BACKGROUND: Acute Disseminated Encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, characterize by multiple white matter hyperintensities on T2 MRI. Patients usually present with subacute progressive encephalopathy and polyfocal neurological deficits. Possible treatments are corticosteroids, immunoglobulins and plasma exchange. Full clinical recovery is seen in more than half of the cases.
METHODS: We describe a case of a 62-year-old patient presenting with thunderclap headache as the first symptom, two weeks after an upper respiratory tract infection. The clinical course was complicated by progressive coma and intracranial hypertension mandating external ventricular drainage and sedation. Initial treatment with methylprednisolone was unsuccessful but clinical resolution and radiological regression was achieved after plasma exchanges and cyclophosphamide.
CONCLUSIONS: To our knowledge, this is the first reported case of ADEM presenting with thunderclap headache. Intracranial hypertension with the need for invasive neuromonitoring and pressure management is also a very rare complication of ADEM. In this report, we describe the findings of the literature review concerning ADEM, thunderclap headache and intracranial hypertension.

BACKGROUND: Pediatric headache is an increasing medical problem that has adverse effects on children\'s quality of life, academic performance, and social functioning. Children with primary headaches exhibit enhanced sensory sensitivity compared to their healthy peers. However, comprehensive investigations including multimodal sensory sensitivity assessment are lacking. This study aimed to compare sensory sensitivity of children with primary headaches with their healthy peers across multiple sensory domains.
METHODS: The study included 172 participants aged 6 to 17 years (M = 13.09, SD = 3.02 years; 120 girls). Of these 80 participants were patients with migraine, 23 were patients with tension-type headache, and 69 were healthy controls. The following sensory measures were obtained: Mechanical Detection Threshold (MDT), Mechanical Pain Threshold (MPT), Mechanical Pain Sensitivity (MPS), detection and pain threshold for Transcutaneous Electrical Nerve Stimulation (TENS), olfactory and intranasal trigeminal detection threshold, and odor identification ability. Sensory sensitivity was compared between groups with a series of Kruskal-Wallis tests. Binomial regression models were used to compare the relative utility of sensory sensitivity measures in classifying participants into patients and healthy controls, as well as into patients with migraine and tension-type headache.
RESULTS: Patients with migraine had lower MPT measured at the forearm than patients with tension-type headaches and healthy controls. MPS was higher in patients with migraine than in healthy controls. All patients with headaches had lower detection threshold of TENS and higher olfactory sensitivity. Healthy controls showed increased intranasal trigeminal sensitivity. Scores in MPS, TENS, and olfactory and trigeminal thresholds were significantly predicting presence of primary headaches. Additionally, scores in MPT, olfactory and trigeminal threshold were positive predictors of type of headache.
CONCLUSIONS: Children with primary headaches exhibit different sensory profiles than healthy controls. The obtained results suggest presence of increased overall, multimodal sensitivity in children with primary headaches, what may negatively impact daily functioning and contribute to further pain chronification.
BACKGROUND: The study was registered in the German Registry of Clinical Trials (DRKS) DRKS00021062.

OBJECTIVE: Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene-related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years.
METHODS: This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope.
RESULTS: PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results.
CONCLUSIONS: Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.

