OBJECTIVE: To evaluate the long-term safety (≥12 months) of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) or its receptor in migraine prevention by synthesising evidence from clinical trials and real-world studies. We focus on drug discontinuation due to adverse events and the type and frequency of adverse events. This is the first review to analyse the effects of the long-term use of all anti-CGRP (receptor) mAbs, aiming to provide novel insights for clinical practice and future treatment strategies. METHODS: We systematically searched PubMed, Cochrane Library, and ClinicalTrials.gov for studies with ≥12 months of anti-CGRP (receptor) mAb use between January 2013 and April 2025. A random-effects meta-analysis of proportions (logit transformation, inverse variance weighting, restricted maximum likelihood) was performed to estimate pooled discontinuation and adverse event rates. Risk of bias was assessed using the ROBINS-I score. RESULTS: From a total of 1,499 records, 14 met the inclusion criteria and were eligible for data analysis. These 14 records corresponded to 11 individual studies with observational durations all exceeding 12 months. Seven studies investigated erenumab, two eptinezumab, and one each fremanezumab and galcanezumab. All studies were judged to have a severe risk of bias due to their underlying design. The overall pooled proportion of treatment discontinuation for any reason among patients receiving anti-CGRP (receptor) mAbs was 23%, whereas the pooled proportion of discontinuation specifically due to adverse events was substantially lower at 3%. Time-trend analysis showed that adverse event–related discontinuation remained low (<5%) beyond the first year, while overall adverse event incidence was high at baseline (>70%) but did not further increase with prolonged follow-up. CONCLUSION: Evidence on long-term use of anti-CGRP (receptor) mAbs over 12 months remains limited, but our analysis indicates good tolerability with consistently low adverse event-related discontinuation, no emergent safety signals, and largely non-serious, stable adverse event profiles. However, heterogeneity and study-level bias warrant cautious interpretation, highlighting the need for long-term clinical studies and continued real-world surveillance (e.g. registries). CLINICAL TRIAL NUMBER: Not applicable.
In the sustainable development goals (SDG) context of seeking universal health coverage, the expanding gap between the supply of specialized and primary health-care providers of headache-related health care and the care needs of the very large number of people affected by headache is a formidable but not insoluble public-health challenge. Structured headache services provide a cost-effective framework wherein controlled patient flows enable the care needs of people with headache to be met at appropriate levels, but these services may still be overwhelmed by inappropriate demand.Community pharmacists are an underutilized resource, potentially well able to provide the solution. To do so, they must, as a profession, be integrated into structured headache services.What remains to be determined is how to achieve this integration in an encouraging climate for change, which recognises the potential for relieving strained health-care systems and meeting a range of health-care needs by expanding pharmacists' scope of practice.This position statement on behalf of the European Headache Federation (EHF) and Lifting The Burden (LTB) is formally endorsed by the International Pharmaceutical Federation (FIP).
Prospective, randomized, controlled trials of intravenous immunoglobulin (IVIG) maintenance therapy in myasthenia gravis (MG) are lacking. In this trial, we evaluated the safety and efficacy of caprylate/chromatography-purified IVIG; (IGIV-C) in patients with generalized MG undergoing standard care. Sixty-two patients enrolled in this phase 2, multicenter, international, randomized trial (1:1 IGIV-C [2 g/kg loading dose; 1 g/kg every 3 weeks through week 21] or placebo). Efficacy was assessed by changes in Quantitative MG (QMG) score at week 24 versus baseline (primary endpoint) and percentage of patients with clinical improvement in QMG, MG Composite (MGC), and MG-Activities of Daily Living (MG-ADL) scores (secondary endpoints). Safety assessments reported all adverse events (AEs). The change in QMG at 24 weeks was -5.1 for IGIV-C and -3.1 for placebo (p = .187). Seventy percent of patients in the IGIV-C group had improvement in MG-ADL (≥2-point decrease) versus 40.6% in the placebo group (p = .025). Patients showing clinical improvement in QMG and MGC (≥3-point decrease) were 70.0% for IGIV-C versus 59.4% for placebo (p = .442) and 60.0% for IGIV-C versus 53.1% for placebo (p = .610). IGIV-C was well tolerated; serious AEs were similar between arms. Three of four MG exacerbations requiring hospitalizations occurred in the IGIV-C arm with one death. Several efficacy parameters showed numerical results greater than those seen in the placebo group. This was a small study and may have been underpowered to see significant differences. Additional studies may be warranted to fully determine the efficacy of IVIG maintenance therapy in MG.
