor agonists - has just reached the international market. Here, we review preclinical studies from the late 1990s and more recent clinical research that contributed to the development of the ditans and led to their approval for acute migraine treatment by the US Food and Drug Administration and the European Medicines Agency.

The prevalence and burden of medication overuse headache in Greece.

OBJECTIVE: To estimate the prevalence and burden of medication overuse headache in a representative sample of the Greek population, aged 18-70 years old. METHODS: This is a cross-sectional descriptive observational study performed by quantitative computer-assisted telephone interviews, using a standardized 37-item questionnaire for headaches. The prevalence of medication overuse headache was estimated in the general population and compared within the groups formed by factors such as age, gender, diagnosis of headache type, prophylactic treatment used, geographical regions, social class, workdays lost and loss of productivity. RESULTS: 1197 (12.0%) participants reported headaches affecting performance out of 10,008 interviewees. The estimated prevalence of medication overuse headache in the general population was 0.7% (95% CI: 0.5-0.9). The female to male ratio was 3.6:1. The proportion of medication overuse headache was largest in the 35-54 age group, followed by the over 55 group. The Aegean islands and Crete were the regions with the highest proportion of medication overuse headache. Among participants with headaches, the proportion of medication overuse headache was 5.8% (95% CI: 4.4%-7.1%); 6.3% (95% CI: 4.7%-7.9%) among females and 4.4% (95% CI: 2.2%-6.6%) among males. In the same headache group, the proportion of medication overuse headache by prophylactic treatment for headache was 19.0% (95% CI: 9.5%-29.1%) for recipients and 5.0% (95% CI: 3.8-6.3) for non-recipients. The mean absenteeism in people with medication overuse headache was 1.0 days/month (95% CI: 0.4-1.6) and the mean presenteeism 6.3 days/month (95% CI: 3.9-8.7). The social class stratification showed a significant effect between the medication overuse headache in the sample of the general population and the C2 class, corresponding to skilled manual labour (OR: 0.7, CI: 0.5-0.9). In people with chronic migraine, and chronic tension type headache, as differentiated by the 37-item questionnaire, the proportion of medication overuse headache in the headache group estimated to be 50.5% (95% CI: 40.8%-60.1%) and 45.9%, (95% CI: 29.9%-62.0%) respectively. The group of people with acute headache medication overuse fulfilling the rest of the diagnostic criteria for medication overuse headache, except from the number of headache days per month (≥15 days/month), had a prevalence of 2.0% (95% CI: 1.75-2.30) and a proportion of 17.0% (95% CI: 14.8%-19.1%) among people with headache. In the episodic types of headache, the proportion of acute headache medication overuse was higher in the subgroup of people with high frequency episodic migraine, 24.9% (95% CI: 18.8%-31.0%), while it was 10.8% (95% CI: 8.2%-13.5%), for the low frequency episodic migraine and 8.5% (95% CI: 5.5%-10.4%), for the episodic tension type headache. CONCLUSION: The prevalence of medication overuse headache in the general population in Greece and its proportion among the people with headache belongs to the lower part of the range of the reported literature, while the 3.6:1 female to male ratio is in agreement with it. In the same line, the impact of absenteeism and presenteeism on the workplace renders the condition alarming socio-economic health problem demanding immediate health policy planning.

The evolution of comprehensive genetic analysis in neurology: Implications for precision medicine.

Technological advancements have facilitated the availability of reliable and thorough genetic analysis in many medical fields, including neurology. In this review, we focus on the importance of selecting the appropriate genetic test to aid in the accurate identification of disease utilizing currently employed technologies for analyzing monogenic neurological disorders. Moreover, the applicability of comprehensive analysis via NGS for various genetically heterogeneous neurological disorders is reviewed, revealing its efficiency in clarifying a frequently cloudy diagnostic picture and delivering a conclusive and solid diagnosis that is essential for the proper management of the patient. The feasibility and effectiveness of medical genetics in neurology require interdisciplinary cooperation among several medical specialties and geneticists, to select and perform the most relevant test according to each patient's medical history, using the most appropriate technological tools. The prerequisites for a comprehensive genetic analysis are discussed, highlighting the utility of appropriate gene selection, variant annotation, and classification. Moreover, genetic counseling and interdisciplinary collaboration could improve diagnostic yield further. Additionally, a sub-analysis is conducted on the 1,502,769 variation records with submitted interpretations in the Clinical Variation (ClinVar) database, with a focus on neurology-related genes, to clarify the value of suitable variant categorization. Finally, we review the current applications of genetic analysis in the diagnosis and personalized management of neurological patients and the advances in the research and scientific knowledge of hereditary neurological disorders that are evolving the utility of genetic analysis towards the individualization of the treatment strategy.

