Encephalitis in Patients with COVID-19: A Systematic Evidence-Based Analysis.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly infects the respiratory system, several investigations have shown the involvement of the central nervous system (CNS) along the course of the illness, with encephalitis being one of the symptoms. The objective of this systematic review was to evaluate the characteristics (clinical, neuro-radiological aspects, and laboratory features) and outcomes of encephalitis in COVID-19 patients. PubMed, Scopus, and Google Scholar databases were searched from 1 December 2019 until 21 July 2022 to identify case reports and case series published on COVID-19 associated with encephalitis. The quality of the included studies was assessed by the Joanna Briggs Institute critical appraisal checklists. This systematic review included 79 studies, including 91 COVID-19 patients (52.7% male) experiencing encephalitis, where 85.6% were adults (49.3 ± 20.2 years), and 14.4% were children (11.2 ± 7.6 years). RT-PCR was used to confirm 92.2% of the COVID-19 patients. Encephalitis-related symptoms were present in 78.0% of COVID-19 patients at the time of diagnosis. In these encephalitis patients, seizure (29.5%), confusion (23.2%), headache (20.5%), disorientation (15.2%), and altered mental status (11.6%) were the most frequently reported neurologic manifestations. Looking at the MRI, EEG, and CSF findings, 77.6%, 75.5%, and 64.1% of the patients represented abnormal results. SARS-CoV-2-associated or -mediated encephalitis were the most common type observed (59.3%), followed by autoimmune encephalitis (18.7%). Among the included patients, 66.7% were discharged (37.8% improved and 28.9% fully recovered), whereas 20.0% of the reported COVID-19-positive encephalitis patients died. Based on the quality assessment, 87.4% of the studies were of high quality. Although in COVID-19, encephalitis is not a typical phenomenon, SARS-CoV-2 seems like a neuropathogen affecting the brain even when there are no signs of respiratory illness, causing a high rate of disability and fatality.

A cross-sectional study on the association between Helicobacter pylori infection and headache.

BACKGROUND: The relationship between chronic Helicobacter pylori (HP) infection and headache has been discussed for long; nevertheless, the results of the studies are still contrasting. OBJECTIVE: This cross-sectional study is aimed to investigate a possible association between HP and headache, mainly migraine. METHODS: We screened, by a self-administered questionnaire, the subjects undergoing a breath test or an esophagogastroduodenoscopy. Migraine was diagnosed according to the international criteria. RESULTS: A total of 3914 patients underwent a breath test and 2200 an esophagogastroduodenoscopy at two hospitals, in Piedmont (Italy), in a 5-year period; a total of 1362 questionnaires were included in the study. The mean age of the subjects was 53 years; there were 777 women (57%). HP was detected in 364 (27%) subjects. A total of 702 (51%) subjects suffered from headache: migraine with aura was diagnosed in 176 subjects (176/702, i.e., 25% of the headache group; 176/1362, i.e., 13% of the total population); migraine without aura in 98 subjects (98/702, i.e., 14% of the headache group; 98/1362, i.e., 7% of the total). The logistic regression model did not detect any significant association between HP infection and headache, while a significant association between HP and headache frequency (p =0.009) was found, independently of age, gender, comorbidity, and diagnostic category. CONCLUSION: Our study does not reveal an association between chronic HP infection and migraine. However, since HP is significantly associated with higher headache frequency, a role for HP as a risk factor for headache chronification, possibly underlain by inflammatory mechanisms, may be supposed.

Melatonin and Sleep Disturbances in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by sleep, behavioral, memory, and cognitive deteriorations. Sleep disturbance (SD) is a major disease burden in AD, which has a reciprocal relationship with AD pathophysiology. It aggravates memory, behavioral, and cognitive complications in AD. Different studies have found that melatonin hormone levels reduce even in the pre-clinical stages of AD. Melatonin is the primary sleep-regulating hormone and a potent antioxidant with neuroprotective roles. The decrease in melatonin levels can thus promote SD and AD neuropathology. Exogenous melatonin has the potential to alleviate neuropathology and SD in AD by different mechanisms. Various studies have been conducted to assess the efficacy of exogenous melatonin to treat SD in AD. Though most of the studies suggest that melatonin is useful to ameliorate SD in AD, the remaining studies show opposite results. The timing, dosage, and duration of melatonin administration along with disease condition, genetic, environmental, and some other factors can be responsible for the discrepancies between the studies. More extensive trials with longer durations and higher dosage forms and studies including bright light therapy and melatonin agonists (ramelteon, agomelatine, and tasimelteon) should be performed to determine the efficacy of melatonin to treat SD in AD.