Soluble urokinase plasminogen activator receptor (suPAR) has garnered attention as a potential blood-based biomarker for low-grade chronic inflammation. However, its specific association with migraine, including its subtypes, remains to be elucidated. We sought to examine the association of plasma suPAR levels with migraine and its subtypes. In this single-centre, cross-sectional study, plasma was collected at a single time point in adults with migraine and sex-matched healthy controls from October 2020 to June 2022. The quantification of plasma suPAR levels was performed in a blinded fashion using a validated enzyme-linked immunosorbent assay. Plasma suPAR levels were compared between participants with migraine (including subgroups) and healthy controls. Plasma samples were analysed from 634 eligible participants with migraine [mean (SD) age, 44.0 (12.2) years; 568 (89.6%) females] and 154 healthy controls [mean (SD), 41.3 (11.8%) years; 132 (86%) females]. Plasma suPAR levels were 6.7% higher (95% CI: 0.1-13.6%; P = 0.045, adjusted for age, sex, body mass index and smoking) in participants with migraine with aura, when compared with healthy controls. Further analysis revealed no difference in plasma suPAR levels between the overall migraine group and healthy controls (3.7%; 95% CI: -0.7-8.2%; P = 0.097), as well as between participants with migraine without aura and healthy controls (2.5%; 95% CI: -2.9-8.3%; P = 0.81). Similarly, plasma suPAR levels did not differ across participants with episodic migraine, chronic migraine and healthy controls. Finally, we found no difference when comparing participants with migraine at time of blood sampling with participants with non-migraine headache (1.0%; 95% CI: -5.7-8.2; P > 0.99), participants without headache (1.2%; 95% CI: -4.2-7.0%; P > 0.99) or healthy controls (4.5%; 95% CI: -1.9-11.3%; P = 0.39). Elevated plasma suPAR levels in migraine with aura indicate the presence of low-grade chronic inflammation. Future research should explore the role of suPAR in the neurobiologic underpinnings of migraine with aura.
BackgroundStructural imaging offers insight into migraine pathogenesis. Magnetic resonance imaging (MRI) morphometry plays a crucial role in identifying these alterations, yet the clinical significance remains debated. While gray matter volume and cortical curvature are commonly analyzed, cortical thickness offers a more direct measure of cytoarchitectural differences and neuroplastic changes in migraine. Advanced structural MRI techniques, including surface-based morphometry and voxel-based morphometry, have provided insights into cortical thickness alterations in migraine. These methods enable high-resolution assessment of brain morphometry, revealing dynamic changes associated with migraine phases and treatment.MethodsThis narrative review synthesizes findings from cortical thickness studies, focusing on methodological approaches, variations in imaging sequences and study designs, including cross-sectional and longitudinal studies.ResultsStudies using surface-based morphometry (i.e. SBM) and voxel-based morphometry (i.e. VBM) have reported inconsistent findings. Increased thickness is frequently observed in pain-processing regions, such as the somatosensory cortex, insula and anterior cingulate cortex reflecting hyperexcitability or maladaptive neuroplasticity. by contrast, cortical thinning has been noted in regions such as the orbitofrontal cortex, posterior cingulate cortex and visual cortex, suggesting neuronal loss or impaired cortical integrity. Differences between episodic and chronic migraine further highlight progressive structural changes associated with disease burden. Emerging evidence also suggests that preventive treatments, including calcitonin gene-related peptide monoclonal antibodies and botulinum toxin A, may reverse some of these cortical alterations, particularly in treatment responders.ConclusionsCortical thickness analysis provides valuable insights into migraine pathophysiology, offering a potential biomarker for disease progression and treatment response. However, inconsistencies across studies highlight the need for standardized MRI protocols and larger longitudinal investigations to clarify the clinical relevance of cortical thickness changes in migraine.
