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.

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.

Migraine: epidemiology and systems of care.

Migraine is a neurovascular disorder that affects over 1 billion people worldwide. Its widespread prevalence, and associated disability, have a range of negative and substantial effects not only on those immediately affected but also on their families, colleagues, employers, and society. To reduce this global burden, concerted efforts are needed to implement and improve migraine care that is supported by informed health-care policies. In this Series paper, we summarise the data on migraine epidemiology, including estimates of its very considerable burden on the global economy. First, we present the challenges that continue to obstruct provision of adequate care worldwide. Second, we outline the advantages of integrated and coordinated systems of care, in which primary and specialist care complement and support each other; the use of comprehensive referral and linkage protocols should enable continuity of care between these systems levels. Finally, we describe challenges in low and middle-income countries, including countries with poor public health education, inadequate access to medication, and insufficient formal education and training of health-care professionals resulting in misdiagnosis, mismanagement, and wastage of resources.

Headache in idiopathic/genetic epilepsy: Cluster analysis in a large cohort.

OBJECTIVE: The link between headache and epilepsy is more prominent in patients with idiopathic/genetic epilepsy (I/GE). We aimed to investigate the prevalence of headache and to cluster patients with regard to their headache and epilepsy features. METHODS: Patients aged 6-40 years, with a definite diagnosis of I/GE, were consecutively enrolled. The patients were interviewed using standardized epilepsy and headache questionnaires, and their headache characteristics were investigated by experts in headache. Demographic and clinical variables were analyzed, and patients were clustered according to their epilepsy and headache characteristics using an unsupervised K-means algorithm. RESULTS: Among 809 patients, 508 (62.8%) reported having any type of headache; 87.4% had interictal headache, and 41.2% had migraine. Cluster analysis revealed two distinct groups for both adults and children/adolescents. In adults, subjects having a family history of headache, ≥5 headache attacks, duration of headache ≥ 24 months, headaches lasting ≥1 h, and visual analog scale scores > 5 were grouped in one cluster, and subjects with juvenile myoclonic epilepsy (JME), myoclonic seizures, and generalized tonic-clonic seizures (GTCS) were clustered in this group (Cluster 1). Self-limited epilepsy with centrotemporal spikes and epilepsy with GTCS alone were clustered in Cluster 2 with the opposite characteristics. For children/adolescents, the same features as in adult Cluster 1 were clustered in a separate group, except for the presence of JME syndrome and GTCS alone as a seizure type. Focal seizures were clustered in another group with the opposite characteristics. In the entire group, the model revealed an additional cluster, including patients with the syndrome of GTCS alone (50.51%), with ≥5 attacks, headache lasting >4 h, and throbbing headache; 65.66% of patients had a family history of headache in this third cluster (n = 99). SIGNIFICANCE: Patients with I/GE can be clustered into distinct groups according to headache features along with seizures. Our findings may help in management and planning for future studies.

Latent class cluster analysis identified hidden headache phenotypes in COVID-19: impact of pulmonary infiltration and IL-6.

BACKGROUND AND OBJECTIVE: Clinical studies on COVID-19 headache are limited. This prospective study aimed to define headache characteristics, associated clinical and laboratory factors, and treatment response in COVID-19. METHODS: Cross-sectional study enrolled 287 patients diagnosed with COVID-19 and hospitalized on a regular ward during the pandemic. All patients were examined face to face and followed by a neurologist during their stay in the hospital. The characteristics, concomitant symptoms, treatment responses, and laboratory findings of COVID-19-associated headaches were recorded. RESULTS: Eighty-three COVID-19 patients reported headache (28.9%), in which 85.5% had no prior headaches. Mean age was 48.40 ± 15.90 and 58% was men. Compared to COVID-19 patients without headache (n = 204), patients with headache showed significantly higher frequency of pulmonary involvement (76%) and increased D-dimer levels. Fifty-nine percent of headaches responded iv paracetamol 1000 mg, and 85% of the paracetamol unresponsive headaches were relieved by greater occipital nerve (GON) blocks. Latent class cluster analysis identified 2 distinct class of bilateral, frontal, throbbing headaches: severe (VAS > 84), longer (> 14 h), frequent (> 7 headache days), paracetamol unresponsive-GON responsive headaches (85%), with pulmonary involvement (100%), and higher IL-6 levels (> 90 pg/mL) were classified in cluster 1. Cluster 2 included moderately affected patients (VAS > 54, > 6 h, > 4 days, 60% pulmonary involvement, > 20 pg/mL IL-6) and paracetamol responsive headaches (96%). VAS scores showed positive linear correlation with IL-6 levels (p < 0.001; r = 0.567). CONCLUSION: The intensity, duration, frequency, bilateral frontal location, and treatment response of COVID-19 headache was related to pulmonary involvement and IL-6 levels, which indicated a role of inflammation in determining the headache manifestations in moderately affected hospitalized patients. ROC curve cutoff values pointed that VAS > 70 severity, > 9 h duration, > 5 headache days, and IL-6 > 43 pg/mL levels can be diagnostic for COVID-19 headache. GON blocks can effectively abort headache when patients are unresponsive to paracetamol, and other NSAIDs are avoided during the SARS-CoV-2 infection.

