The glymphatic system in migraine and other headaches.

Glymphatic system is an emerging pathway of removing metabolic waste products and toxic solutes from the brain tissue. It is made of a network of perivascular spaces, filled in cerebrospinal and interstitial fluid, encompassing penetrating and pial vessels and communicating with the subarachnoid space. It is separated from vessels by the blood brain barrier and from brain tissue by the endfeet of the astrocytes rich in aquaporin 4, a membrane protein which controls the water flow along the perivascular space. Animal models and magnetic resonance (MR) studies allowed to characterize the glymphatic system function and determine how its impairment could lead to numerous neurological disorders (e.g. Alzheimer's disease, stroke, sleep disturbances, migraine, idiopathic normal pressure hydrocephalus). This review aims to summarize the role of the glymphatic system in the pathophysiology of migraine in order to provide new ways of approaching to this disease and to its therapy.

Diagnosis of atrial fibrillation in young patients with ischemic stroke: A systematic review and meta-analysis.

INTRODUCTION: The recommended cardiac rhythm evaluation to determine the etiology of ischemic stroke (IS) is similar in all patients regardless of their age and includes an electrocardiogram and at least a 24-hour heart rhythm monitoring. However, it is known that the main causes of IS vary according to patients' age. There is a higher preponderance of arterial dissections and patent foramen ovale in younger patients, while atrial fibrillation (AF) is more common in older patients. AIMS: To determine the proportion of AF in young IS reported in the literature and determine if young IS patients found to have AF had known structural cardiac pathology. METHODS: Systematic review of the literature searching PubMed and Embase for articles published since their inception to August 2020. Inclusion criteria were studies including at least 10 patients, aged 14-50 years-old, clinical or radiological diagnosis of IS and quantification of patients found to have AF. We conducted a meta-analysis using a random-effects model and calculated pooled proportions with 95% confidence intervals. RESULTS: 8331 articles were screened, 154 were selected for full-text review. 43 studies were included in our final analysis (902800 patients). The proportion of AF in young IS overall was 3.1% [95%CI 2.4-3.7], I2 93.88%. Sub-analysis revealed a proportion of AF of 3.8% [95% CI 0.3-7.3] in lower-middle-income economies, versus 5.4% [95% CI 3-7.9] in upper-middle-income economies, and 2.2% [95% CI 1.6-2.8] in high-income economies. Only 3 studies mentioned the proportion of patients with AF that had structural cardiac pathology. CONCLUSION: The proportion of AF in young IS was low. More studies are needed to better understand if young IS patients diagnosed with AF had a priori known structural cardiac pathology that could increase the probability of finding AF. This could lead to a reevaluation of the need for 24 hours cardiac rhythm evaluation in young patients without cardiac pathology.

Gestational exposure to erenumab-The outcome of three pregnancies.

Erenumab is a monoclonal antibody (mAb) approved for the preventive treatment of migraine. While preclinical studies on calcitonin gene-related peptide mAbs did not identify any reproductive toxicity, pregnant and breastfeeding women were excluded from the pivotal human studies, and therefore the safety of calcitonin gene-related peptide medications in this population must be studied. So far, postmarketing data of accidental exposures have not brought to light any specific toxicities. Three women treated with erenumab in our series conceived while exposed to the drug. All had previous successful pregnancies, were on erenumab for more than 6 months, and had ≥80% reduction in headache frequency. The one who stopped erenumab only 1 month before conceiving had a spontaneous abortion during the first trimester due to a gestational trophoblastic neoplasia and has since conceived with an uneventful gestation. The other two women stopped treatment during the first trimester, and both pregnancies went to term with no complications. All babies have shown normal development. No plausible explanation relates the mechanism of action of erenumab and the serious complication that occurred in one patient. Continuous follow-up and reporting of all exposures are encouraged to gather safety data on pregnant and nursing women and on the development of the newborns. So far, immediately stopping the drug is advised and may contribute to decreasing the potential risks.

