Prevalence and Trajectories of Post-COVID-19 Neurological Manifestations: A Systematic Review and Meta-Analysis.

INTRODUCTION: The aim of this systematic review and meta-analysis was to evaluate the prevalence of thirteen neurological manifestations in people affected by COVID-19 during the acute phase and at 3, 6, 9 and 12-month follow-up time points. METHODS: The study protocol was registered with PROSPERO (CRD42022325505). MEDLINE (PubMed), Embase, and the Cochrane Library were used as information sources. Eligible studies included original articles of cohort studies, case-control studies, cross-sectional studies, and case series with ≥5 subjects that reported the prevalence and type of neurological manifestations, with a minimum follow-up of 3 months after the acute phase of COVID-19 disease. Two independent reviewers screened studies from January 1, 2020, to June 16, 2022. The following manifestations were assessed: neuromuscular disorders, encephalopathy/altered mental status/delirium, movement disorders, dysautonomia, cerebrovascular disorders, cognitive impairment/dementia, sleep disorders, seizures, syncope/transient loss of consciousness, fatigue, gait disturbances, anosmia/hyposmia, and headache. The pooled prevalence and their 95% confidence intervals were calculated at the six pre-specified times. RESULTS: 126 of 6,565 screened studies fulfilled the eligibility criteria, accounting for 1,542,300 subjects with COVID-19 disease. Of these, four studies only reported data on neurological conditions other than the 13 selected. The neurological disorders with the highest pooled prevalence estimates (per 100 subjects) during the acute phase of COVID-19 were anosmia/hyposmia, fatigue, headache, encephalopathy, cognitive impairment, and cerebrovascular disease. At 3-month follow-up, the pooled prevalence of fatigue, cognitive impairment, and sleep disorders was still 20% and higher. At six- and 9-month follow-up, there was a tendency for fatigue, cognitive impairment, sleep disorders, anosmia/hyposmia, and headache to further increase in prevalence. At 12-month follow-up, prevalence estimates decreased but remained high for some disorders, such as fatigue and anosmia/hyposmia. Other neurological disorders had a more fluctuating occurrence. DISCUSSION: Neurological manifestations were prevalent during the acute phase of COVID-19 and over the 1-year follow-up period, with the highest overall prevalence estimates for fatigue, cognitive impairment, sleep disorders, anosmia/hyposmia, and headache. There was a downward trend over time, suggesting that neurological manifestations in the early post-COVID-19 phase may be long-lasting but not permanent. However, especially for the 12-month follow-up time point, more robust data are needed to confirm this trend.

International Headache Society global practice recommendations for the acute pharmacological treatment of migraine.

BACKGROUND: In an effort to improve migraine management around the world, the International Headache Society (IHS) has here developed a list of practical recommendations for the acute pharmacological treatment of migraine. The recommendations are categorized into optimal and essential, in order to provide treatment options for all possible settings, including those with limited access to migraine medications. METHODS: An IHS steering committee developed a list of clinical questions based on practical issues in the management of migraine. A selected group of international senior and junior headache experts developed the recommendations, following expert consensus and the review of available national and international headache guidelines and guidance documents. Following the initial search, a bibliography of twenty-one national and international guidelines was created and reviewed by the working group. RESULTS: A total of seventeen questions addressing different aspects of acute migraine treatment have been outlined. For each of them we provide an optimal recommendation, to be used whenever possible, and an essential recommendation to be used when the optimal level cannot be attained. CONCLUSION: Adoption of these international recommendations will improve the quality of acute migraine treatment around the world, even where pharmacological options remain limited.

Dairy and Headaches: What is the Connection?

