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OBJECTIVE: Idiopathic intracranial hypertension (IIH) is a neurometabolic disease with an increasing incidence. The pathophysiology is unknown, but improvement of diagnosis and management requires discovery of novel biomarkers. Our objective was to identify such candidate biomarkers in IIH, and secondarily, test for associations between identified metabolites and disease severity. METHODS: This is a prospective case-control study with collection of cerebrospinal fluid (CSF), serum, and clinical data from new-onset, treatment-naïve patients with IIH (n = 60). Patients were included consecutively from 2 tertiary headache centers in Denmark, and age, sex, and body mass index (BMI) -matched healthy controls (n = 35) were recruited. Clinical data were retrieved at ocular remission (n = 55). Samples were analyzed using non-targeted mass spectrometry. RESULTS: Serum sphingosine 1-phosphate (S1P), adenosine, and glutamate were 0.46-fold (q < 0.0001), 0.25-fold (q = 0.0048), and 0.44-fold (q < 0.0001) lower, respectively, in IIH. CSF stearoyl-lysophosphatidylcholine (LysoPC-18) and 2-palmitoyl-lysophosphatidylcholine (LysoPC-16) were 0.42 (q = 0.0025) and 0.37 (q < 0.001) -fold lower. LysoPC-18 was higher in patients with moderate-severe versus mild papilledema (p = 0.022). LysoPC-18 correlated positively with retinal nerve fiber layer thickness (p = 0.0012, r = 0.42) and inversely with mean deviation on automated perimetry (p = 0.01, r = -0.35). Higher baseline serum S1P (p = 0.018) and lower CSF LysoPC-16 (p = 0.003) were associated with optic nerve atrophy at ocular remission. Pathway analysis suggests dysregulated lipid metabolism and redox disturbances in new-onset IIH. INTERPRETATION: We identify perturbed metabolism in new-onset IIH. S1P and LysoPC-16 demonstrate potential prognostic value due to association with subsequent optic nerve atrophy. This association between specific, differential metabolites and outcome provides substantial evidence for novel biomarkers of clinical significance that should be the focus of further targeted studies. ANN NEUROL 2024;96:595-607.
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Biomarcadores , Pseudotumor Cerebral , Humanos , Feminino , Masculino , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Adulto , Pseudotumor Cerebral/sangue , Pseudotumor Cerebral/líquido cefalorraquidiano , Pseudotumor Cerebral/complicações , Estudos de Casos e Controles , Estudos Prospectivos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Importance: The magnetic resonance imaging (MRI) criteria currently used to diagnose idiopathic intracranial hypertension (IIH) are based on expert opinion and have limited accuracy. Additional neuroimaging signs have been proposed and used with contradictory results; thus, prospective evidence is needed to improve diagnostic accuracy. Objective: To provide evidence-based, accurate MRI signs for IIH diagnosis. Design, Setting, and Participants: This prospective cohort study was conducted from January 2018 to May 2021 with 3 validation cohorts at 2 Danish headache centers and with 3 independent international cohorts. Consecutive patients with suspected IIH were enrolled. Eligibility required the clinical suspicion of IIH, age 18 years or older, and written informed consent. The validation cohorts comprised patients with confirmed IIH from Austria and the US, and patients without IIH from the US. Data analysis was performed from December 2021 to August 2023. Exposure: Standardized diagnostic workup was performed to classify cases according to current criteria, and blinded evaluation of cerebral radiological diagnostics and papilledema was performed. Main Outcomes and Measures: The primary outcomes were MRI signs associated with IIH as assessed by univariate analyses. An MRI score estimating papilledema was calculated using machine learning. Internal validation of associations with lumbar puncture opening pressure and outcome and external validation of accuracy were performed in 3 cohorts. Results: Of 192 eligible patients (185 women [96.4%]; median [IQR] age, 28.0 [23.0-35.0] years), 110 were classified as having IIH, 4 as having probable IIH, and 1 as having suspected IIH without papilledema; 77 did not have IIH and served as controls, with corresponding age, sex, and weight. Papilledema at diagnosis was associated with perioptic subarachnoid space distension (56 patients [68.3%] vs 21 patients [41.2%]), posterior globe flattening (53 patients [66.3%] vs 10 patients [21.3%]), optic nerve disc protrusion (35 patients [30.4%] vs 2 patients [2.3%]), and transverse sinus venous stenosis (75 patients [79.8%] vs 29 patients [46.8%]). The papilledema-estimating MRI score showed optimal balance between sensitivity (49%) and specificity (87%) when 2 of the 3 latter signs were present and was associated with the lumbar puncture opening pressure and ophthalmological outcome. The score showed strong diagnostic accuracy in the external validation cohorts (587 patients; area under the receiver operating characteristic curve, 0.86) and outperformed the current (2013) diagnostic MRI criteria. Conclusions and Relevance: The findings of this cohort study of patients with IIH and controls suggest that an evidence-based MRI score including posterior globe flattening, optic nerve disc protrusion, and transverse sinus stenosis can estimate the presence of papilledema more accurately than the current diagnostic criteria.