Update on "Treatment of orthostatic headache without intracranial hypotension: A case report" - nine years later.

BACKGROUND: In 2013, one of the authors described a 36-year-old female with orthostatic headache without documented intracranial hypotension or evidence of cerebrospinal fluid leak, despite extensive workup. Headache was unresponsive to conservative treatment since 2010, showed only transient benefit after repeated epidural blood patches while vitamin A supplementation resulted in progressive improvement. CASE: Since 2013, the patient followed a relapsing and remitting course yet relapse control became difficult after a drug induced liver injury required vitamin A discontinuation in 2017, when her headache became chronic. Greater occipital nerve blocks provided pain relief as alternative but were stopped due to the pandemic and her latest severe relapse, in late 2020, required not only restarting anaesthetic blocks and aggressive medication management, but also reassessing and treating comorbidities (obstructive sleep apnoea and major depressive disorder) with modest benefit. CONCLUSION: Orthostatic headache without intracranial hypotension is rare, with only 28 cases reported so far, all treated empirically and all treatment options revealing to be mostly ineffective. Vitamin A anecdotally appeared to be useful in our case but had to be stopped for severe side effects, so unfavourable long-term prognosis, in ours and 2/3 of the reported cases, seems to be the rule in this intriguing entity.

Therapeutic inertia in relapsing-remitting multiple sclerosis.

BACKGROUND: Therapeutic inertia (TI) is defined as a failure to initiate or intensify treatments despite evidence of disease activity. Its prevalence and determining factors in Relapsing-Remitting Multiple Sclerosis (RRMS) patients in Portugal are not known. The main objective of this work was to ascertain the prevalence of TI in RRMS and its determining factors. METHODS: We conducted a multicentre retrospective observational study of RRMS patients followed in MS Clinics of six Portuguese hospitals with at least one medical appointment in 2018. TI was defined as the absence of treatment initiation or intensification when therapeutic goals were unmet, that is when there was evidence of disease activity based on the definition of "no evidence of disease activity" (NEDA) which refers to absence of clinical relapses, absence of disease progression measured by expanded disability status scale (EDSS) and absence of new disease activity (new T2 lesions/enhancing lesion) on magnetic resonance imaging (MRI) over the period of observation. RESULTS: We included 427 patients with RRMS meeting inclusion criteria, 69.6% females, with a mean age of 41.66 years old. The mean age at diagnosis was 33.17 years old and the average number of years since diagnosis was 8.72. MS relapses were reported on 54 patients. Moderate to severe relapses were reported in 59.3%. Median EDSS score was 1.5. Intention to get pregnant was explicit in 39 patients, representing 18.8% of the women at childbearing age. Among the 365 patients who had an MRI, 23.8% had new T2 lesions and 7.4% had enhancing lesions. Regarding DMT, 72.8% were treated with interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate, 20.6% were under fingolimod, natalizumab, rituximab, and cladribine, and the remaining 6.6% were without treatment. Adverse events were reported in 12.9% of patients, and 10.1% mentioned preferences regarding the treatment. TI was present in 80 (18.7%) patients, representing 54.8% of those with potential to inertia. Patients with a radiologically less active disease, who were already on a DMT and who had no adverse events from their current treatment were more likely to have TI (p<0,05). Also, patients followed in centers classified as higher level of care (level 1) had more TI compared with patients followed in centers of levels 2 and 3. CONCLUSION: TI was present in 1 in 5 patients, exceeding half of the sample with the potential to inertia, corroborating the high prevalence of TI in other studies. The determining factors of TI were the absence of relapses or the occurrence of mild relapses, being already on DMT, absence of adverse events, and follow-up in higher care level centers. TI is a topic rarely addressed in MS and this work highlights the importance of therapeutic optimization in these patients. Further studies should be held to explore the factors that influence TI once they have a great impact on therapeutic decisions.