Rasmussen's encephalitis (RE) is a rare condition of unknown etiology that causes a severe chronically neurological disorder with mostly affecting children. The main clinical feature of RE includes frequent seizures with drug-resistant, unilateral hemispheric atrophy, and progressive neurological deficits. In this review, we summarized five pathogenesis on the basis of the current research including virus infection, antibody-mediated degeneration, cell-mediated immunity, microglia-induced degeneration, and genetic mutations. So far, no exact virus in RE brain tissue or definite antigen in humoral immune system was confirmed as the determined etiology. The importance of cytotoxic CD8+ T lymphocytes and activated microglial and the role of their immune mechanism in RE development are gradually emerging with the deep study. Genetic researches support the notion that the pathogenesis of RE is probably associated with single nucleotide polymorphisms on immune-related genes, which is driven by affecting inherent antiretroviral innate immunity. Recent advances in treatment suggest immunotherapy could partially slows down the progression of RE according to the histopathology and clinical presentation, which aimed at the initial damage to the brain by T cells and microglia in the early stage. However, the cerebral hemispherectomy is an effective means to controlling the intractable seizure, which is accompanied by neurological complications inevitably. So, the optimal timing for surgical intervention is still a challenge for RE patient. On the contrary, exploration on other aspects of pathogenesis such as dysfunction of adenosine system may offer a new therapeutic option for the treatment of RE in future.
The present study aimed to investigate whether levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine pre-treated with erenumab, a monoclonal CGRP receptor antibody. In this double-blind, placebo-controlled, two-way cross-over study, adults with migraine without aura received a subcutaneous injection of 140 mg of erenumab on day 1. Subsequently, they were randomized to receive a 20-minute infusion of 0.05 mg/ml levcromakalim or placebo on two experimental days separated by at least one week (between days 8 and 21). The primary endpoint was the difference in the incidence of migraine attacks between levcromakalim and placebo during the 12-hour post-infusion period. In total, 16 participants completed the study. During the 12-hour observation period, 14 (88%) of 16 participants experienced migraine attacks after levcromakalim, compared to two (12%) after placebo (p < 0.001). The area under the curve for median headache intensity was greater after levcromakalim than placebo (p < 0.001). Levcromakalim elicited dilation of the superficial temporal artery during the first hour after infusion, a response absent following placebo (p < 0.001). The induction of migraine attacks via opening of KATP channels appears independent of CGRP receptor activation.Trial Registration: ClinicalTrials.gov, Identifier NCT05889442.
Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk-benefit profile of RTX in pediatric-onset multiple sclerosis are scarce. In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed. Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38-0.92) to 0.03 (95% CI 0.02-0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70-2.48) to 0.08 (95% CI 0.03-0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30-3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis.
We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start. Using a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011-2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories. We identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories. In this cohort of actively treated RRMS, patients' processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start.
Autoimmune encephalitis (AE) comprises a group of rare, severe neuroinflammatory conditions. Current biomarkers of neuroinflammation are often normal in AE which therefore can be difficult to rule out in patients with seizures, cognitive and/or neuropsychiatric symptoms. Cerebrospinal fluid (CSF) soluble CD27 (sCD27) and soluble B-cell maturation antigen (sBCMA) have high sensitivity for neuroinflammation in other neuroinflammatory conditions. In this exploratory study we investigate the potential of sCD27 and sBCMA in CSF as biomarkers of neuroinflammation in AE. Concentrations of sCD27 and sBCMA were measured in CSF from 40 AE patients (20 patients were untreated (12 with anti-N-Methyl-d-Aspartate receptor antibodies (NMDA) and 8 with anti-Leucine-rich Glioma-Inactivated 1 antibodies (LGI1)), and 37 symptomatic controls (SCs). CSF concentrations of sCD27 were increased in untreated NMDA AE patients (median 1571 pg/ml; p < 0.001) and untreated LGI1 AE patients (median 551 pg/ml; p < 0.05) compared to SCs (median 250 pg/ml). CSF sBCMA was increased in untreated NMDA AE patients (median 832 pg/ml) compared to SCs (median 429 pg/ml). CSF sCD27 and sBCMA correlated with the CSF cell count. Receiver operating characteristic curve analysis of untreated AE patients versus SCs showed an area under the curve of 0.97 for sCD27 and 0.76 for sBCMA. CSF sCD27 is a suitable biomarker of neuroinflammation in AE with an ability to discriminate patients with NMDA AE and LGI1 AE from symptomatic controls. CSF sCD27 may be suited for ruling out AE and other neuroinflammatory conditions in the early phase of the diagnostic work-up.