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Imageamento por Ressonância Magnética , Papiledema , Pseudotumor Cerebral , Humanos , Feminino , Masculino , Imageamento por Ressonância Magnética/métodos , Adulto , Estudos Prospectivos , Pseudotumor Cerebral/diagnóstico por imagem , Pseudotumor Cerebral/complicações , Papiledema/diagnóstico por imagem , Pessoa de Meia-Idade , Estudos de Coortes , Sensibilidade e Especificidade , DinamarcaRESUMO
BACKGROUND: Evidence indicates that physical activity reduces stress and promote a myriad of health-enhancing effects through anti-inflammatory mechanisms. However, it is unknown whether these mechanisms interfere in the association between psychosocial job stress and headache disorders. OBJECTIVE: To test whether physical activity and its interplay with the systemic inflammation biomarkers high-sensitivity C-reactive protein (hs-CRP) and acute phase glycoproteins (GlycA) would mediate the associations between job stress and headache disorders. METHODS: We cross-sectionally evaluated the baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) regarding job stress (higher demand and lower control and support subscales), migraine and tension-type headache (ICHD-2 criteria), self-reported leisure-time physical activity, and plasma hs-CRP and GlycA levels. Conditional process analyses with a sequential mediation approach were employed to compute path coefficients and 95 % confidence intervals (CI) around the indirect effects of physical activity and biomarkers on the job stress-headache relationship. Separate models were adjusted for sex, age, and depression and anxiety. Further adjustments added BMI smoking status, and socioeconomic factors. RESULTS: In total, 7,644 people were included in the study. The 1-year prevalence of migraine and tension-type headache were 13.1 % and 49.4 %, respectively. In models adjusted for sex, age, anxiety, and depression, the association between job stress (lower job control) and migraine was mediated by physical activity [effect = -0.039 (95 %CI: -0.074, -0.010)] but not hs-CRP or GlycA. TTH was associated with higher job control and lower job demand, which was mediated by the inverse associations between physical activity and GlycA [Job Control: effect = 0.0005 (95 %CI: 0.0001, 0.0010); Job Demand: effect = 0.0003 (95 %CI: 0.0001, 0.0007]. Only the mediating effect of physical activity in the job stress-migraine link remained after further adjustments including socioeconomic factors, BMI, smoking, and the exclusion of major chronic diseases. CONCLUSION: In the ELSA-Brasil study, physical activity reversed the link between job stress and migraine independently of systemic inflammation, while the LTPA-mediated downregulation of GlycA was associated with lower job stress-related TTH.
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Biomarcadores , Proteína C-Reativa , Exercício Físico , Inflamação , Análise de Mediação , Estresse Ocupacional , Humanos , Masculino , Feminino , Brasil/epidemiologia , Pessoa de Meia-Idade , Inflamação/metabolismo , Inflamação/sangue , Adulto , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Estudos Transversais , Exercício Físico/fisiologia , Biomarcadores/sangue , Estresse Ocupacional/epidemiologia , Estudos Longitudinais , Estresse Psicológico/metabolismo , Cefaleia do Tipo Tensional/epidemiologia , Cefaleia do Tipo Tensional/sangue , Transtornos de Enxaqueca/epidemiologia , Cefaleia/epidemiologia , Cefaleia/metabolismo , IdosoRESUMO
BACKGROUND: Cluster headache presents in an episodic and chronic form, between which patients can convert during the course of disease. We aimed to quantify the rate of cluster headache patients changing phenotype within one and five years and investigate the earlier proposed association between chronification and having side-shifting attacks. METHODS: In total, 430 cluster headache patients well-characterized according to current International Classification of Headache Disorders criteria, who were all participants in a prior transition-study, were re-interviewed in an observational, retrospective, cross-sectional follow-up study design at the Danish Headache Center. RESULTS: The transition rate for the whole cohort was 6.5% within one year and 19.8% within five years. The risk of becoming chronic if episodic was 4.0% within one year and 12.3% within five years. For conversion from chronic to episodic, the corresponding risk was 11.1% and 25.0%, respectively. Alterations in attack-side were reported in 32% of all chronic patients, generating an odds ratio of 2.24 of being chronic as opposed to episodic if experiencing side-shifting attacks. CONCLUSIONS: A higher transition rate since the original cross-sectional study demonstrates cluster headache as a non-static condition. Identifying a risk of transition within one and five years, based on current phenotype along with high odds of being chronic when experiencing a shift of attack-side, offers a valuable clinical compass in the dialogue with the patient.