PURPOSE OF REVIEWS: Headaches represent a prevalent and burdensome health condition, affecting individuals of all ages worldwide. While dietary factors have been implicated in headache pathophysiology, the association between dairy consumption and headaches remains controversial and inadequately understood. This comprehensive review systematically examines the existing literature to elucidate the relationship between dairy intake and headaches, addressing methodological challenges, potential biases, and gaps in the current knowledge. RECENT FINDINGS: A thorough search of electronic databases identified relevant observational studies, clinical trials, and mechanistic investigations exploring the impact of dairy consumption on headache incidence, frequency, severity, and duration. Methodological considerations, including study design, measurement of exposure and outcome variables, confounding factors, and sources of bias, were critically evaluated to assess the strength of evidence and validity of findings. Despite heterogeneity across studies, emerging evidence suggests a complex and multifaceted relationship between dairy intake and headaches, influenced by individual characteristics, dietary patterns, headache subtype, and study context. While some studies report a positive association between dairy consumption and headaches, others indicate no significant effect or potential therapeutic benefits of dairy restriction. Mechanistic insights suggest plausible biological mechanisms, including neuroinflammatory pathways, neurotransmitter modulation, vascular effects, and gut-brain interactions, which may mediate the observed associations. Future research directions encompass longitudinal studies, mechanistic investigations, stratified analyses, randomized controlled trials, and exploration of the gut microbiota to further elucidate the underlying mechanisms and inform evidence-based dietary recommendations for headache management. This integrative review underscores the importance of interdisciplinary collaboration and personalized approaches to address the complex interplay between diet, headaches, and overall health.

The link between cutaneous allodynia and pain/sensitivity in teeth and gums during migraine episodes.

BACKGROUND: Migraine is one of the most common primary headaches worldwide, while toothache is the most common pain in the orofacial region. The association of migraine pain, and oral pain is unknown. This study aims to investigate the association between migraine and dental and gingival pain with the presence of allodynia. METHODS: A questionnaire comprising demographic data with the ID-Migraine (IDM) tool, an Allodynia Symptom Checklist (ASC), and inquiries about pain and sensitivity in the teeth and gums during migraine attacks was administered to the participants and 762 responded the survey. The study classified participants based on the ASC, and the relationship between allodynia and pain/sensitivity in the teeth and/or gums during migraine attacks was analyzed. The statistical analyses utilized Chi-square tests and the Fisher-Exact test. RESULTS: Among 762 migraine patients, 430 (56.44%) were classified as allodynia (+), while 332 (43.56%) were classified as allodynia (-) (p < 0.001). Additionally, 285 participants (37.5%) reported experiencing pain and sensitivity in the teeth and gums during migraine attacks, with a significant relationship observed between allodynia and pain/sensitivity in the teeth and/or gums during migraine attacks (p < 0.001). CONCLUSION: The findings of this study have important clinical implications. For migraine patients who are non-allodynic, the presence of pain and sensitivity in their teeth and gums during migraine attacks may indicate underlying dental diseases or the need for dental treatment especially root canal treatment. However, for allodynic patients, such symptoms may not necessarily indicate the presence of dental diseases or the need for dental treatment especially root canal treatment. These results underscore the significance of considering the presence of allodynia in the assessment and management of oral symptoms during migraine attacks.

Secondary headache disorders in Turkey, the Middle East, Asia, and Africa: A cross-sectional, multicenter study.