Thrombophilic alterations, migraine, and vascular disease: results from a case-control study.

BACKGROUND: The association between thrombophilic alterations, migraine, and vascular events has been broadly investigated but not been completely clarified. METHODS: In this cross-sectional, case-control study, we included consecutive outpatients diagnosed with migraine referring to a tertiary headache center. Migraine patients were matched to headache-free control subjects. All participants were evaluated for free protein S anticoagulant, functional protein C anticoagulant, homocysteine, and antiphospholipid antibodies (aPLs). History of ischemic stroke (IS) or transient ischemic attack (TIA), coronary heart disease, and peripheral venous thrombosis was also ascertained. RESULTS: We included 329 migraine patients and 329 control subjects (mean age 41 years, 77% women in both groups). Among migraine patients, 239 (72.6%) had migraine without aura and 90 (27.4%) had migraine with aura. Migraine patients had more frequently arterial hypertension, hypercholesterolemia, history of IS or TIA and, peripheral venous thrombosis compared to control subjects, whereas we found no differences in diabetes mellitus, BMI, and coronary heart disease between the two groups. At least one thrombophilic alteration was detected in 107 (32.5%) migraine patients and in 74 (22.5%) control subjects (OR = 1.66, 95% CI 1.17-2.35, p = 0.004). We identified an association of migraine with aPL positivity (OR = 2.6, 95% CI 1.5-4.7, p = 0.001) and with free protein S deficiency (OR = 4.7, 95% CI 1.6-14.0, p = 0.002), whereas we found no differences in protein C deficiency, APCR, and hyperhomocysteinemia between the two groups. Furthermore, aPL positivity and free protein S deficiency were more common in migraine patients with and without aura than in control subjects. We found that in migraine patients, aPL positivity was associated with both IS or TIA (OR = 5.6, 95% CI 1.5-20.4, p = 0.009) and with coronary heart disease (OR = 27.6, 95% CI 1.4-531.1, p = 0.028), whereas free protein S deficiency was associated with IS or TIA only (OR = 14.3, 95% CI 2.8-74.4, p = 0.002). CONCLUSIONS: Our research documented a significative higher prevalence of aPL positivity and protein S deficiency in migraineurs than in controls. Data also showed an association between these alterations and some vascular thrombotic events in migraine patients. We can argue that thrombophilic disorders associated with migraine may contribute to the occurrence of vascular events.

Prevalence of Headache in Patients With Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis of 14,275 Patients.

Background: Coronavirus disease 2019 (COVID-19) started to spread globally since December 2019 from Wuhan, China. Headache has been observed as one of the clinical manifestations in COVID-19 patients. We aimed to conduct a comprehensive systematic review and meta-analysis to estimate the overall pooled prevalence of headache in COVID-19 patients. Methods: PubMed, Scopus, ScienceDirect, and Google Scholar databases were searched to identify studies published between December 2019 and March 2020. Adult (≥18 years) COVID-19 patients were considered eligible. We used random-effects model to estimate the pooled prevalence with 95% confidence intervals (CIs). Quality assessment was done using the Joanna Briggs Institute critical appraisal tools. This study is registered with PROSPERO (CRD42020182529). Results: We identified 2,055 studies, of which 86 studies (n = 14,275, 49.4% female) were included in the meta-analysis. Overall, the pooled prevalence of headache in COVID-19 patients was 10.1% [95% CI: 8.76-11.49]. There was no significant difference of headache prevalence in severe or critical vs. non-severe (RR: 1.05, p = 0.78), survived (recovered or discharged) vs. non-survived (RR: 1.36, p = 0.23), and ICU vs. non-ICU (RR: 1.06, p = 0.87) COVID-19 patients. We detected 64.0, 34.9, and 1.1% of the included studies as high, moderate, and low quality, respectively. Conclusions: From the first 4-month data of the outbreak, headache was detected in 10.1% of the adult COVID-19 patients.

Novelty in Inflammation and Immunomodulation in Migraine.