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Cefaleia Histamínica , Humanos , Cefaleia Histamínica/epidemiologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Seguimentos , Estudos Transversais , Estudos Retrospectivos , Doença Crônica , Progressão da DoençaRESUMO
Cluster headache, characterised by attacks of severe, recurrent, unilateral headache and ipsilateral cranial autonomic symptoms, remains a primary headache with an elusive pathophysiology. Recent advances have introduced effective treatments and broadened understanding of the clinical features of cluster headache. These features are similar in patients globally, but regional differences in prevalence and burden exist. International collaborations have led to identification of eight genetic loci associated with cluster headache. The pathophysiological mechanisms are still not fully understood but recent studies show that targeting the trigeminal autonomic reflex by neurostimulation, or targeting the neuropeptide calcitonin gene-related peptide (CGRP), might lessen the attack burden. The US Food and Drug Administration has approved galcanezumab, a monoclonal antibody targeting CGRP, as the first specific preventive treatment for episodic cluster headache. However, a preventive effect was not replicated in chronic cluster headache, and the European Medicines Agency did not approve galcanezumab, restricting its availability in Europe. Owing to the low prevalence of cluster headache, continued collaboration through multicentre clinical trials and data sharing will be imperative for further breakthroughs in understanding and management.
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Cefaleia Histamínica , Cefaleia Histamínica/terapia , Cefaleia Histamínica/diagnóstico , Cefaleia Histamínica/fisiopatologia , Cefaleia Histamínica/epidemiologia , Humanos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Gerenciamento ClínicoRESUMO
BACKGROUND: Idiopathic intracranial hypertension is a secondary headache disorder potentially causing visual loss. Neurofilament light chain is a candidate, prognostic biomarker, but further studies of neuronal biomarkers are needed. Our objective was to investigate neurofilament light chain in cerebrospinal fluid (cNfL) and plasma (pNfL), amyloid-beta 42 (Aß-42), total-tau and phosphorylated-tau in cerebrospinal fluid in new-onset idiopathic intracranial hypertension. METHODS: Prospective case-control study including new-onset idiopathic intracranial hypertension and age, sex and BMI matched controls. Biomarkers were compared between patients and controls and related to papilledema, visual fields and opening pressure. RESULTS: We included 37 patients and 35 controls. Patients had higher age-adjusted cNfL (1.4 vs. 0.6 pg/mL, p-adjusted < 0.001), pNfL (0.5 vs. 0.3 pg/mL, p-adjusted < 0.001) and total-tau/Aß-42 (0.12 vs. 0.11, p-adjusted = 0.039). Significant, positive linear correlations were found between cNfL, pNfL, total-tau/Aß-42 and opening pressure. Patients with severe papilledema had elevated cNfL compared to mild-moderate papilledema (median cNfL: 4.3 pg/mL (3.7) versus 1.0 pg/mL (1.4), p-adjusted = 0.009). cNFL was inversely associated with perimetric mean deviation (r = -0.47, p-adjusted < 0.001). CONCLUSIONS: cNfL, pNfL and total-tau/Aß-42 were elevated in new-onset idiopathic intracranial hypertension. cNfL was associated with severity of papilledema and visual field defects at diagnosis. This indicates early axonal damage. Neurofilament light chain is a candidate biomarker for disease severity.