The present study investigates the wearing-off effect in adults with chronic migraine treated with erenumab or fremanezumab. This real-world observational study was based on pre-collected headache diaries from chronic migraine patients in treatment with either monthly injections of 140 mg of erenumab or 225 mg of fremanezumab. Consistent wearing-off was defined as an increase of ≥2 weekly migraine days in the last week compared to the second week over two consecutive 4-week treatment periods. The primary endpoint was wearing-off in the total population. The secondary endpoints were difference in wearing-off in (i) a subgroup of patients treated with erenumab and fremanezumab and (ii) consistent wearing-off in patients with a ≥30% reduction in monthly migraine days, compared to baseline, in the two consecutive treatment months. In total, 100 patients (erenumab: n = 60, fremanezumab: n = 40) were included. Sixty-two out of 100 (62%) patients had consistent ≥30% treatment response on antibody therapy in both months (erenumab: n = 36, fremanezumab: n = 26). There was no consistent wearing-off over the two consecutive months from week 2 to week 4 (3.04%, p = 0.558). There was no wearing-off within the erenumab (p = 0.194) or the fremanezumab (p = 0.581) groups. Among the ≥30% treatment responders, there was no consistent wearing-off over the two consecutive months (2.6%, p = 0.573). There was no wearing-off in treatment responders, which is in alignment with premarketing data from placebo-controlled phase III studies. These data suggest that patients should be informed upfront that no wearing-off effect is expected because anxiety for attacks at the end of the month per se may generate migraine attacks.
The incidence of stroke has been declining in Finland, as well as in Europe. However, it is unclear whether the incidence of transient ischemic attack (TIA) is also decreasing. In fact, the TIA incidence in the Finnish population has never been reported. Therefore, here we investigated the incidence of TIA in the Eastern Finnish population in 2017. All patients with suspected TIA, from a defined catchment area, were referred to a neurological emergency unit at Kuopio University Hospital (KUH) in the Northern Savonia region of Eastern Finland, which had a population of 246,653 in 2017. The original study population comprised TIA patients diagnosed based on the WHO TIA criteria in 2017. Incidence rates were calculated by dividing the number of TIA cases by the number of people in different age groups. Among 432 patients with a suspected TIA referred to the neurological emergency unit at Kuopio University Hospital in 2017, 293 were living in Northern Savonia and were ultimately diagnosed with TIA after neurological examinations. The number of first-ever TIAs was 211. The crude incidence of all TIA was 122/100,000 inhabitants, and of first-ever TIA was 86/100,000. The age-standardized incidence (European population 2010) of the first-ever TIA was calculated to be 64/100,000. The mean age of first-ever TIA patients was 70 years: 72 years for women versus 68 years for men. We found a high incidence of TIA in Eastern Finland.
Pituitary adenylate cyclase-activating polypeptide (PACAP), structurally related to vasoactive intestinal peptide (VIP), is one of the important mediators in the pathogenesis of migraine and is known to dilate cranial arteries and induce headache and migraine. Our objective was to determine whether Lu AG09222-an investigational humanized monoclonal antibody directed against PACAP ligand-would inhibit the PACAP-signaling cascade by abolishing its vasodilatory and headache-inducing abilities. In a randomized, double-blind, parallel-group, single-dose, placebo-controlled study of Lu AG09222, healthy volunteers aged 18-45 years without history of headache disorders were randomly allocated to three treatment sequences (1:2:2) on two experimental infusion visits with 9 ± 3 days' interval: placebo + saline + saline (n = 5), placebo + PACAP38 + VIP (n = 10), and Lu AG09222 + PACAP38 + VIP (n = 10). The primary outcome measure was area under the curve (AUC) of the change in superficial temporal artery (STA) diameter from 0 to 120 min after start of infusion of PACAP38. The study was conducted at the Danish Headache Center in Copenhagen, Denmark. In participants who received Lu AG09222 + PACAP38 infusion, there was a significantly lower STA diameter (mean (SE) [95% CI] AUC ‒35.4 (4.32) [‒44.6, ‒26.3] mm × min; P < 0.0001) compared to participants who received placebo + PACAP38 infusion. Secondary and explorative analysis revealed that PACAP38 infusion induced an increase in facial blood flow, heart rate and mild headache, and indicated that these PACAP38-induced responses were inhibited by Lu AG09222. This proof-of-mechanism study demonstrated that Lu AG09222 inhibited PACAP38-induced cephalic vasodilation and increases in heart rate, and reduced concomitant headache. Lu AG09222 may be a potential therapy against migraine and other PACAP-mediated diseases. ClinicalTrials.gov: NCT04976309. Registration date: July 19, 2021.