HMGB1, NLRP3, IL-6 and ACE2 levels are elevated in COVID-19 with headache: a window to the infection-related headache mechanism.

BACKGROUND AND AIM: Pathogenesis of COVID-19 -related headache is unknown, though the induction of the trigeminal neurons through inflammation is proposed. We aimed to investigate key systemic circulating inflammatory molecules and their clinical relations in COVID-19 patients with headache. METHODS: This cross-sectional study enrolled 88 COVID-19 patients, hospitalized on a regular ward during the second wave of the pandemic. Clinical characteristics of COVID-19 patients were recorded, and laboratory tests were studied. RESULTS: The mean ages of 48 COVID-19 patients with headache (47.71 ± 10.8) and 40 COVID-19 patients without headache (45.70 ± 12.72) were comparable. COVID-19 patients suffered from headache had significantly higher serum levels of HMGB1, NLRP3, ACE2, and IL-6 than COVID-19 patients without headache, whereas CGRP and IL-10 levels were similar in the groups. Angiotensin II level was significantly decreased in the headache group. COVID-19 patients with headache showed an increased frequency of pulmonary involvement and increased D- dimer levels. Furthermore, COVID-19 was more frequently associated with weight loss, nausea, and diarrhea in patients with headache. Serum NLRP3 levels were correlated with headache duration and hospital stay, while headache response to paracetamol was negatively correlated with HMGB1 and positively associated with IL-10 levels. CONCLUSION: Stronger inflammatory response is associated with headache in hospitalized COVID-19 patients with moderate disease severity. Increased levels of the circulating inflammatory and/or nociceptive molecules like HMGB1, NLRP3, and IL-6 may play a role in the potential induction of the trigeminal system and manifestation of headache secondary to SARS-CoV-2 infection.

Are Migraine Patients at Increased Risk for Symptomatic Coronavirus Disease 2019 Due to Shared Comorbidities?

The coronavirus disease 2019 (COVID-19) pandemic has rapidly transformed the whole world and forced us to look through comorbid diseases and risk factors from a different perspective. COVID-19 shows some inherent risk factors like cardiovascular comorbidities independent from age, gender, and geographic location. One of the most peculiar features of the COVID-19 pandemic is that severe acute respiratory syndrome coronavirus 2 respiratory infections disproportionately impact patients with hypertension, diabetes, and other cardiovascular comorbidities rather than those with allergic respiratory diseases and immune-compromised conditions. Migraine is a complex neuro-vasculo-inflammatory disorder that is also packed frequently with certain medical conditions including vascular disorders, hypertension, allergic diseases such as asthma and systemic inflammatory disorders. Accordingly, 2 different questions arise during the pandemic: (1) Do share comorbidities of cardiovascular diseases and hypertension increase the risk of symptomatic COVID-19 for migraine patients? (2) Do comorbid allergic and atopic diseases, including asthma act as opposite influencers alongside with female gender? This paper focuses on the co-existence of comorbidities of COVID-19, in comparison with migraine, based on a wide clinical dataset and available reports. Discussed mechanisms include potential strategic roles of angiotensin-converting enzyme 2, angiotensin-II, and nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 inflammasome, playing remarkable parts in the pathogenesis of COVID-19 and migraine. There are also some clues about the importance of endothelial and pericyte dysfunction and neuroinflammation in COVID-19 infection, related to complications and survival of the patients. The large epidemiological studies as well as basic research, focusing on migraine patients with COVID-19 will clarify these vital questions during the upcoming periods.