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Biomarcadores , Proteínas de Neurofilamentos , Pseudotumor Cerebral , Humanos , Feminino , Masculino , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Adulto , Pseudotumor Cerebral/diagnóstico , Pseudotumor Cerebral/líquido cefalorraquidiano , Pseudotumor Cerebral/sangue , Pseudotumor Cerebral/complicações , Estudos Prospectivos , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Pessoa de Meia-Idade , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangueRESUMO
BACKGROUND: Nurses work at headache centres throughout Europe, and their care for migraine patients is acknowledged. However, the specific roles and tasks of nursing vary, and a unified understanding is lacking, posing challenges to knowledge sharing and research. OBJECTIVES: Using an e-Delphi study method, the objective is to obtain healthcare professional headache experts' opinions on nursing-specific roles and tasks and combine this into consensus statements for nurse recommendations for migraine treatment. METHODS: A three-round questionnaire study was conducted with nurses and neurologists from 18 specialised headache centres in 10 countries. In round 1, statements were compiled from a systematic examination of existing literature and expert opinions. In rounds 2 and 3, the experts rated the importance of statements (from round 1) on a 5-point Likert scale. Statements were analysed using a content analysis method, and the consensus of pre-defined statements was evaluated with gradually increased predetermined criteria using descriptive statistics. RESULTS: Twenty-one experts, representing all 10 countries, participated. The predetermined consensus of ≥70% agreement was reached for 42 out of the initial 63 statements. These statements formed the final recommendations within two themes: "The nurses' roles and tasks in the clinical setting" and "The nurses' roles and tasks in educating patients and colleagues." The consensus level of statements was strong, with 40% receiving unanimous agreement (100%) and 97% achieving relatively high agreement (>80%). CONCLUSION: Nursing plays a vital role with diverse tasks in migraine care. This study offers practical recommendations and a framework for nurses, equipping them with a clinical tool to enhance care and promote a coordinated approach to migraine treatment.
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Consenso , Técnica Delphi , Papel do Profissional de Enfermagem , Humanos , Europa (Continente) , Cefaleia/terapia , Cefaleia/enfermagem , Inquéritos e Questionários , Feminino , Masculino , Adulto , Transtornos de Enxaqueca/enfermagem , Transtornos de Enxaqueca/terapia , Enfermeiras e Enfermeiros , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. METHODS: We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. RESULTS: The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%-47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%-37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. INTERPRETATION: Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024;95:1149-1161.
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Cefaleia Histamínica , Hipogonadismo , Hormônio Luteinizante , Testosterona , Humanos , Masculino , Cefaleia Histamínica/genética , Cefaleia Histamínica/sangue , Estudos de Casos e Controles , Adulto , Hipogonadismo/genética , Hipogonadismo/sangue , Estudos Prospectivos , Pessoa de Meia-Idade , Testosterona/sangue , Hormônio Luteinizante/sangue , Globulina de Ligação a Hormônio Sexual/genéticaRESUMO
BACKGROUND: Headache burden is substantial in idiopathic intracranial hypertension. The classification of idiopathic intracranial hypertension headache by the International Classification of Headache Disorders (ICHD) is an important tool for research and clinical purposes. METHODS: We phenotyped headaches and tested sensitivity and specificity of the ICHD-3 criteria for idiopathic intracranial hypertension headache in a prospective cohort of patients suspected of idiopathic intracranial hypertension at two tertiary headache centers. RESULTS: Sensitivity was 93% and specificity was 100% of ICHD-3 criteria for idiopathic intracranial hypertension-related headache validated in idiopathic intracranial hypertension (n = 140) and patients in whom idiopathic intracranial hypertension was suspected but disproven (n = 103). The phenotype of new/worsened headaches related to idiopathic intracranial hypertension suspicion was equally migraine-like (p = 0.76) and tension-type-like (p = 0.08). Lumbar puncture opening pressure was higher (p < 0.0001) and pulsatile tinnitus more frequent (p < 0.0001) in idiopathic intracranial hypertension patients, but neither improved the applicability of the headache criteria, nor did papilledema. CONCLUSION: Headache phenotype is not distinct in idiopathic intracranial hypertension. ICHD-3 criteria for idiopathic intracranial hypertension headache are sensitive and specific, but simplicity can be improved without compromising accuracy. We propose that a new or worsened headache temporally related to active idiopathic intracranial hypertension is a sufficient criterion for idiopathic intracranial hypertension headache regardless of headache phenotype or accompanying symptoms, and that elements of idiopathic intracranial hypertension diagnostics (papilledema and opening pressure) be segregated from headache criteria.Trial Registration: ClinicalTrials.gov Identifier: NCT04032379.
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Cefaleia , Fenótipo , Pseudotumor Cerebral , Sensibilidade e Especificidade , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cefaleia/diagnóstico , Cefaleia/classificação , Cefaleia/etiologia , Classificação Internacional de Doenças , Estudos Prospectivos , Pseudotumor Cerebral/diagnóstico , Pseudotumor Cerebral/complicaçõesRESUMO
BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues. METHODS: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA. RESULTS: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands. CONCLUSION: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.