Migraine is an evolving, and sometimes lifelong disorder. The prevalence of episodic migraine peaks among individuals aged in their late 30s, implying a tendency for the disorder to remit with increasing age thereafter, whereas chronic migraine is more likely to persist into later life. Diagnosis and treatment of migraine in older adults, defined as individuals aged 60 years or older, is rendered more complex by increasing probabilities of atypical clinical features and comorbidities, with patients' comorbidities sometimes limiting their therapeutic options. However, the changing clinical presentation of migraine over an individual's lifespan is not well characterised. The neurobiological basis of remission in older adults remains unclear, although vascular, neuronal, and hormonal changes are likely to be involved. Long-term longitudinal studies of individuals with migraine would be particularly informative, with the potential not only to suggest new research directions, but also to lead to the identification of novel therapeutic agents. Although several novel migraine medications are becoming available, their effectiveness, tolerability, and safety often remain uncertain in older adults, who have commonly been excluded from the evaluation of these agents in randomised controlled trials, or who constitute only a small proportion of study populations. There is a need to recognise these limitations in the available evidence, and the specific, and often unmet, clinical needs of older adults with migraine, not least because older adults constitute an increasing proportion of populations worldwide.
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis presents commonly with psychiatric symptoms. One cohort of these patients reported that antipsychotic administration led to neuroleptic intolerance (NI) in 19% of them, which was preventable by a prompt encephalitis diagnosis. To date, there is no clear description of the "neuroleptic intolerance" spectrum in general or during anti-NMDAR encephalitis. We aimed to synthesize epidemiological and clinical characteristics of patients with NI and confirmed anti-NMDAR encephalitis, the time to the encephalitis diagnosis, the disease course, outcomes at discharge, and associated factors. We systematically searched three databases, to include clinical cases, case series, and observational studies. Additionally, we reported one clinical case. Results were summarized using narrative synthesis and the quality of the included studies was assessed. We included 22 records representing 40 patients (28 females; mean age, 24.6). Overall, the evidence quality was low. Initially, most cases were admitted in psychiatric wards (70%) with purely psychiatric symptoms (37.5%). However, most of them developed subtle concomitant neurological symptoms. The mean time to anti-NMDAR encephalitis diagnosis was 26.7 days, which was triggered by the NI in six patients. We found no association between clinical variables as delayed diagnosis, admission to psychiatric wards or the presence of malignancy with outcome variables as unfavorable outcomes at discharge, ICU, or mechanical ventilation requirement. A thorough neurological examination in young patients with new-onset psychiatric symptoms could help emergency physicians, neurologists, and psychiatrists suspect anti-NMDAR encephalitis earlier. Awareness of NI as a potential side effect during suspected or confirmed anti-NMDAR encephalitis is encouraged.