Headache characteristics in COVID-19 pandemic-a survey study.

BACKGROUND: Headache is the most common COVID-19-related neurological symptom. We aimed to reveal diagnostic clues of headache for COVID-19 infection and to investigate the course of primary headaches during the pandemic. METHODS: We developed a detailed web-based questionnaire screening the characteristics and course of headaches besides clinical COVID-19 features. The participants were grouped according to being diagnosed with COVID-19 infection or not, and having previous or new-onset headaches. The COVID-19 related headache features and their associations with other clinical features were investigated. A binary logistic regression model was performed to differentiate the characteristics of headache related to COVID-19. FINDINGS: A total of 3458 participants (2341 females;67.7%, 1495 healthcare workers;43.2%) with a mean age of 43.21 ± 11.2 years contributed to the survey. Among them, 262 participants had COVID-19 diagnosis and 126 (48.1%) were male. The rate of males in the group without COVID-19 was 31% (991 out of 3196 participants) showing significant gender difference between groups (p < 0.000). COVID-19 related headaches were more closely associated with anosmia/ageusia and gastrointestinal complaints (p < 0.000 and p < 0.000), and showed different characteristics like pulsating, pressing, and even stabbing quality. Logistic regression analyses showed that bilateral headache, duration over 72 h, analgesic resistance and having male gender were significant variables to differentiate COVID-19 positive patients from those without COVID-19 (p = 0.04 for long duration and p < 0.000 for others). A worsening of previous primary headaches due to the pandemic-related problems was not reported in the majority of patients. INTERPRETATION: Bilateral, long-lasting headaches, resistance to analgesics and having male gender were more frequent in people with COVID-19 in conjunction with anosmia/ageusia and gastrointestinal complaints. These features may be helpful for diagnosing the headache related to COVID-19 during the pandemic.

Co-occurrence of migraine and atopy in children and adolescents: myth or a casual relationship?

PURPOSE OF REVIEW: To clarify the causal relationship between migraine and atopic disorders in children and adolescents. RECENT FINDINGS: Migraine headache and atopic disorders including asthma are both common functional syndromes of childhood in which nature of the relationship is still debated. Attacks may induce in both disorders upon exposure to potential triggers in genetically susceptible individuals. Clinical phenotype manifests by temporary dysfunction of target tissue mediated by inflammation triggered by specific agents. Clinical features also change after puberty because of the partial effect of female sex hormones on the process. Appropriate definition of the syndrome and differentiating from other disorders are necessary not only for correct diagnosis, but also for planning of management strategies in children. Allergic rhinosinusitis needs to be differentiated from migraine even in experienced clinics. Questioning the presence of cranial autonomic symptoms is important clue in the differential diagnosis. Atopic disorder screening is particularly required in the diagnosis of migraine in childhood and adolescents. The link between both disorders of childhood seems to be far from a coincidence and some common inflammatory mechanisms are shared. SUMMARY: On the basis of clinical features, laboratory findings and some practical clues in children, accurate diagnosis of migraine and atopic disorders are very critical for physicians, pediatricians and algologists.

Accompanying migrainous features in pediatric migraine patients with restless legs syndrome.

The present study aimed to examine the frequency of restless legs syndrome (RLS) in pediatric patients with migraine and tension-type headache (TTH) and to investigate accompanying migrainous symptoms, sleep characteristics, as well as levels of serum ferritin between the pediatric migraine patients with RLS and those without RLS. We included 65 consecutive patients diagnosed with migraine, 20 patients with TTH, and 97 headache-free children in our study. Demographic, clinical, and laboratory data were noted. The presence of a primary headache was diagnosed using the ICHD-II criteria, and RLS was determined with face-to-face interviews conducted by an experienced neurologist based on the revised International RLS Study Group criteria for pediatrics. The frequency of RLS in pediatric migraine and TTH patients was significantly higher than in the controls (p = 0.0001 and p = 0.025, respectively). The frequencies of allodynia, vertigo/dizziness, and self-reported frequent arousals were significantly higher, and serum ferritin levels were significantly lower in migraine patients with RLS compared to those without RLS (p = 0.05, p = 0.028, p = 0.02, and p = 0.038, respectively). Our study suggests that the frequency of RLS is higher in pediatric migraine and TTH patients compared to controls. Therefore, pediatric headache patients should be questioned about the presence of RLS, as this co-occurrence may lead to more frequent accompanying migrainous symptoms and sleep disturbances.