Reversible cerebral vasoconstriction syndrome (RCVS) is a complex and etiologically diverse neurovascular disorder that typically presents with severe thunderclap headaches (TCH) as the primary symptom, accompanied by reversible vasoconstriction of the cerebral arteries. The clinical course may include focal neurological deficits or epileptic seizures. There are two types: idiopathic RCVS and secondary RCVS, the latter triggered by various substances, medical interventions, or diseases. In clinical practice, various medical specialists may initially encounter this condition, underscoring the importance of accurate recognition and diagnosis of RCVS. The clinical course often appears monophasic and self-limiting, with recurrences reported in only 1.7% of cases annually. Complications such as cerebral hemorrhages and cerebral ischemia can lead to death in 5-10% of cases. This article utilizes a case study to explore RCVS, its complications, and the diagnostic procedures involved.
UNASSIGNED: Das reversible zerebrale Vasokonstriktionssyndrom (RCVS) ist eine komplexe und ätiologisch vielfältige neurovaskuläre Erkrankung, die typischerweise mit Donnerschlagkopfschmerz („thunderclap headache“, TCH) als Hauptkriterium sowie einer reversiblen sekundären Vasokonstriktion der Hirnarterien einhergeht. Das RCVS kann mit oder ohne fokal-neurologische Defizite oder epileptische Anfälle verlaufen. Man unterscheidet zwischen einem idiopathischen RCVS und einem sekundären RCVS, welches durch verschiedene Substanzen, medizinische Eingriffe oder Erkrankungen ausgelöst wird. Den ersten Kontakt mit dieser Erkrankung haben in der täglichen Praxis verschiedene Spezialisten; die richtige Erkennung und Diagnose von RCVS bleiben weiterhin eine Herausforderung. Der klinische Verlauf ist in der Regel monophasisch und selbstlimitierend, wobei Rezidive lediglich in 1,7 % der Fälle pro Jahr auftreten. Komplikationen wie Hirnblutungen und zerebrale Ischämien führen in 5–10 % der Fälle zum Tod. In dieser Arbeit wird ein Fallbeispiel verwendet, um das RCVS und seine Komplikationen vorzustellen sowie die diagnostischen Verfahren zu erläutern.

OBJECTIVE: To investigate the prevalence of neuroimaging in patients with primary headaches and the clinician-based rationale for requesting neuroimaging in China.
METHODS: This study included patients with primary headaches admitted to hospitals and clinicians in China. We identified whether neuroimaging was requested and the types of neuroimaging conducted.
METHODS: This was a cross-sectional study, and convenience sampling was used to recruit patients with primary headaches. Clinicians were interviewed using a combination of personal in-depth and topic-selection group interviews to explore why doctors requested neuroimaging.
METHODS: We searched for the diagnosis of primary headache in the outpatient and inpatient systems according to the International Classification of Diseases-10 code of patients admitted to six hospitals in three provincial capitals by 2022.We selected three public and three private hospitals with neurology specialties that treated a corresponding number of patients.
RESULTS: Among the 2263 patients recruited for this study, 1942 (89.75%) underwent neuroimaging. Of the patients, 1157 (51.13%) underwent magnetic resonance imaging (MRI), 246 (10.87%) underwent both head computed tomography (CT) and MRI, and 628 (27.75%) underwent CT. Fifteen of the 16 interviewed clinicians did not issue a neuroimaging request for patients with primary headaches. Furthermore, we found that doctors issued a neuroimaging request for patients with primary headaches mostly, to exclude the risk of misdiagnosis, reduce uncertainty, avoid medical disputes, meet patients\' medical needs, and complete hospital assessment indicators.
CONCLUSIONS: For primary headaches, the probability of clinicians requesting neuroimaging was higher in China than in other countries. There is considerable room for improvement in determining appropriate strategies to reduce the use of low-value care for doctors and patients.

Reversible cerebral vasoconstriction syndrome (RCVS) is a complex neurovascular disorder characterized by repetitive thunderclap headaches and reversible cerebral vasoconstriction. The pathophysiological mechanism of this mysterious syndrome remains underexplored and there is no clinically available molecular biomarker. To provide insight into the pathogenesis of RCVS, this study reported the first landscape of dysregulated proteome of cerebrospinal fluid (CSF) in patients with RCVS (n  =  21) compared to the age- and sex-matched controls (n  =  20) using data-independent acquisition mass spectrometry. Protein-protein interaction and functional enrichment analysis were employed to construct functional protein networks using the RCVS proteome. An RCVS-CSF proteome library resource of 1054 proteins was established, which illuminated large groups of upregulated proteins enriched in the brain and blood-brain barrier (BBB). Personalized RCVS-CSF proteomic profiles from 17 RCVS patients and 20 controls reveal proteomic changes involving the complement system, adhesion molecules, and extracellular matrix, which may contribute to the disruption of BBB and dysregulation of neurovascular units. Moreover, an additional validation cohort validated a panel of biomarker candidates and a two-protein signature predicted by machine learning model to discriminate RCVS patients from controls with an area under the curve of 0.997. This study reveals the first RCVS proteome and a potential pathogenetic mechanism of BBB and neurovascular unit dysfunction. It also nominates potential biomarker candidates that are mechanistically plausible for RCVS, which may offer potential diagnostic and therapeutic opportunities beyond the clinical manifestations.

