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IntroductionHeadache is the most prevalent neurological manifestation in adults and one of the leading causes of disability worldwide. In children and adolescents, headaches are arguably responsible for a remarkable impact on physical and psychological issues, yet high-quality evidence is scarce.Material and methodsWe searched cross-sectional and cohort studies in Embase, Medline, Web of Science, and Cochrane databases from January 1988 to June 2022 to identify the prevalence of headaches in 8–18 years old individuals. The risk of bias was examined with the Joanna Briggs Institute (JBI) scale. A random-effects model was used to estimate the pooled prevalence of pediatric headache. Subgroup analyses based on headache subtypes were also conducted.ResultsOut of 5,486 papers retrieved electronically, we identified 48 studies that fulfilled our inclusion criteria. The pooled prevalence of primary headaches was 11% for migraine overall [95%CI: 9–14%], 8% for migraine without aura (MwoA) [95%CI: 5–12%], 3% for migraine with aura (MwA) [95%CI:2–4%] and 17% for tension-type headache (TTH) [95% CI: 12–23%]. The pooled prevalence of overall primary headache in children and adolescents was 62% [95% CI: 53–70%], with prevalence in females and males of 38% [95% CI: 16–66%] and 27% [95% CI: 11–53%] respectively. After the removal of studies ranked as low-quality according to the JBI scale, prevalence rates were not substantially different. Epidemiological data on less common primary headaches, such as trigeminal autonomic cephalalgias, were lacking.ConclusionWe found an overall remarkably high prevalence of primary headaches in children and adolescents, even if flawed by a high degree of heterogeneity. Further up-to-date studies are warranted to complete the picture of pediatric headache-related burden to enhance specific public interventions.

BackgroundAnti-acetylcholine receptor antibodies (AChR Abs) are detected in 85% of myasthenia gravis (MG) patients, at higher rates in patients with late-onset disease. AChR Ab frequency is generally thought to be much lower in ocular MG (OMG), although recent studies reported positivity rates higher than 70%. We hypothesized that the improved AChR Ab diagnostic yield in OMG could be related to an increased frequency of late-onset disease, as observed in generalized MG.MethodsWe compared OMG patients, with disease onset before or after 1998, for the age of onset, sex, presence of thymoma, immunosuppressive therapy rate, AChR Ab positivity, and follow-up duration. All patients had a follow-up ≥ 2 years. AChR Abs were tested by radioimmunoassay.ResultsThe study included 133 patients. Disease onset occurred before 1998 in 54/133 cases (41%). Age of onset, the proportion of late-onset patients, and AChR Ab positivity rate were significantly increased in the more recent population. Thymoma frequency was similar in the two series. On multivariate analysis, the only variable predicting AChR Ab positivity was the age at onset ≥ 50 years (OR = 6.50, 95% CI = 2.70–15.63, p < 0.0001).ConclusionsOur results confirm that current AChR Ab positivity in OMG may be higher than generally thought. In our population, this finding was associated with an increased frequency of late-onset cases.

Objective Several studies examined stress factors in both adult and pediatric patients with migraine, but few of them have analyzed coping strategies adopted to deal with stressful events in pediatric age. In particular, some of these studies have focused on specific migraine populations or have not employed standardized instruments. Our study used a standardized tool to investigate the coping strategies adopted by patients with primary migraine in dealing with stressful events. We aimed at exploring: 1) Coping responses to stressful events and their possible association with migraine characteristics such as headache frequency, pain intensity and use of prophylactic treatment; (2) Potential differences in anxiety and depression symptoms based on migraine characteristics, and (3) Association between migraine characteristics, coping strategies, and psychological aspects. Methods We studied 81 adolescents (mean age 13.8 ± 1.6 years; 18 M and 63 F). They were divided into: (1) high frequency (weekly to daily episodes) and low frequency (≤ 4 episodes per month); (2) mild and severe pain; (3) need for prophylactic treatment or not. To evaluate patients’ anxiety, depression and coping strategies we used respectively SAFA-A, SAFA-D and CRI-Y questionnaires. Results School and socialization represent the most commonly reported stressful events among our patients with migraine. Patients with high frequency of headache tend to adopt maladaptive coping strategies in “Logical Analysis” ( p  = 0.012), “Positive Reappraisal” ( p  = 0.002) and “Total Approach” ( p  = < 0.001). Moreover, patients with a high frequency of headache showed higher anxiety and depression scores ( p  = < 0.050). On the other hand, lower scores in some subscales of anxiety and depression emerged in high frequency patients who used “Logical Analysis” maladaptively ( p  = < 0.050). Conclusion Adolescents with a more disabling migraine pattern tend to employ maladaptive coping strategies focused on active behavioral responses to the stressful events.