BACKGROUND: Migraine is a diffuse and disabling disease. Its pathophysiology is complex and involves both central and peripheral dysfunctions. OBJECTIVE: This review will discuss the pathogenesis of migraine from the origin of the neuro-inflammatory theory, to the modern pathophysiological model and the latest therapies. METHODS: PUBMED and EMBASE (up to May 2019) were searched for: migraine, inflammation, immunomodulation. An additional search was carried out from the bibliography of previous review articles. RESULTS: Migraine was thought to be mainly a vascular disorder, according to the so-called "vascular theory". Based on animal models, a new hypothesis called "the neuro-inflammatory" was conceived at the end of the 20th century. The growing knowledge about the trigeminovascular system and its role in the inflammatory-pain pathway, allowed to identify other specific neurotransmitters, such as the Calcitonin Gene-Related Peptide and Pituitary Adenylate Cyclase-Activating Peptide. Evidence was provided that the inflammatory-pain system could become sensitised and, due to this sensitisation, the pain could also perpetuate, even in the absence of any triggers of the migraine attack. At last, brain immune cells modification during cortical spreading depression in migraine was demonstrated, along with the existence and function of the glymphatic system. The better comprehension of the immune system abnormalities allowed the development of new immunomodulating drugs: the monoclonal antibodies against the CGRP or the CGRP receptor. Moreover, new insights into the molecular mechanism of CGRP, and the function of C-fibres and Aδ-fibres, highlighted the mechanism of action of Botulinum Toxin type A in the treatment of chronic migraine.

Antiphospholipid antibodies in epilepsy: A systematic review and meta-analysis.

BACKGROUND: Autoimmunity is believed to play an important causative role in the pathogenesis of epilepsy. There are evidences for the presence of autoantibodies in patients with epilepsy. To date, many studies have assessed the presence of antiphospholipid antibodies (aPLs) in epilepsy patients, though the relationship has been inconclusive. AIMS: The aim of this systematic review and meta-analysis was to evaluate the presence of aPLs in epileptic patients as compared to healthy controls. METHODS: Five electronic databases (PubMed, Web of Science, Embase, Scopus and Google Scholar) were searched systematically. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. Quality assessment was carried out by using the modified 9-star Newcastle-Ottawa Scale (NOS). L'Abbé plots were generated to visually inspect heterogeneity while publication bias was evaluated via visualization of contour- enhanced funnel plots, and Begg's and Egger's tests. RESULTS: Based on the inclusion criteria, 14 studies were selected involving 1248 epilepsy patients and 800 healthy controls. The majority of epilepsy was categorised as generalised or partial and none had comorbidity with autoimmune diseases. Significant presence of both anticardiolipin (aCL) antibodies (OR: 5.16, 95% CI: 3.21-8.28, p < 0.00001) and anti-ß2- glycoprotein I (anti-ß2-GPI) antibodies (OR: 2.95, 95% CI: 1.07-8.11, p = 0.04) exhibited comorbid association with epilepsy patients as compared to healthy controls. Subgroup analyses revealed that presence of aCL antibodies was more specifically observed in paediatrics (OR: 4.57, 95% CI: 2.57-8.15, p < 0.00001) than adults (OR: 4.24, 95% CI: 1.80-10.01, p = 0.001). The odds of aCL antibody presence was higher in partial epilepsy patients (OR: 7.88, 95% CI: 3.23-19.24, p < 0.00001) than that of generalised (OR: 3.76, 95% CI: 2.15-6.59, p < 0.00001) and in Asian epileptic patients (OR: 9.56, 95% CI: 2.69-33.95, p = 0.0005) than Europeans (OR: 4.35, 95% CI: 2.74-6.92, p < 0.00001). The presence of anti-ß2-GPI antibodies was significant in paediatric (OR: 6.44, 95% CI: 1.39-29.89, p = 0.02) and African population with epilepsies (OR: 10.59, 95% CI: 1.22-92.25, p = 0.03). NOS of the majority of the studies (11/14) indicated a high methodological quality. No substantial heterogeneity was observed either from the quantitative analysis or from the L'Abbé plots while no significant publication bias was detected from funnel plots; Begg's and Egger's tests. CONCLUSION: Since none of the epilepsy subjects exhibited any comorbid autoimmune disorders, significant presence of aCL and anti-ß2-GPI antibodies indicate towards their contribution in immune-mediated general pathogenesis of epilepsy.