BACKGROUND: We recently found headache disorders to be highly prevalent among children (aged 6-11 years) and adolescents (aged 12-17) in Iran (gender- and age-adjusted 1-year prevalences: migraine 25.2%, tension-type headache 12.7%, undifferentiated headache [UdH] 22.1%, probable medication-overuse headache [pMOH] 1.1%, other headache on ≥ 15 days/month [H15+] 3.0%). Here we report on the headache-attributed burden, taking evidence from the same study.
METHODS: In a cross-sectional survey, following the generic protocol for the global schools-based study led by the Global Campaign against Headache, we administered the child and adolescent versions of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) structured questionnaire in 121 schools, purposively selected to reflect the country\'s diversities. Pupils self-completed these in class, under supervision. Headache diagnostic questions were based on ICHD-3 criteria but for the inclusion of UdH (defined as mild headache with usual duration < 1 h). Burden enquiry was across multiple domains.
RESULTS: The analysed sample (N = 3,244) included 1,308 (40.3%) children and 1,936 (59.7%) adolescents (1,531 [47.2%] male, 1,713 [52.8%] female). The non-participating proportion was 3.4%. Mean headache frequency was 3.9 days/4 weeks, and mean duration 1.8 h. Estimated mean proportion of time in ictal state was 1.1% (1.4% for migraine, 16.5% for pMOH). Symptomatic medication was consumed on a mean of 1.6 days/4 weeks. Lost school time averaged 0.4 days/4 weeks overall (2%, assuming a 5-day week), but was eleven-fold higher (4.3 days; 22%) for pMOH. For most headache types, days of reported limited activity were several-fold more than days lost from school (45% for pMOH, 25% for other H15+). Almost one in 12 parents (7.9%) missed work at least once in 4 weeks because of their son\'s or daughter\'s headache. Emotional impact and quality-of-life scores reflected these measures of burden.
CONCLUSIONS: Headache, common in children and adolescents in Iran, is associated with symptom burdens that may be onerous for some but not for most. However, there are substantial consequential burdens, particularly for the 1.1% with pMOH and the 3.0% with other H15+, who suffer educational disturbances and potentially major life impairments. These findings are of importance to educational and health policies in Iran.

BACKGROUND: The Global Burden of Disease (GBD) study is increasingly well informed with regard to headache disorders, but sub-Saharan Africa (SSA) remains one of the large regions of the world with limited data directly derived from population-based studies. The Global Campaign against Headache has conducted three studies in this region: Ethiopia in the east, Zambia in the south and Cameroon in Central SSA. Here we report a similar study in Benin, the first from West SSA.
METHODS: We used the same methods and questionnaire, applying cluster-randomized sampling in three regions of the country, randomly selecting households in each region, visiting these unannounced and randomly selecting one adult member (aged 18-65 years) of each household. The HARDSHIP structured questionnaire, translated into Central African French, was administered face-to-face by trained interviewers. Demographic enquiry was followed by diagnostic questions based on ICHD-3 criteria.
RESULTS: From 2,550 households with eligible members, we recruited 2,400 participants (participating proportion 94.1%). Headache ever was reported by almost all (95.2%), this being the lifetime prevalence. Headache in the last year was reported by 74.9%. Age-, gender- and habitation-adjusted estimates of 1-year prevalence were 72.9% for all headache, 21.2% for migraine (including definite and probable), 43.1% for TTH (also including definite and probable), 4.5% for probable medication-overuse (pMOH) and 3.1% for other headache on ≥ 15 days/month. One-day (point) prevalence of headache was 14.8% according to reported headache on the day preceding interview.
CONCLUSIONS: Overall, these findings are evidence that headache disorders are very common in Benin, a low-income country. The prevalence of pMOH, well above the estimated global mean of 1-2%, is evidence that poverty is not a bar to medication overuse. The findings are very much the same as those in a similar study in its near neighbour, Cameroon. With regard to migraine, they are reasonably in accord with two of three earlier studies in selected Beninese populations, which did not take account of probable migraine. This study adds to the hitherto limited knowledge of headache in SSA.