BACKGROUND: This multicenter cross-sectional study aimed to determine the frequency and characteristics of secondary headaches in different geographic regions, including Turkey, the Middle East, Asia, and Africa. METHODS: Patients were admitted to the study on a particular day each week for five consecutive weeks between 1 April and 16 May 2022. Before the study, all researchers underwent a constructed briefing about the use and code of the ICHD-3 criteria. The study was conducted in two stages. In the first stage, data on secondary headaches were compared between the regions. In the second stage, the sub-diagnoses of secondary headaches were analyzed only in Turkey. RESULTS: A total of 4144 (30.0%) of the 13,794 patients reported headaches as the main symptoms at admission. A total of 422 patients were excluded from the study. In total, 1249 (33.4%) of 3722 patients were diagnosed as having secondary headaches (Turkey [n = 1039], Middle East [n = 80], Asia [n = 51], Africa [n = 79]). The frequency of secondary headaches (Turkey 33.6%, Africa 30.1%, Middle East 35.5%, Asia 35.4%) did not differ significantly between the regions (p > 0.05). The most common subtype of secondary headaches was headache attributed to substances or their withdrawal in all the studied regions. There was a female predominance in all regions, but it was lower in Africa than in Turkey. The severity and density of headaches differed significantly between the regions, with patients from Africa reporting milder pain than patients from other regions. In Turkey, the most common sub-diagnoses of secondary headaches were medication overuse headache, idiopathic intracranial hypertension, and cervicogenic headache. CONCLUSION: In the present study, one in three patients with a headache had a secondary headache. Headache attributed to substances or their withdrawal was the most common subtype of secondary headaches in all the studied regions. The female predominance of secondary headaches was lower in Africa than in Turkey. The severity and density of headaches differed significantly between regions, with patients from Africa reporting milder pain.

Real-life experiences with galcanezumab and predictors for treatment response in Turkey.

BACKGROUND: The complexity of clinical practice extends far beyond the controlled settings of trials, and there is a need for real-world studies aimed at identifying which patients will respond to anti-CGRP monoclonal antibodies in different countries. This study aimed to investigate the efficacy and safety of galcanezumab in treating migraine in a real-life setting in Turkey, as well as identify predictors of treatment response. METHODS: A total of 476 patients who diagnosed with migraine according to ICHD-3 criteria and treated with galcanezumab by headache specialists were voluntarily participated in this cross-sectional study. Galcanezumab is indicated for the prevention of migraine in adults who have at least 4 monthly migraine days in Turkey. All patients filled out a survey on Google Form that comprised 54 questions, addressing various aspects such as demographics, migraine characteristics, previous use of acute symptomatic medication, failures with preventive drug classes, comorbidities, most bothersome symptoms, as well as the interictal burden of migraine. RESULTS: Among the participants, 89.3% reported that galcanezumab treatment was beneficial for them. A decrease in the frequency (80.0%), severity (85.7%), and acute medication usage for migraine attacks (71.4%) was reported with galcanezumab treatment. An adverse effect related to galcanezumab was reported in 16.3% of cases, but no serious adverse reactions were observed. Remarkably, 14.3% of participants reported no longer experiencing any headaches, and 18.9% did not require any acute treatment while receiving galcanezumab treatment. A logistic regression model showed that male gender, lack of ictal nausea, and previous failure of more than 2 prophylactic agents may predict the non-responders. CONCLUSIONS: The first large series from Turkey showed that galcanezumab treatment is safe and effective in most of the patients diagnosed with migraine by headache experts in the real-life setting. Patients reported a significant decrease in both ictal and interictal burden of migraine and expressed satisfaction with this treatment.

Mitochondrial metabolism related markers GDF-15, FGF-21, and HIF-1α are elevated in pediatric migraine attacks.