A Prospective, Observational Study Assessing Effectiveness, Safety, and QoL of Greek Patients with Multiple Sclerosis Under Treatment with Fingolimod.

INTRODUCTION: Fingolimod is the first approved oral therapy for relapsing-remitting multiple sclerosis (RRMS). The present study aimed to further characterize fingolimod's safety profile, and to assess the patient-reported treatment satisfaction and impact of fingolimod on the quality of life (QoL) of patients with multiple sclerosis (MS) treated in routine care in Greece. METHODS: This was a multicenter, prospective, observational, 24-month study conducted in Greece by hospital-based and private practice neurologists who specialize in MS. Eligible patients had initiated fingolimod within 15 days in accordance with the locally approved label. Safety outcomes included any adverse event (AE) observed during the study period and efficacy outcomes included both objective (disability progression and 2-year annualized relapse rate) and patient-reported assessments (Treatment Satisfaction Questionnaire for Medication (TSQM) v1.4 and the EuroQol (EQ)-5-dimension (5D) 3-level instruments). RESULTS: A total of 489 eligible patients (age 41.2 ± 9.8 years; 63.7% female; 4.2% treatment-naive) were exposed to fingolimod for a median of 23.7 months. During the observation period, 20.5% of the participants experienced 233 AEs. Lymphopenia (8.8%), leukopenia (4.2%), hepatic enzyme increased (3.4%), and infections (3.0%) were the most common. Most patients (89.3%) did not experience disability progression; the 2-year annualized relapse rate decreased by 94.7% compared to baseline. The median EQ-visual analogue scale (VAS) was 74.5 at month 24 vs. 65.0 at enrollment (p < 0.001) and the EQ-5D index score was 0.80 vs. 0.78, respectively. Significant improvements were noted in the TSQM global satisfaction and effectiveness domain scores between 6 and 24 months post enrollment (median scores at month 24, 71.4 and 66.7, respectively) (p < 0.001). Significant increases from enrollment to the 24th month were also noted in the patients' global satisfaction and effectiveness domain scores [mean change of 7.4 ± 17.7 (p = 0.005) and mean increase of 5.4 ± 16.2) (p = 0.043), respectively]. CONCLUSION: In the real-world setting of Greece, fingolimod demonstrates a clinical benefit and a predictable and manageable safety profile, which contribute towards high patient-reported treatment satisfaction and improvements in the QoL of patients with MS.

Meta-analysis of placebo-arm dropouts in osteoporosis randomized-controlled trials and implications for nocebo-associated discontinuation of anti-osteoporotic drugs in clinical practice.