BACKGROUND: The Global Campaign against Headache is conducting a series of population-based studies to fill the large geographical gaps in knowledge of headache prevalence and attributable burden. One major region not until now included is South America. Here we present a study from Peru, a country of 32.4 million inhabitants located at the west coast of South America, notable for its high Andes mountains.
METHODS: The study was conducted in accordance with the standardized methodology used by the Global Campaign. It was a cross-sectional survey using cluster randomised sampling in five regions to derive a nationally representative sample, visiting households unannounced, and interviewing one randomly selected adult member (aged 18-65 years) of each using the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire translated into South American Spanish. The neutral screening question (\"Have you had headache in the last year?\") was followed by diagnostic questions based on ICHD-3 and demographic enquiry.
RESULTS: The study included 2,149 participants from 2,385 eligible households (participating proportion 90.1%): 1,065 males and 1,084 females, mean age 42.0 ± 13.7 years. The observed 1-year prevalence of all headache was 64.6% [95% CI: 62.5-66.6], with age-, gender- and habitation-adjusted prevalences of 22.8% [21.0-24.6] for migraine (definite + probable), 38.9% [36.8-41.0] for tension-type headache (TTH: also definite + probable), 1.2% [0.8-1.8] for probable medication-overuse headache (pMOH) and 2.7% [2.1-3.5] for other headache on ≥ 15 days/month (H15+). One-day prevalence of headache (reported headache yesterday) was 12.1%. Migraine was almost twice as prevalent among females (28.2%) as males (16.4%; aOR = 2.1; p < 0.001), and strongly associated with living at very high altitude (aOR = 2.5 for > 3,500 versus < 350 m).
CONCLUSIONS: The Global Campaign\'s first population-based study in South America found headache disorders to be common in Peru, with prevalence estimates for both migraine and TTH substantially exceeding global estimates. H15 + was also common, but with fewer than one third of cases diagnosed as pMOH. The association between migraine and altitude was confirmed, and found to be strengthened at very high altitude. This association demands further study.

BACKGROUND: The series of population-based studies conducted by the Global Campaign against Headache has, so far, included Pakistan and Saudi Arabia from the Eastern Mediterranean Region. The Maghreb countries of North Africa, also part of this Region, are geographically apart and culturally very different from these countries. Here we report a study in Morocco.
METHODS: We applied the standardised methodology of Global Campaign studies, with cluster-randomized sampling in regions of Morocco selected to be representative of its diversities. In three of these regions, in accordance with this methodology, we made unannounced visits to randomly selected households and, from each, interviewed one randomly selected adult member (aged 18-65 years) using the HARDSHIP structured questionnaire translated into Moroccan Arabic and French. In a fourth region (Fès), because permission for such sampling was not given by the administrative authority, people were randomly stopped in streets and markets and, when willing, interviewed using the same questionnaire. This was a major protocol violation.
RESULTS: We included 3,474 participants, 1,074 (41.7%) from Agadir, 1,079 (41.9%) from Marrakech, 422 (16.4%) from Tétouan and 899 from Fès. In a second protocol violation, interviewers failed to record the non-participating proportion. In the main analysis, excluding Fès, observed 1-year prevalence of any headache was 80.1% among females, 68.2% among males. Observed 1-day prevalence (headache yesterday) was 17.8%. After adjustment for age and gender, migraine prevalence was 30.8% (higher among females [aOR = 1.6]) and TTH prevalence 32.1% (lower among females [aOR = 0.8]). Headache on ≥ 15 days/month (H15+) was very common (10.5%), and in more than half of cases (5.9%) associated with acute medication overuse (on ≥ 15 days/month) and accordingly diagnosed as probable medication-overuse headache (pMOH). Both pMOH (aOR = 2.6) and other H15+ (aOR = 1.9) were more common among females. In the Fès sample, adjusted prevalences were similar, numerically but not significantly higher except for other H15+.
CONCLUSIONS: While the 1-year prevalence of headache among adults in Morocco is similar to that of many other countries, migraine on the evidence here is at the upper end of the global range, but not outside it. H15 + and pMOH are very prevalent, contributing to the high one-day prevalence of headache.