Psychiatric outcomes after COVID-19 have been of high concern during the pandemic; however, studies on a nationwide level are lacking. To estimate the risk of mental disorders and use of psychotropic medication among individuals with COVID-19 compared with individuals not tested, individuals with SARS-CoV-2-negative test results, and those hospitalized for non-COVID-19 infections. This nationwide cohort study used Danish registries to identify all individuals who were alive, 18 years or older, and residing in Denmark between January 1 and March 1, 2020 (N = 4 152 792), excluding individuals with a mental disorder history (n = 616 546), with follow-up until December 31, 2021. Results of SARS-CoV-2 polymerase chain reaction (PCR) testing (negative, positive, and never tested) and COVID-19 hospitalization. Risk of new-onset mental disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00-F99) and redeemed psychotropic medication (Anatomical Therapeutic Chemical classification codes N05-N06) was estimated through survival analysis using a Cox proportional hazards model, with a hierarchical time-varying exposure, reporting hazard rate ratios (HRR) with 95% CIs. All outcomes were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and job status. A total of 526 749 individuals had positive test results for SARS-CoV-2 (50.2% men; mean [SD] age, 41.18 [17.06] years), while 3 124 933 had negative test results (50.6% women; mean [SD] age, 49.36 [19.00] years), and 501 110 had no tests performed (54.6% men; mean [SD] age, 60.71 [19.78] years). Follow-up time was 1.83 years for 93.4% of the population. The risk of mental disorders was increased in individuals with positive (HRR, 1.24 [95% CI, 1.17-1.31]) and negative (HRR, 1.42 [95% CI, 1.38-1.46]) test results for SARS-CoV-2 compared with those never tested. Compared with individuals with negative test results, the risk of new-onset mental disorders in SARS-CoV-2-positive individuals was lower in the group aged 18 to 29 years (HRR, 0.75 [95% CI, 0.69-0.81]), whereas individuals 70 years or older had an increased risk (HRR, 1.25 [95% CI, 1.05-1.50]). A similar pattern was seen regarding psychotropic medication use, with a decreased risk in the group aged 18 to 29 years (HRR, 0.81 [95% CI, 0.76-0.85]) and elevated risk in those 70 years or older (HRR, 1.57 [95% CI, 1.45-1.70]). The risk for new-onset mental disorders was substantially elevated in hospitalized patients with COVID-19 compared with the general population (HRR, 2.54 [95% CI, 2.06-3.14]); however, no significant difference in risk was seen when compared with hospitalization for non-COVID-19 respiratory tract infections (HRR, 1.03 [95% CI, 0.82-1.29]). In this Danish nationwide cohort study, overall risk of new-onset mental disorders in SARS-CoV-2-positive individuals did not exceed the risk among individuals with negative test results (except for those aged ≥70 years). However, when hospitalized, patients with COVID-19 had markedly increased risk compared with the general population, but comparable to risk among patients hospitalized for non-COVID-19 infections. Future studies should include even longer follow-up time and preferentially include immunological biomarkers to further investigate the impact of infection severity on postinfectious mental disorder sequelae.
Despite the pervasiveness of migraine, the underlying pathophysiological mechanisms initiating migraine attacks are far from well understood and are matter of scientific debate. In this narrative review, we discuss key evidence for that suggest a peripheral origin or central origin and provide directions for future studies that may provide further clarification. Migraine pathogenesis is considered to involve the trigeminovascular system, a term that encompasses the trigeminal nerve and its axonal projections to the intracranial blood vessels. Beyond any doubt both peripheral and central mechanisms are involved in migraine pathogenesis, but an unresolved question is the how the initial activation occurs in a migraine attack. Evidence favoring a peripheral origin of migraine attacks, i.e., initial events occur outside of the blood-brain barrier, include the importance of sensitization of perivascular sensory afferents early on in a migraine attack. Evidence favoring a central origin include the occurrence of prodromal symptoms, migraine aura, and activation of structures within the central nervous system early in and during a migraine attack. Both peripheral and central mechanisms are likely involved in a migraine attack, e.g., peripheral nociceptive input is necessary for pain transmission and cortical activity is necessary for pain perception. Yet, the debate of whether migraine attacks are initiated a peripheral or central site remains unresolved. The increased focus on prodromal symptoms and on the development of a human model of migraine aura will possibly provide key arguments needed to answer this question in the near future. Until then, we cannot draw firm conclusions and the debate goes on. Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=NC0nlcKohz0 .