OBJECTIVE: The purpose of this study was to investigate the serum levels of mitochondrial metabolism/reactive oxygen species (ROS)-related peptides (hypoxia inducible factor-1α [HIF-1α], fibroblast growth factor-21 [FGF-21], growth differentiation factor-15 [GDF-15]) and key migraine-related neuropeptides (calcitonin gene-related peptide [CGRP], pituitary adenylate cyclase-activating peptide-38 [PACAP-38], substance P [SP], and vasoactive intestinal peptide [VIP]) during migraine attacks and to evaluate their diagnostic value in pediatric migraine. BACKGROUND: There is increasing evidence for the important role of impairment in oxidative mitochondrial metabolism in the pathophysiology of migraine. Potential biomarkers that may reflect the relationship between migraine and mitochondrial dysfunction are unclear. METHODS: A total of 68 female pediatric migraine patients without aura and 20 female healthy controls aged 8-18 years, admitted to the hospital, were enrolled in this cross-sectional study. Serum concentrations of these molecules were determined by enzyme-linked immunosorbent assays, and clinical features and their possible diagnostic value were analyzed. RESULTS: Serum levels of HIF-1α (252.4 ± 51.9 [mean ± standard deviation]) pg/mL), GDF-15 (233.7 ± 24.7 pg/mL), FGF-21 (96.1 ± 13.1 pg/mL), CGRP (44.5 ± 11.3), and PACAP-38 (504.7 ± 128.9) were significantly higher in migraine patients compared to healthy controls (199.8 ± 26.8, 192.8 ± 20.7, 79.3 ± 4.1, 34.1 ± 3.5 and 361.2 ± 86.3 pg/mL, respectively). The serum levels of these peptides were also higher in patients with chronic migraine than in patients with episodic migraine, and higher in the ictal period than in the interictal period. A positive correlation was found between attack frequency and both HIF-1α and FGF-21 levels in migraine patients. Serum levels of VIP and SP were not different between the migraine patients and healthy controls. CONCLUSION: Migraine attacks are accompanied by elevated HIF-1α, FGF-21, GDF-15, CGRP, and PACAP-38 in medication-naive pediatric patients with migraine. Elevated circulating mitochondrial metabolism/ROS-related peptides suggest a mitochondrial stress in pediatric migraine attacks and may have potential diagnostic value in monitoring disease progression and treatment response in children. Novel approaches intervening with mitochondrial metabolism need to be investigated.

Peri-ictal headache: An underestimated prognostic finding associated with idiopathic epilepsies.

OBJECTIVE: There are a handful of studies investigating peri-ictal headache (PIH) and its clinical associations in patients with idiopathic/genetic epilepsies (I/GE). This multi-center study aimed to investigate PIH, which is an ignored comorbid condition in patients with I/GE, by headache experts and epileptologists working together. METHODS: The data were collected from a cross-sectional large study, using two structured questionnaires for headache and epilepsy features, fulfilled by neurologists. Headaches were classified according to the International Classification of Headache Disorders, third edition, whereas seizure and syndrome types were diagnosed according to International League Against Epilepsy criteria. The patients with a headache starting 24 hours before the onset of the seizure (preictal) or within 3 hours after the seizure (postictal) were defined as patients with PIH. We compared demographic and clinical differences between two groups of patients with and without PIH statistically and used ROC curves to determine a threshold of the total number of seizure triggers associated with the occurrence of PIH. RESULTS: Among 809 (531 females, 65.6%) consecutive patients with I/GE, 105 (13%) patients reported PIH (22 preictal, 82 postictal headaches, and one with both types). Peri-ictal headache was more frequently reported by females and those having a family history of migraine or epilepsy, and it was significantly associated with lower rates of seizure freedom for more than five years, drug resistance, and use of polytherapy, remarkably. Moreover, ROC curves showed that having more than 3 seizure triggers was associated with the presence of PIH. CONCLUSION: Our findings revealed that PIH may be linked to poor outcomes in I/GEs and seems to be related to a lower ictal threshold precipitated by multiple triggers. Future prospective studies will illuminate the unknown underlying mechanisms and appropriate management strategies for PIH to improve the prognosis.

The Efficacy of Physical Therapy and Rehabilitation Approaches in Chronic Migraine: A Systematic Review and Meta-Analysis.