Experts' opinion about the primary headache diagnostic criteria of the ICHD-3rd edition beta in children and adolescents.

BACKGROUND: The 2013 International Classification of Headache Disorders-3 (ICHD-3) was published in a beta version to allow the clinicians to confirm the validity of the criteria or to suggest improvements based on field studies. The aim of this work was to review the Primary Headache Disorders Section of ICHD-3 beta data on children and adolescents (age 0-18 years), and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the literature available on pediatric headache, they made observations and proposed suggestions for the primary headache disorders section of ICHD-3 beta data on children and adolescents. RESULTS: Some headache disorders in children have specific features which are different from those seen in adults and which should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psycho-social basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD-3 more appropriate for use with children.

Experts' opinion about the pediatric secondary headaches diagnostic criteria of the ICHD-3 beta.

BACKGROUND: The 2013 International Classification of Headache Disorders-3 was published in a beta version to allow clinicians to confirm the validity of the criteria or suggest improvements based on field studies. The aim of this work was to review the Secondary Headache Disorders and Cranial Neuralgias and Other Headache Disorders sections of ICHD-3 beta data on children and adolescents (age 0-18 years) and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the available literature on pediatric headache, they made observations and proposed suggestions for the mentioned headache disorders on children and adolescents. RESULTS: Some headache disorders in children have specific features, which are different from adults that should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psychosocial basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD-3 more appropriate for use in children.

SNP Variation in MicroRNA Biogenesis Pathway Genes as a New Innovation Strategy for Alzheimer Disease Diagnostics: A Study of 10 Candidate Genes in an Understudied Population From the Eastern Mediterranean.

Alzheimer disease (AD) is a common complex neurodegenerative disorder accounting for nearly 50% to 70% of dementias worldwide. Yet the current diagnostic options for AD are limited. New diagnostic innovation strategies focusing on novel molecules and pathways are sorely needed. In this connection, microRNAs (miRNAs) are conserved small noncoding RNAs that regulate posttranscriptional gene expression and are vital for neuronal development and its functional sustainability. Conceivably, biological pathways responsible for the biogenesis of miRNAs represent a veritable set of upstream candidate genes that can be potentially associated with the AD pathophysiology. Notably, whereas functional single-nucleotide polymorphisms (SNPs) in miRNA biogenesis pathway genes have been studied in other complex diseases, surprisingly, virtually no such study has been conducted on their relevance in AD. Moreover, novel diagnostics identified in easily accessible peripheral tissues such as the whole blood samples represent the initial entry or gateway points on the biomarker discovery critical path for AD. To the best of our knowledge, we report here the first association study of functional SNPs, as measured by real-time PCR in 10 "upstream" candidate genes critically situated on the miRNA biogenesis pathway, in a large sample of AD patients (N=172) and healthy controls (N=109) in a hitherto understudied world population from the Mersin region of the Eastern Mediterranean. We observed a significant association between 2 candidate genes and AD, TARBP2 rs784567 genotype and AD (χ=6.292, P=0.043), and a trend for RNASEN rs10719 genotype (χ=4.528, P=0.104) and allele (P=0.035). Functional SNP variations in the other 8 candidate genes (DGCR8, XPO5, RAN, DICER1, AGO1, AGO2, GEMIN3, and GEMIN4) did not associate with AD in our sample. Given the putative biological importance of miRNA biogenesis pathways, these emerging data can provide a new foundation to stimulate future debate and genetic investigations of AD, focusing on new molecular mechanisms such as miRNA biogenesis, particularly in accessible peripheral tissues for novel molecular diagnostics for dementia.

Chronic Migraine in Children and Adolescents.

Chronic migraine is defined as having more than 15 headache days in a month, half of these showing migraine features, for at least 3 months. It is a chronic painful syndrome with aspects such as psychiatric comorbid, decreased quality of life, and environmental and intrinsic psychological factors that make face-to-face treatment difficult. Children and adolescent migraine differ from adults as a result of growing brain and evolving disorder. In this paper, we will emphasize the definition, diagnosis, epidemiology, burden of life, and management of chronic migraine in children and adolescent.