Alpha-Lipoic Acid Shows Promise to Improve Migraine in Patients with Insulin Resistance: A 6-Month Exploratory Study.

Alpha-lipoic acid (ALA) is known to lower insulin resistance (IR), which is common among migraineurs. To assess the effect of ALA on headache in migraineurs with IR, we performed an exploratory study on a cohort of patients with migraine, followed at our Headache Center. The 32 patients took ALA 400 mg b.i.d. for 6 months in addition to their on-going treatment. The percentage of patients with a reduction of at least 50% of the attacks was 0.53 (confidence interval [95% CI] 0.36-0.70) at 2 months, 0.56 (0.39-0.73) at 4 months, and 0.69 (0.53-0.85) at 6 months. The incidence rate ratio of attacks at 6 months versus baseline was 0.48 (0.43-0.53, P < .001), corresponding to a mean (95% CI) number of attacks of 5 (4-6) versus 11 (10-12). The number of days of treatment in the previous month was 7.7 (6.8-8.7) at baseline, 5.4 (4.6-6.2) at 2 months, 5.3 (4.5-6.1) at 4 months, and 4.3 (3.6-5.0) at 6 months. Baseline and 120-min glucose and insulin and quantitative insulin sensitivity check index (QUICKI) and the Stumvoll index did not change at 6 months versus baseline. This exploratory study shows that the administration of ALA may be associated with a reduction in the number of attacks and the days of treatment in migraineurs with IR. A randomized controlled trial is needed to test this possibility.

Migraine in Systemic Autoimmune Diseases.

BACKGROUND AND OBJECTIVE: Migraine and systemic autoimmune diseases are 2-3-fold more common in women and various studies have reported an association between the two pathologies. METHODS: This review takes into account epidemiological studies involving migraine and systemic lupus erythematosus, antiphospholipid syndrome, Sjogren's syndrome, and other diffuse connective tissue diseases. This scientific literature analysis consists of the main articles found in Medline with a search up to April 2017. RESULTS: Many epidemiological studies were carried out on patients suffering from systemic lupus erythematosus. Results showed that headache and migraine are more prevalent in systemic lupus erythematosus patients compared to controls, especially migraine with aura. Patients with Lupus and migraine show a higher lupus activity and association with Raynaud and/or antiphospholipids in these populations are contradictory. There are not enough data to establish an association between antiphospholipid syndrome and migraine. However, data are more consistent between antiphospholipid carrier condition and migraine. Systemic sclerosis is a rare disease, for this reason the amount of available data on this disorder are scanty. However, some studies reported an association between headache, migraine and systemic sclerosis, especially where gliotic brain lesions and Raynaud are coexisting. Finally, large propensity cohort population based studies suggested that systemic autoimmune diseases are more frequent in patients suffering from migraine. CONCLUSION: An attempt at explaining the possible link between these disorders and migraine is discussed at the end of the review. Several autoimmune alterations are shared by most autoimmune diseases and headache types. Endothelial dysfunction is the only alteration that is common among all these disorders.

Coexistence of antiphospholipid antibodies and cephalalgia.

Background The occurrence of antiphospholipid antibodies (aPLs) and headache comorbidity in the presence or absence of underlying autoimmune diseases remains unclear. Aim The aim of this review was to summarize the relationship between headache and aPLs based on evidences from cohort studies and case reports, in addition to examining the treatment strategies that resolved headache in aPLs-positive individuals. Methods A comprehensive literature search was conducted through PubMed, ISI Web of Science and Google Scholar. A total of 559 articles were screened and the appropriate articles were selected based on quality and level of evidence. Results Cohort studies (n = 27) from Europe, North America and Asia demonstrated comorbidity of aPLs and headache in antiphospholipid syndrome, systemic lupus erythematosus (SLE) and neuropsychiatric SLE patients. Significantly higher association between migraine and aPLs was observed (n = 170/779; p < 0.0001) in individuals without any underlying diseases. Our analysis of shortlisted case reports (n = 17) showed that a higher frequency of anticardiolipin antibodies were present in subjects with different autoimmune disorders (70.6%). Corticosteroids were highly effective in resolving headache in aPLs-positive individuals. Conclusion Higher frequency of comorbidity between aPLs and headache was observed in healthy individuals and patient cases. Therefore, experimental studies are warranted to evaluate the aPLs-induced pathogenic mechanism of headache.