Teriflunomide is a disease modifying treatment (DMT) approved for relapsing-remitting multiple sclerosis (RRMS) in adults and children. It reduces lymphocyte proliferation by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and thereby the pyrimidine synthesis. Although most DMTs in multiple sclerosis (MS) modulate or inhibit the immune system in the periphery, the efficacy may improve if the agent also targets immune activity within the central nervous system (CNS), acts as a neuro-protective and enhances neuro-regeneration. The objective of this study was to determine the passage of teriflunomide over the blood-cerebrospinal fluid barrier (BCSFB). Plasma and cerebrospinal fluid (CSF) teriflunomide concentrations were determined at steady state in 12 patients with RRMS, treated with oral teriflunomide 14 mg once daily. Included patients were all clinically stable without relapse or disability worsening within 6 months prior from baseline and were on no other immune modulating or immunosuppressive drugs. The mean teriflunomide concentrations in plasma and CSF were 38775 (SEM ± 7256) ng/mL and 68 (SEM ± 15) ng/mL, respectively. The passage over the BCSFB was 0.17 % (SEM ± 0.01). While no correlation was found between the function of the BCSFB assessed with the albumin ratio and the CSF teriflunomide concentration, the CSF and plasma teriflunomide concentrations were highly correlated (rs = 0.90, < 0.0001). Further studies are warranted to determine if the obtained CSF teriflunomide concentration reflects that in the CNS and is able to influence inflammatory and degenerative processes within the CNS.
Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system. The glycosphingolipid sulfatide, a lipid particularly enriched in the myelin sheath, has been shown to be involved the maintenance of this specific membrane structure. Sulfatide in cerebrospinal fluid (CSF) may reflect demyelination, a dominating feature of MS. We investigated the diagnostic utility of CSF sulfatide isoform levels to separate different courses or phenotypes of MS disease. This was a mono-center, cross-sectional study of relapsing-remitting MS (RRMS) (n = 45) and progressive MS (PMS) (n = 42) patients (consisting of primary PMS (n = 17) and secondary PMS (n = 25)) and healthy controls (n = 19). In total, 20 sulfatide isoforms were measured in CSF by liquid chromatography-mass spectrometry. CSF total sulfatide concentrations, as well as CSF sulfatide isoform distribution, did not differ across the study groups, and their levels were independent of disease course/phenotype, disease duration, time to conversion to secondary PMS, age, and disability in MS patients. CSF sulfatide isoforms lack diagnostic and prognostic utility as a biomarker for progressive MS.
Alemtuzumab (ALZ) is an immune reconstitution therapy for treating relapsing-remitting multiple sclerosis (RRMS). However, ALZ increases the risk of secondary autoimmune diseases (SADs). We explored whether the detection of autoimmune antibodies (auto-Abs) could predict the development of SADs. We included all patients with RRMS in Sweden who initiated ALZ treatment (n = 124, 74 female subjects) from 2009 to 2019. The presence of auto-Abs was determined in plasma samples obtained at the baseline and at 6, 12, and 24 months of follow-up, as well as in a subgroup of patients (n = 51), it was determined in plasma samples obtained at the remaining 3-month intervals up to 24 months. Monthly blood tests, urine tests, and the assessment of clinical symptoms were performed for monitoring safety including that of SADs. Autoimmune thyroid disease (AITD) developed in 40% of patients, within a median follow-up of 4.5 years. Thyroid auto-Abs were detected in 62% of patients with AITD. The presence of thyrotropin receptor antibodies (TRAbs) at the baseline increased the risk of AITD by 50%. At 24 months, thyroid auto-Abs were detected in 27 patients, and 93% (25/27) developed AITD. Among patients without thyroid auto-Abs, only 30% (15/51) developed AITD (p < 0.0001). In the subgroup of patients (n = 51) with more frequent sampling for auto-Abs, 27 patients developed ALZ-induced AITD, and 19 of them had detectable thyroid auto-Abs prior to the AITD onset, with a median interval of 216 days. Eight patients (6.5%) developed non-thyroid SAD, and none had detectable non-thyroid auto-Abs. We conclude that monitoring thyroid auto-Abs, essentially TRAbs, may improve the surveillance of AITD associated with ALZ treatment. The risk for non-thyroid SADs was low, and monitoring non-thyroid auto-Abs did not seem to provide any additional information for predicting non-thyroid SADs.