Dropout from placebo arms in randomized-controlled trials is a surrogate for nocebo responses, resulting from patients' negative expectations to treatment. Among 16,460 placebo-treated patients in oral anti-osteoporotic drug trials, nocebo dropouts were 8% on average, being higher in older patients. This implies that nocebo may contribute to the osteoporosis treatment gap in clinical practice. PURPOSE: Osteoporosis is a common disease requiring long-term treatment. Despite the availability of effective anti-osteoporotic drugs, adherence to treatment is low. Nocebo, a behavior mostly related to the negative expectations to a certain treatment, decreases adherence and negatively affects treatment outcomes and health-related care costs in chronic diseases. Since in double-blind placebo-controlled randomized trials any unfavorable outcome leading to discontinuation in placebo arms is considered as nocebo, we aimed to investigate the size of nocebo response in patients participating in osteoporosis trials. METHODS: We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for dropouts due to reported adverse events in the placebo arms (nocebo dropouts) in all double-blind trials investigating anti-osteoporotic drugs published between January 1993 and March 2022. Only data on bisphosphonates and selective estrogen receptor modulators (SERMs) were analyzed (Prospero registration number CRD42020212843). RESULTS: Data from 44 trials were extracted. In 16,460 placebo-treated patients, the pooled nocebo-dropout was 8% both for bisphosphonates (average: 0.08; range 0.01-0.27; 95%CI 0.06-0.10) and SERMs (average: 0.08; range 0.03-0.15; 95%CI 0.05-0.13). Nocebo-dropouts were higher in bisphosphonate trials enrolling individuals ≥ 65 years (11%) (n = 18) compared to trials enrolling younger individuals (6%) (n = 18) (average: 0.11; 95%CI 0.08-0.13 vs. average: 0.06; 95%CI 0.05-0.08, respectively, p = 0.001). Participants' sex, dosing-intervals, publication year, or severity of osteoporosis had no impact on the nocebo-dropouts. CONCLUSION: Almost 1 in 10 osteoporosis patients receiving placebo in trials of bisphosphonates and SERMs experiences AEs leading to dropout, implying that nocebo contributes to treatment-discontinuation in clinical practice. Efforts to identify and minimize nocebo, especially in older patients, are warranted.

Current perspectives on the recognition and diagnosis of low CSF pressure headache syndromes.

INTRODUCTION: Headaches occur when cerebrospinal fluid (CSF) pressure drops following dural puncture or trauma or spontaneously. As the features of these headaches and their accompanying symptoms might not be typical, low CSF pressure headache syndromes, and spontaneous intracranial hypotension in particular, are often misdiagnosed and underdiagnosed. AREAS COVERED: The aim of this narrative review is to summarize the most recent evidence regarding the clinical presentation and the diagnosis of low CSF pressure headache syndromes. EXPERT OPINION: The clinical spectrum low CSF pressure headache syndromes varies significantly and key signs might be missing. Low CSF pressure headache syndromes should be included in the differential diagnosis of any case of refractory headache, even when the headache is not orthostatic, or there are normal neuroimaging findings, and/or lumbar puncture opening pressure is within normal limits. Future research should focus on controlled interventional studies on the treatment of low CSF pressure headache syndromes, which are currently lacking.

The nocebo phenomenon in the COVID-19 pandemic: a nocebodemic effect.

INTRODUCTION: The COVID-19 pandemic had remarkable effects on psychological distress. The main stressors were prolonged quarantine and social isolation, fear of infection and death, stigmatization, infodemic, financial difficulties, and job loss. These negative stressors, which affect mental and physical health, make people more vulnerable to nocebo-related risk behaviors. We aimed to summarize data on nocebo behaviors, such as the negative psychological consequences of the COVID-19 pandemic in terms of how people perceive and interpret medical services and treatments. AREAS COVERED: Limited data were found from randomized controlled trials with SARS-CoV-2 vaccines and from surveys on healthy people, healthcare workers, and patients with chronic pain disorders. EXPERT OPINION: Studies have shown nocebo effects among participants in SARS-CoV-2 vaccines trials, among patients with chronic pain, and among healthcare workers. These effects were widely amplified during the pandemic era, prefiguring a 'nocebodemic effect' to describe the massive negative interpretation of health services and medical treatments. Greater awareness of these findings could reduce the impact of the 'nocebodemic effect' and increase public trust in science.

B-Cell Targeted Therapies in Patients with Multiple Sclerosis and Incidence of Headache: A Systematic Review and Meta-Analysis.