Headache prevalence and related symptoms, family history, and treatment habits in a representative population of children in Alba, Italy.

BACKGROUND: Headache is a widespread disorder in children, but little is known about the headache prevalence in northwest Italy, on less frequent migraine equivalents, family history, and treatment habits in children. METHOD: This is an epidemiologic population-based study of a representative sample of children aged 3 to 11 years, conducted in Alba, Italy. We used a self-administered questionnaire to acquire information on gender, age, headache, possible migraine equivalents, family history for various diseases, and treatment habits. RESULTS: We distributed the questionnaire to 1152 children, and a total of 649 questionnaires were successfully completed. In the preschool age, 10.3% (seven boys and nine girls) of children suffered from headache. In school-age children, the prevalence of headache was 31.4% (75 boys and 80 girls; 27% in 6 year olds and 41% at age 9 years). We found a significant correlation between headache and abdominal pain in the entire sample and with cyclic vomiting syndrome and dizziness in school-age children only. Headache correlated significantly with a family history of headache, thyroid diseases, diabetes, hypertension, and vascular diseases. Headache was treated with drugs, primarily paracetamol, in 60 of the 171 (35%) children who reported headache and in 61% of the children with migraine; no subjects were treated with triptans. CONCLUSIONS: Headache is widespread in children, with a high prevalence of associated symptoms and family history for many other headache-related disorders.

Sneddon's syndrome presenting with severe disabling bilateral headache.

Sneddon's syndrome is a rare vascular disease affecting mainly skin and brain arterioles leading to their occlusion due to excessive endothelial proliferation. The two main features of this syndrome are livedo reticularis and lacunar subcortical infarcts. Here, we describe the case of a 64-year-old woman presenting with a 4-year history of a throbbing, bilateral, parieto-occipital headache associated with facial pain, but without any other accompanying symptom. The pain, initially misdiagnosed as atypical trigeminal neuralgia, worsened up to chronic daily and such severely disabling headache that she was constrained to bed. She presented with reduced cognitive functions, diffuse and severe livedo reticularis, severe myalgias and mild stiffness. All diagnostic test for different diseases were performed and other diseases excluded except for Sneddon's syndrome. Her symptoms were reduced firstly using acetylsalicylic acid, then ticlopidine 250 mg bid was begun and then Pentoxyphillin, resulting in a significant improvement of symptoms with the disappearance of headache. Her worsening in the first year was characterized by obsessive-compulsive behaviours, body-image misperceptions and panic attacks, improved for a period using olanzapine. Considering this case, we remark the importance of using headache classification to avoid diagnostic errors, secondly, we describe an atypical manifestation of Sneddon's syndrome and therapeutic efficacy of using ticlopidine and pentoxyphillin.

Insulin metabolism is altered in migraineurs: a new pathogenic mechanism for migraine?

BACKGROUND: Migraine is a complex biochemical dysfunction attributed to a disorder of the trigeminal and hypothalamic pathways. Impairment of glucose metabolism has been reported in migraine, but data are scanty and inconsistent. OBJECTIVE: The main aim was to verify whether migraineurs have abnormalities of the glucose and insulin metabolism. We also studied correlations between blood glucose and insulin and between insulin levels and migraine severity. PATIENTS AND METHODS: Patients with migraine or headache other than migraine, and healthy volunteers were included. All had general blood tests and a standard oral glucose tolerance test after a 12-hour fast, and glucose and insulin were measured. RESULTS: Over a 6-month period, we recruited 84 migraineurs (73 women, 11 men), 25 patients with nonmigraine headache (20 women, 5 men), and 26 healthy controls (24 women, 2 men). Multivariate analysis confirmed a significant difference between groups for glucose levels (P < .0001), but no significant time interaction. The differences were mostly between migraine and healthy controls (P < .0001) and to a lesser extent between other headaches and healthy controls (P < .05). A significant difference between groups was also found for insulin (P < .0001), with a significant time interaction. The difference was confirmed for migraine compared to other headaches (P < .0001) and healthy controls (P < .0001). CONCLUSIONS: Blood glucose levels may be high in headache patients, but do not seem to be specific to migraineurs. Insulin levels were higher in migraineurs, and seemed specific to this group. These findings are in keeping with recent reports on the effects of insulin on brain functions and lend support to the possibility that insulin is involved in the pathogenesis of migraine.