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Acetazolamida , Disruptores Endócrinos , Estro , Ratos Sprague-Dawley , Topiramato , Animais , Feminino , Topiramato/farmacologia , Acetazolamida/farmacologia , Acetazolamida/toxicidade , Disruptores Endócrinos/toxicidade , Ratos , Estro/efeitos dos fármacos , Hormônio Luteinizante/sangue , Frutose/toxicidade , Frutose/análogos & derivados , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Progesterona/sangue , Hormônio Foliculoestimulante/sangue , Hormônios Esteroides Gonadais/sangue , Estradiol/sangue , Ovário/efeitos dos fármacos , Ovário/metabolismoRESUMO
BACKGROUND: Idiopathic intracranial hypertension (IIH) occurs more frequently in obese females of childbearing age. A link between eating disorders and poor outcome has been suggested but remains unproven. METHODS: This prospective field study at two tertiary headache centers included patients with clinically suspected IIH after standardized diagnostic work-up. Eating disorders were evaluated using validated questionnaires (EDQs). Primary outcome was the impact of eating disorders on IIH severity and outcome, secondary outcome was the prevalence and type of eating disorders in IIH compared to controls. RESULTS: We screened 326 patients; 143 patients replied to the EDQs and were classified as 'IIH' or 'non-IIH' patients. The demographic profile of EDQ-respondents and non-respondents was similar. Presence of an eating disorder did not impact IIH severity (lumbar puncture opening pressure (p = 0.63), perimetric mean deviation (p = 0.18), papilledema (Frisén grad 1-3; p = 0.53)) nor IIH outcome (optic nerve atrophy (p = 0.6), impaired visual fields (p = 0.18)). Moreover, we found no differences in the prevalence and type of eating disorders when comparing IIH with non-IIH patients (p = 0.09). CONCLUSION: Eating disorders did not affect IIH severity or outcome. We found the same prevalence and distribution pattern of eating disorders in IIH and non-IIH patients advocating against a direct link between IIH and eating disorders.
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Transtornos da Alimentação e da Ingestão de Alimentos , Hipertensão Intracraniana , Papiledema , Pseudotumor Cerebral , Feminino , Humanos , Pseudotumor Cerebral/complicações , Pseudotumor Cerebral/epidemiologia , Pseudotumor Cerebral/diagnóstico , Papiledema/diagnóstico , Campos Visuais , Obesidade/complicações , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/complicações , Hipertensão Intracraniana/complicaçõesRESUMO
BACKGROUND: The role of calcitonin gene-related peptide (CGRP) in the cyclic pattern of cluster headache is unclear. To acquire biological insight and to comprehend why only episodic cluster headache responds to CGRP monoclonal antibodies, we examined whether plasma CGRP changes between disease states (i.e. bout, remission and chronic) and controls. METHODS: The present study is a prospective case-control study. Participants with episodic cluster headache were sampled twice (bout and remission). Participants with chronic cluster headache and controls were sampled once. CGRP concentrations were measured in plasma with a validated radioimmunoassay. RESULTS: Plasma was collected from 201 participants diagnosed with cluster headache according to the International Classification of Headache Disorders, 3rd edition, and from 100 age- and sex-matched controls. Overall, plasma CGRP levels were significantly lower in participants with cluster headache compared to controls (p < 0.05). In episodic cluster headache, CGRP levels were higher in bout than in remission (mean difference: 17.1 pmol/L, 95% confidence interval = 9.8-24.3, p < 0.0001). CGRP levels in bout were not different from chronic cluster headache (p = 0.266). CONCLUSIONS: Plasma CGRP is unsuitable as a diagnostic biomarker of cluster headache or its disease states. The identified reduced CGRP levels suggest that CGRPs role in cluster headache is highly complex and future investigations are needed into the modulation of CGRP and its receptors.
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Peptídeo Relacionado com Gene de Calcitonina , Cefaleia Histamínica , Humanos , Estudos de Casos e Controles , Cefaleia Histamínica/sangue , Cefaleia Histamínica/diagnóstico , Cefaleia , Projetos de PesquisaRESUMO
OBJECTIVE: To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH). BACKGROUND: CCH is an excruciating and difficult-to-treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited. METHODS: In this small open-label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow-up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose. RESULTS: The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow-up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = -0.81), implicating this neural pathway in treatment response. CONCLUSION: Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted.