BACKGROUND: Multiple Sclerosis treatment with B-cell targeted therapies may be associated with an increased incidence of headache. We aimed to find and compare the association of B-cell targeted therapies with the incidence of headache in patients with Multiple Sclerosis. METHODS: In a systematic based approach, the following databases were searched from inception until the 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. Only randomized clinical trials (RCTs) enrolling patients with Multiple Sclerosis comparing B-cell targeted therapies (Rituximab, Ocrelizumab, Ofatumumab, Ublituximab or Cladribine) with placebo were selected for the systematic review and further meta-analysis. PRISMA guidelines were followed at all stages of the systematic review. The primary outcome was an all-cause headache of B-cell targeting therapy in patients with Multiple Sclerosis. RESULTS: Nine RCTs were included. Compared with placebo, treatment with B-cell targeting therapies revealed a trend in headache risk, but it was not statistically significant (Relative Risk 1.12 [95% Confidence Interval 0.96-1.30]; p = 0.15; I2 = 9.32%). Surprisingly, in a sub-group analysis, Cladribine was statistically significant for an increase in headache risk (RR 1.20 [95% CI 1.006-1.42]; p = 0.042; I2 = 0%; 3 studies with 2107 participants). CONCLUSIONS: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Sub-analyses revealed a significant association between Cladribine alone and an increased incidence of headache. Whereas a purinergic signaling cascade is proposed as a mechanism of action, further research is needed to unravel the underlying pathogenetic mechanism of headache induction and establish headache prevention strategies.

Understanding frontal lobe function in epilepsy: Juvenile myoclonic epilepsy vs. frontal lobe epilepsy.

AIM: To compare neuropsychological function in juvenile myoclonic epilepsy (JME) and frontal lobe epilepsy (FLE) since frontal circuitry is involved in both conditions. By drawing on previously theory-guided hypotheses and findings, a particular emphasis is placed on the way different cognitive-pathophysiological mechanisms act upon to produce frontal dysfunction in JME (frontal-executive and attention-related problems: vigilance, reaction times, processing speed, and response inhibition) and in FLE (reflecting the coproduct of the functional deficit zone), respectively. METHODS: A total of 16 patients with JME, 34 patients with FLE, and 48 normal controls, all matched for age and education, were administered a comprehensive battery of tests to assess frontal-executive functions, as well as attention, memory, and learning domains. Participants did not take medications other than antiepileptics or have a psychiatric history. RESULTS: Patients with FLE overall showed worse neuropsychological performance compared to both JME and HCs. With respect to JME, patients with FLE did significantly worse in measures of verbal and nonverbal executive function, short-term-, and long-term- auditory-verbal memory and learning, immediate and delayed episodic recall, visual attention and motor function, visuo-motor coordination and psychomotor speed, speed of visual information processing, and vocabulary. Patients with JME performed significantly worse compared to FLE only in associative semantic processing, while the former outperformed all groups in vocabulary, visuomotor coordination, and psychomotor speed. CONCLUSION: We suggest that selective impairments of visual- and mostly auditory-speed of information processing, vigilance, and response inhibition may represent a salient neuropsychological feature in JME. These findings suggest the existence of an aberrantly working executive-attention system, secondary to pathological reticulo-thalamo-cortical dynamics. Contrariwise, cortically (frontal and extra-frontal) and subcortically induced malfunction in FLE is determined by the functional deficit zone i.e., the ensemble of cortical and subcortical areas that are functionally abnormal between seizures.

Visual snow: A systematic review and a case series.

BACKGROUND: Visual Snow Syndrome is a recently recognized neurological condition presenting, continuous, tiny dots across the entire visual field, accompanied by nyctalopia, photophobia and palinopsia that persist for months. It may be part of migraine aura spectrum, yet its definition is still questionable. Diagnostic criteria for Visual Snow Syndrome are included in the supplemental material of ICHD-3. We aimed to summarize recent data to improve the understanding of Visual Snow Syndrome. METHODS: After presenting four new cases, we conducted a PRISMA systematic search in PubMed/MEDLINE and Embase databases using the keyword "visual snow" with specific inclusion and exclusion criteria. RESULTS: From the 855 articles identified 30 were included for the qualitative analysis. These reports covered five aspects related to Visual Snow Syndrome: epidemiology, clinical features, comorbidities, pathophysiology, and treatment. We found limited data concerning Visual Snow Syndrome's epidemiology (one study). Clinical presentation (22 articles) and the comorbidities (migraine with aura and tinnitus most often, five reports) are described in detail. The pathophysiology of Visual Snow Syndrome is only approached with hypotheses, but several neuroimaging studies have been identified (seven articles). Treatment is based on single case reports only. CONCLUSION: Data for Visual Snow Syndrome are few and not strong enough to support Visual Snow Syndrome as a medical identity. Further investigation is needed.