Background Recently, there has been increasing interest in the possible role of the gut microbiota (GM) in the onset of migraine. Our aim was to verify whether bacterial populations associated with intestinal dysbiosis are found in pediatric patients with migraine. We looked for which metabolic pathways, these bacteria were involved and whether they might be associated with gut inflammation and increased intestinal permeability. Methods Patients aged between 6 and 17 years were recruited. The GM profiling was performed by the 16S rRNA metataxonomics of faecal samples from 98 patients with migraine and 98 healthy subjects. Alpha and beta diversity analyses and multivariate and univariate analyses were applied to compare the gut microbiota profiles between the two group. To predict functional metabolic pathways, we used phylogenetic analysis of communities. The level of indican in urine was analyzed to investigate the presence of metabolic dysbiosis. To assess gut inflammation, increased intestinal permeability and the mucosal immune activation, we measured the plasmatic levels of lipopolysaccharide, occludin and IgA, respectively. Results The α-diversity analysis revealed a significant increase of bacterial richness in the migraine group. The β-diversity analysis showed significant differences between the two groups indicating gut dysbiosis in patients with migraine. Thirty-seven metabolic pathways were increased in the migraine group, which includes changes in tryptophan and phenylalanine metabolism. The presence of metabolic dysbiosis was confirmed by the increased level of indican in urine. Increased levels of plasmatic occludin and IgA indicated the presence of intestinal permeability and mucosal immune activation. The plasmatic LPS levels showed a low intestinal inflammation in patients with migraine. Conclusions Pediatric patients with migraine present GM profiles different from healthy subjects, associated with metabolic pathways important in migraine.

Background Chronic migraine (CM) negatively impacts the quality of life of 2 to 4% of pediatric patients. In adults, CM is frequently linked to medication overuse headache (MOH), but there is a much lower prevalence of MOH in children. A suboptimal response to acute therapies may lead to their reduced use, thus preventing MOH development in children and adolescents. The frequency of patients with CM who do not respond to acute therapies was examined in the present study. We investigated whether the prevalence of MOH was different between responders and non-responders. We also examined whether patients receiving prophylactic therapy had an improved response to acute therapy. Finally, we investigated if there was a difference in the frequency of psychiatric comorbidities between responders and non-responders. Methods We retrospectively analysed clinical data of all chronic pediatric migraineurs under the age of 18 referred to the Headache Centre at Bambino Gesù Children Hospital in June 2021 and February 2023. ICHD3 criteria were used to diagnose CM and MOH. We collected demographic data, including the age at onset of migraine and the age of the CM course. At baseline and after 3 months of preventive treatment, we evaluated the response to acute medications. Neuropsychiatric comorbidities were referred by the children’s parents during the first attendance evaluation. Results Seventy patients with CM were assessed during the chosen period. Paracetamol was tried by 41 patients (58.5%), NSAIDs by 56 patients (80.0%), and triptans by 1 patient (1.4%). Fifty-one participants (73%) were non-responder to the abortive treatment. The presence of MOH was detected in 27.1% of the whole populations. Regarding our primary aim, MOH was diagnosed in 29% of non-responder patients and 22% of responders ( p  > 0.05). All patients received preventative treatment. After 3 months of preventive pharmacological therapy, 65.4% of patients who did not respond to acute medications achieved a response, while 34.6% of patients who were non-responder remain non-responder ( p  < 0.05). Prophylactic therapy was also effective in 69% of patients who responded to acute medication ( p  < 0.05). Psychiatric comorbidities were detected in 68.6% of patients, with no difference between responders and non-responders (72.2% vs. 67.3%; p  = 0.05). Conclusions Despite the high prevalence of unresponsiveness to acute therapies in pediatric CM, it does not act as a protective factor for MOH. Moreover, responsiveness to acute drugs is improved by pharmacological preventive treatment and it is not affected by concomitant psychiatric comorbidities.

Bickerstaff brainstem encephalitis (BBE) is a rare, immune-mediated disease characterized by the acute onset of external ophthalmoplegia, ataxia, and consciousness disturbance. It has a complex multifactorial etiology, and a preceding infectious illness is seen in the majority of cases. Immune-mediated neurological syndromes following COVID-19 vaccination have been increasingly described. Here we report the case of a child developing BBE 2 weeks after COVID-19 vaccination. Despite nerve conduction studies and CSF analysis showing normal results, BBE was diagnosed on clinical ground and immunotherapy was started early with a complete recovery. Later, diagnosis was confirmed by positive anti-GQ1b IgG in serum. Even if there was a close temporal relationship between disease onset and COVID-19 vaccination, our patient also had evidence of a recent Mycoplasma pneumoniae infection that is associated with BBE. Indeed, the similarity between bacterial glycolipids and human myelin glycolipids, including gangliosides, could lead to an aberrantly immune activation against self-antigens (i.e., molecular mimicry). We considered the recent Mycoplasma pneumoniae infection a more plausible explanation of the disease onset. Our case report suggests that suspect cases of side effects related to COVID-19 vaccines need a careful evaluation in order to rule out well-known associated factors before claiming for a causal relationship.