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Cefaleia Histamínica , Psilocibina , Humanos , Cefaleia Histamínica/tratamento farmacológico , Hipotálamo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Vias Neurais/diagnóstico por imagem , Psilocibina/efeitos adversosRESUMO
INTRODUCTION: Diabetic neuropathic pain (DNP) is a debilitating complication affecting 15-20% of people with diabetes and is a predictor of depression, poor sleep and decreased quality of life. Current pharmacological treatments are often insufficient and have significant side-effects. Subcutaneous or intradermal botulinumtoxin-A (BonT-A) is an effective and safe treatment for neuropathic pain but is limited by the need to cover the entire affected area with injections. For large cutaneous areas, infiltration of the sensory nerve supply with BonT-A could provide similar effects, with a single injection. We aim to investigate the safety, efficacy, and effects on quality of life, physical activity, depressive symptoms and activities of daily living of perineural injections of BonT-A in patients with DNP of both lower extremities. METHODS: This study is a double-blind, randomised, placebo-controlled clinical trial. 80 participants with moderate to severe DNP of both legs will be randomised 1:1 to receive injections of either 100 units incobotulinumtoxin-A or a saline placebo around each distal sciatic nerve for two cycles of 12 weeks. Average daily pain scores will be recorded once a day from 1 week prior to the first treatment and through the entire study period. Primary outcomes are differences between groups in daily and weekly mean pain scores. Secondary outcomes are levels of physical activity, depression scores, health-related quality of life, activities of daily living, sensory profiles and motor function, recorded at baseline, 4, 12, 16 and 24 weeks. The use of rescue medication and adverse events will be recorded throughout the study period. ETHICS AND DISSEMINATION: The study is approved by the Danish Committee on Health Research Ethics and the Danish Medicines Agency. EU-Clinical Trial Information System (EU: 2022-500727-68-01), clinicaltrials.gov (ID: NCT05623111). Results will be published in peer-reviewed journals in open-access formats and data made available in anonymised form. TRIAL REGISTRATION NUMBER: NCT05623111.
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Diabetes Mellitus , Neuropatias Diabéticas , Humanos , Atividades Cotidianas , Qualidade de Vida , Extremidade Inferior , Dor , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
Background and Objectives: Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure without an identifiable cause that mostly affects obese persons of childbearing age. In this prospective case series, we have evaluated the overall outcome of pregnancy and birth in participants with IIH and their newborn children. We also provide a proposal for the management of pregnant persons with IIH. Methods: In this observational study, neuro-ophthalmological findings, the course of IIH-related symptoms, disease management, and pregnancy outcomes were evaluated. The participants were divided into 3 groups according to the course of the disease during pregnancy: stable, worsened, and new diagnosed. Furthermore, the type of delivery and outcome of newborn children such as gestational age, weight at birth, and the presence of asphyxia were compared between the groups. Results: We observed 47 pregnancies in 42 participants; 2 had spontaneous abortions. There were 19 (47%) participants in the stable, 18 (45%) in the worsened, and 3 (8%) in the new diagnosed groups, respectively. A relapse of IIH occurred in 2 (5%). Worsening of IIH-related symptoms was experienced by 18/37 (49%) participants: headache by 17/18 (94%), tinnitus by 11/18 (61%), and vision by 7/18 (39%) (mostly in the first and second trimester). In 8/18 (44%), the symptoms were transient or alleviated in the second and third trimester. Body mass index before and after pregnancy did not significantly differ among the groups. A total of 8 participants were treated with acetazolamide. The frequency of cesarean section was 17/40 (43%). Preterm delivery occurred in 22%. No increased risk of asphyxia was observed, and all infants, but one, were healthy. Discussion: Worsening of headache, tinnitus, and/or vision were experienced by half of pregnant participants with IIH, mostly transient in the first and second trimester, rarely required specific treatment, and were not identified as a relapse of IIH. There was no difference in gestational age and weight at birth in children among the groups, and no perinatal asphyxia was noted. Weight gain in the participants was not identified as a risk factor for relapse of IIH in pregnancy. The rate of cesarean and preterm delivery was higher than in the non-IIH population. A proposal for the management of IIH in pregnancy is provided.