BACKGROUND: Pharmacological treatment is the primary approach in chronic migraine (CM), although non-drug interventions such as physical therapy are used as adjunct treatments. We aimed to review the efficacy of physical therapy and rehabilitation approaches for CM and their impact on quality of life (QoL) and disability. METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included randomized controlled trials (RCTs) in adults with CM. The primary outcomes were changes in intensity, frequency, duration of headache, disability, and QoL. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) scale. Data synthesis and quantitative analysis were conducted on relevant studies. RESULTS: Seven RCTs were included in the narrative review, and five of them were eligible for quantitative analysis. Aerobic exercise (AE), osteopathic manipulative treatment (OMT), occipital transcutaneous electrical stimulation (OTES), acupressure, hydrotherapy, instrument-assisted soft tissue mobilization (IASTM), facial proprioceptive neuromuscular facilitation (FPNF), and connective tissue massage (CTM) were used in CM. AE combined with pharmacological therapy reduced the frequency, duration, and intensity of headache. OMT combined with medication improved QoL and reduced disability, intensity of pain, and migraine days per month. Hydrotherapy combined with medication also resulted in improvements in the intensity of headache, frequency, and overall QoL. IASTM and OTES reduced the intensity of headache, alleviated neck pain, and improved QoL, although there were conflicting findings following OTES alone on disability and intensity of headache. Both FPNF and CTM reduced the intensity of headache. Acupressure as an adjunct to medication did not show additional benefits on the intensity of headache and QoL. Quantitative analysis of the data showed that manual physical therapy combined with medication reduced the intensity of headache (p = 0.0796), and manual or AE combined with medication reduced the headache days per month (p = 0.047). CONCLUSIONS: A limited number of RCTs investigating the efficacy of physical therapy and rehabilitation approaches show promise in improving headache symptoms, reducing disability, and enhancing QoL in CM. Meta-analysis of the data also supported favorable outcomes for both intensity and headache days per month. Further research is needed to better understand the efficacy, optimal duration, and safety of physical therapy and rehabilitation approaches for CM, and to explore alternative interventions.

COVID-19 vaccination-related headache showed two different clusters in the long-term course: a prospective multicenter follow-up study (COVA-Head Study).

BACKGROUND: Although acute headache following COVID-19 vaccination is widely acknowledged, the long-term progression of these headaches remains poorly understood. Our objective was to identify various phenotypes of prolonged or worsened headaches associated with COVID-19 vaccination and document any changes in these phenotypes over an extended period. Additionally, we aimed to document the diverse headache presentations among patients with pre-existing primary headaches. METHODS: A multinational, prospective observational study was conducted to investigate prolonged or worsened headaches associated with COVID-19 vaccination. Questionnaires assessing COVID-19 vaccination-related headaches at three time points (initial visit, 3rd month follow-up, and 6th month follow-up) were developed for the study. Headache specialists/clinicians evaluated patients using these questionnaires in a prospective manner. Repeated K-means cluster analysis was performed to identify patient profiles with prolonged or worsened headaches related to COVID-19 vaccination. RESULTS: Among the 174 patients included in the study, there was a female-to-male ratio of 128 (73.6%) to 46 (26.4%). The mean age of the patient group was 45.2 ± 13.3 years, and 107 patients (61.5%) had a pre-existing history of primary headaches. Through the analysis, two major clusters were identified based on headache characteristics at each visit. During the first visit (n = 174), Cluster 1 primarily comprised patients with a history of primary headaches, frontal localization of pain, throbbing pain type, more severe headaches accompanied by symptoms such as nausea, phonophobia, photophobia, and osmophobia, and worsened by physical activity. In contrast, Cluster 2 consisted of patients with longer headache durations (over one month) and a stabbing/pressing quality of pain. Patients in Cluster 1 had a higher prevalence of migraine as the pre-existing primary headache disorder compared to Cluster 2 (90.48% vs. 68.18%, respectively; p = 0.005). CONCLUSION: The identification of two distinct phenotypes of prolonged or worsened headaches related to COVID-19 vaccination can provide valuable clinical insights. Having an awareness of the potential worsening of headaches following COVID-19 vaccination, particularly in patients with a primary headache disorder such as migraine, can help clinicians and headache experts anticipate and adjust their treatment strategies accordingly. This knowledge can aid in preplanning treatment modifications and optimize patient care.