Concern of a correlation between disease relapse in patients with acquired demyelinating disorders of central nervous system (CNS) and SARS-CoV2 vaccines has been raised. In this single center study, we retrospectively evaluated safety of SARS-CoV2 vaccination and COVID-19 short-term outcome in pediatric acquired demyelinating disorders of CNS. Patients with multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) with disease onset before 18 years of age were included. Demographic and clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected. We included nine patients with MOGAD. Six patients received SARS-CoV2 vaccination and complained pain at injection site while only one had fever and fatigue. Median follow-up was 28 weeks (range 20-48). Seven patients had COVID-19 occurring with mild flu-like symptoms and median follow-up was 28 weeks (range 24-34). Nobody had disease relapse. Five patients with NMOSD were included. All patients received SARS-CoV2 vaccination (BNT162b2-Pfizer-BioNTech). The median follow-up was 20 weeks (range 14-24) and only two patients complained pain at injection site, fever and fatigue. Three patients had also COVID-19 with mild flu-like symptoms, despite two of them being under immunosuppressive treatment. Lastly, forty-three patients with MS were included. 35 out of 43 received SARS-CoV2 vaccination with a median follow-up of 24 weeks (range 8-36). Fourteen patients had no side effects, while 21 complained mild side effects (mainly pain at injection site) and one experienced a disease relapse with complete recovery after steroid therapy. At vaccination, all but one were under treatment. Sixteen patients had COVID-19 occurring with mild symptoms. COVID-19 outcome was good although many patients were under immunosuppressive treatment. Vaccine-related side effects were frequent but were mild and self-limited. Only one MS patient had a post-vaccination relapse with complete recovery after steroid therapy. In conclusion, our data support the safety of SARS-CoV-2 vaccines in pediatric MS, MOGAD and NMOSD.

Subacute sclerosing panencephalitis (SSPE) is a late complication of measles virus infection that occurs in previously healthy children. This disease has no specific cure and is associated with a high degree of disability and mortality. In recent years, there has been an increase in its incidence in relation to a reduction in vaccination adherence, accentuated by the COVID-19 pandemic. In this article, we take stock of the current evidence on SSPE and report our personal clinical experience. We emphasise that, to date, the only effective protection strategy against this disease is vaccination against the measles virus.

Multiple sclerosis (MS) is a chronic and unpredictable inflammatory disease impacting the central nervous system. The disabling nature of this disease is not limited to only physical symptoms. MS, even at a pediatric age, often includes cognitive impairment, fatigue, and psychological issues, affecting education and social life, causing emotional distress, and reducing quality of life. Despite the paucity of quantitative data in the existing literature, our review demonstrates that the impact of pediatric MS extends beyond the patients themselves, affecting their parents as well. There is evidence suggesting that having a child with MS may be associated with a reduction in the parental quality of life, even in families of MS patients with low or no disability and without clinical relapses. Moreover, an increased risk of parents’ mental illness has been described, particularly in mothers, leading to a heightened utilization of mental health services. Research data show that inadequate information about MS may impact parents’ anxiety and their sense of competence. Since parents’ involvement has been found to also play a role in their child’s adherence to treatment, special attention should be paid to parental psychological health. Additional research exploring family adaptation to their children’s illness is required.

Objective Genetic factors predisposing to late‐onset myasthenia gravis (LOMG) have not been clearly defined yet. However, genome‐wide association studies identified Human Leukocyte Antigen (HLA) Class II alleles as a hotspot in this disease subtype. The aim of this study was to analyze the correlations of HLA Class II alleles with clinical data and titin antibodies in this patient subgroup. Methods This study consecutively enrolled anti‐acetylcholine receptor antibody‐positive, non‐thymoma patients with generalized LOMG. All patients were of Italian ancestry. HLA‐DRB1 and ‐DQB1 genotyping and serum titin antibody testing were performed in this population. Results A total of 107 patients (females: 28/107, 26.2%; median age of onset: 68 years, range: 50‐92) were included. We found a positive association with HLA‐DRB1*07 (P = 1.1 × 10‐5), HLA‐DRB1*14 (P = 0.0251) and HLA‐DQB1*02 (P = 0.0095). HLA‐DRB1*03, HLA‐DRB1*11, and HLA‐DQB1*03 were protective alleles (P = 7.9 × 10‐5, P = 0.0104, and P = 0.0067, respectively). By conditional haplotype analysis, HLA‐DRB1*07‐DQB1*02 was found to be the major risk haplotype (OR = 4.10; 95% C.I.: 2.80‐5.99; P = 6.01 × 10‐11). The mean age at onset was 73.4 years in DRB1*07 homozygotes, 69.7 years in heterozygotes, and 66.6 in non‐carriers (P = 0.0488). DRB1*07 carriers and non‐carriers did not differ in disease severity and response to therapy. Titin antibodies were detected in 61.4% of the cases, having no association with HLA alleles or specific clinical characteristics. Interpretation In our study, we identified the HLA DRB1*07‐DQB1*02 haplotype as a predisposing factor for the development of generalized LOMG in the Italian population.