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OBJECTIVE: To systematically investigate previously examined biomarkers in blood, urine, cerebrospinal fluid, tear fluid, and saliva of patients with cluster headache. BACKGROUND: Cluster headache is a condition with extensive clinical challenges in terms of diagnosis and treatment. Identification of a biomarker with diagnostic implications or as a potential treatment target is highly warranted. METHODS: We conducted a systematic review including peer reviewed full text of studies that measured biochemical compounds in either blood, urine, cerebrospinal fluid, tear fluid, or saliva of patients with cluster headache diagnosed after the implementation of the International Classification of Headache Disorders (1988) written in English, Danish, Swedish, or Norwegian. Inclusion required a minimum of five participants. The search was conducted in PubMed and EMBASE, in September 2022, and extracted data were screened by two authors. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews were followed. The Newcastle-Ottawa Scale was used to assess the risk of bias in case-controlled studies. RESULTS: We included 40 studies involving 832 patients with cluster headache and 872 controls, evaluating 80 potential biomarkers. The risk of bias for case-controlled studies was a median of 6 (range: 3-8) and 20 studies out of 40 (50%) were of fair or good quality. Most studies were identified within three groups: hypothalamic-regulated hormones, inflammatory markers, and neuropeptides. Among the hypothalamic hormones, cortisol was the most frequently investigated (N = 7) and was elevated in cluster headache in most of the studies. The most frequently examined inflammatory marker was interleukin 1 (N = 3), but findings were divergent. Calcitonin gene-related peptide was the most investigated neuropeptide (N = 9) and all studies found increased levels during attacks. CONCLUSION: Biomarker findings have been inconsistent and widely non-specific for cluster headache, which explains why none of the previous studies succeeded in identifying a unique biomarker for cluster headache, but instead contributed to substantiating the underlying pathophysiologic mechanisms. Several of the examined biomarkers could hold promise as markers for disease activity but are unfit for a clear distinction from both controls and other headaches.
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Cefaleia Histamínica , Transtornos da Cefaleia , Humanos , Cefaleia Histamínica/diagnóstico , Cefaleia , Peptídeo Relacionado com Gene de Calcitonina , Biomarcadores/líquido cefalorraquidianoRESUMO
ABSTRACT: Activation of adenosine triphosphate-sensitive potassium (K ATP ) channels has been implicated in triggering migraine attacks. However, whether the opening of these channels provoke cluster headache attacks remains undetermined. The hallmark of cluster headache is a distinct cyclical pattern of recurrent, severe headache episodes, succeeded by intervals of remission where no symptoms are present. In our study, we enrolled 41 participants: 10 with episodic cluster headaches during a bout, 15 in the attack-free remission period, and 17 diagnosed with chronic cluster headaches. Over 2 distinct experimental days, participants underwent a continuous 20-minute infusion of levcromakalim, a K ATP channel opener, or a placebo (isotonic saline), followed by a 90-minute observational period. The primary outcome was comparing the incidence of cluster headache attacks within the postinfusion observation period between the levcromakalim and placebo groups. Six of 10 participants (60%) with episodic cluster headaches in bout experienced attacks after levcromakalim infusion, vs just 1 of 10 (10%) with placebo ( P = 0.037). Among those in the remission phase, 1 of 15 participants (7%) reported attacks after levcromakalim, whereas none did postplacebo ( P = 0.50). In addition, 5 of 17 participants (29%) with chronic cluster headache had attacks after levcromakalim, in contrast to none after placebo ( P = 0.037). These findings demonstrate that K ATP channel activation can induce cluster headache attacks in participants with episodic cluster headaches in bout and chronic cluster headache, but not in those in the remission period. Our results underscore the potential utility of K ATP channel inhibitors as therapeutic agents for cluster headaches.
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Cefaleia Histamínica , Cromakalim , Canais KATP , Humanos , Cefaleia Histamínica/tratamento farmacológico , Masculino , Adulto , Feminino , Cromakalim/uso terapêutico , Pessoa de Meia-Idade , Canais KATP/metabolismo , Método Duplo-Cego , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate. EXPERIMENTAL APPROACH: Female rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross-over studies were performed, where rats received acute (24 h) high doses of acetazolamide and topiramate, and chronic (10 days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT-qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions. KEY RESULTS: We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 min of administration, and in combination doubled the ICP reduction over a 24-h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of the sodium-dependent chloride/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes. CONCLUSIONS AND IMPLICATIONS: Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP.
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Acetazolamida , Pressão Intracraniana , Feminino , Ratos , Animais , Acetazolamida/farmacologia , Acetazolamida/uso terapêutico , Pressão Intracraniana/fisiologia , Topiramato/farmacologiaRESUMO
BACKGROUND: Female sex is a known risk factor of brain disorders with raised intracranial pressure (ICP) and sex hormones have been suggested to alter cerebrospinal fluid (CSF) dynamics, thus impairing ICP regulation in CSF disorders such as idiopathic intracranial hypertension (IIH). The choroid plexus (CP) is the tissue producing CSF and it has been hypothesized that altered hormonal composition could affect the activity of transporters involved in CSF secretion, thus affecting ICP. Therefore, we aimed to investigate if expression of various transporters involved in CSF secretion at CP were different between males and females and between females in different estrous cycle states. Steroid levels in serum was also investigated. METHODS: Female and male rats were used to determine sex-differences in the genes encoding for the transporters Aqp1 and 4, NKCC1, NBCe2, NCBE; carbonic anhydrase enzymes II and III (CA), subunits of the Na+/K+-ATPase including Atp1a1, Atp1b1 and Fxyd1 at CP. The estrous cycle stage metestrus (MET) and estrous (ES) were determined before euthanasia. Serum and CP were collected and subjected to RT-qPCR analysis and western blots. Serum was used to measure steroid levels using liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: Significant differences in gene expression and steroid levels between males and ES females were found, while no differences were found between male and MET females. During ES, expression of Aqp1 was lower (p < 0.01) and NKCC1 was higher in females compared to males. CAII was lower while CAIII was higher in ES females (p < 0.0001). Gene expression of Atp1a1 was lower in ES compared to male (p = 0.0008). Several of these choroidal genes were also significantly different in MET compared to females in ES. Differences in gene expression during the estrus cycle were correlated to serum level of steroid hormones. Protein expression of AQP1 (p = 0.008) and CAII (p = 0.035) was reduced in ES females compared to males. CONCLUSIONS: This study demonstrates for the first time that expression at CP is sex-dependent and markedly affected by the estrous cycle in female rats. Further, expression was related to hormone levels in serum. This opens a completely new avenue for steroid regulation of the expression of CSF transporters and the close link to the understanding of CSF disorders such as IIH.
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Plexo Corióideo , Proteínas de Membrana , Ratos , Feminino , Masculino , Animais , Plexo Corióideo/metabolismo , Proteínas de Membrana/metabolismo , Caracteres Sexuais , Cromatografia Líquida , Espectrometria de Massas em Tandem , Esteroides/metabolismoRESUMO
OBJECTIVE: Caffeine, a non-selective adenosine receptor (AR) antagonist, is the most consumed psychostimulant in the world. Caffeine has been suggested to regulate cerebrospinal fluid secretion and is known both to alleviate and to trigger headache; however, its effect on the regulation of intracranial pressure (ICP) is not known. Therefore, we aimed to investigate the effects of caffeine on ICP and nociceptive responses. METHODS: Female Sprague-Dawley rats were implanted with a novel telemetric device for continuous ICP recordings, which allowed for continuous recordings in freely moving rats. A single dose of caffeine (30 or 120 mg/kg intraperitoneally) was given. In a second group (non-implanted), the acute effects of 30 mg/kg caffeine on periorbital threshold using Von Frey testing and spontaneous behavior were utilized using an automated behavioral registration platform (Laboratory, Animal, Behavior, Observation, Registration and Analysis System) in a randomized cross-over study. Quantitative polymerase chain reaction and immunofluorescence were used to localize ARs in the choroid plexus. RESULTS: A single dose of 30 mg/kg caffeine lowered the ICP by 35% at 165 min after administration (saline: 0.16 ± 0.9 vs caffeine: -1.18 ± 0.9 ΔmmHg, p = 0.0098) and lasted up to 12 h. Administration of 120 mg/kg caffeine showed a faster onset of decrease in ICP within 15 min by 50% (p = 0.0018) and lasted up to 12 h. The periorbital pain thresholds were higher after 1 h (saline: 224.6 ± 15.1 vs caffeine: 289.5 ± 8.7 g, p = 0.005) and lasted up to 5 h. Caffeine-treated rats had increased locomotor activity, speed, and changed grooming behavior. Expression of AR1 was found in the choroid plexus. CONCLUSIONS: This study demonstrates that caffeine has a lowering effect on ICP as an acute treatment. Interestingly, caffeine acutely caused an increased response in cephalic thresholds supporting hypoalgesic effects. Future studies investigating the beneficial effects of caffeine for elevated ICP are warranted.