Neurofilament light chain is elevated in patients with newly diagnosed idiopathic intracranial hypertension: A prospective study.

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.

Exposure to topiramate and acetazolamide causes endocrine disrupting effects in female rats during estrus.

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.

Are the ICHD-3 criteria for headache attributed to idiopathic intracranial hypertension valid? Headache phenotyping and field-testing in newly diagnosed idiopathic intracranial hypertension.

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.

Reduced plasma calcitonin gene-related peptide level identified in cluster headache: A prospective and controlled study.

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.

Perineural injections of incobotulinumtoxin-A for diabetic neuropathic pain of the lower extremities: protocol for a phase II, single-centre, double-blind, randomised, placebo-controlled trial (the PINBOT study).

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.

Acetazolamide and topiramate lower intracranial pressure through differential mechanisms: The effect of acute and chronic administration.

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.

The HortONS study. Treatment of chronic cluster headache with transcutaneous electrical nerve stimulation and occipital nerve stimulation: study protocol for a prospective, investigator-initiated, double-blinded, randomized, placebo-controlled trial.

BACKGROUND: Chronic cluster headache (CCH) is a debilitating primary headache disorder. Occipital nerve stimulation (ONS) has shown the potential to reduce attack frequency, but the occipital paresthesia evoked by conventional (tonic) stimulation challenges a blinded comparison of active stimulation and placebo. Burst ONS offers paresthesia-free stimulation, enabling a blinded, placebo-controlled study. Identification of a feasible preoperative test would help select the best candidates for implantation. This study aims to explore ONS as a preventive treatment for CCH, comparing burst stimulation to tonic stimulation and placebo, and possibly identifying a potential preoperative predictor. METHODS: An investigator-initiated, double-blinded, randomized, placebo-controlled trial is conducted, including 40 patients with CCH. Eligible patients complete a trial with the following elements: I) four weeks of baseline observation, II) 12 weeks of transcutaneous electrical nerve stimulation (TENS) of the occipital nerves, III) implantation of a full ONS system followed by 2 week grace period, IV) 12 weeks of blinded trial with 1:1 randomization to either placebo (deactivated ONS system) or burst (paresthesia-free) stimulation, and V) 12 weeks of tonic stimulation. The primary outcomes are the reduction in headache attack frequency with TENS and ONS and treatment safety. Secondary outcomes are treatment efficacy of burst versus tonic ONS, the feasibility of TENS as a predictor for ONS outcome, reduction in headache pain intensity (numeric rating scale), reduction in background headache, the patient's impression of change (PGIC), health-related quality of life (EuroQoL-5D), self-reported sleep quality, and symptoms of anxiety and depression (Hospital Anxiety and Depression Scale, HADS). Data on headache attack characteristics are registered weekly. Data on patient-reported outcomes are assessed after each trial phase. DISCUSSION: The study design allows a comparison between burst ONS and placebo in refractory CCH and enables a comparison of the efficacy of burst and tonic ONS. It will provide information about the effect of burst ONS and explore whether the addition of this stimulation paradigm may improve stimulation protocols. TENS is evaluated as a feasible preoperative screening tool for ONS outcomes by comparing the effect of attack prevention of TENS and tonic ONS. TRIAL REGISTRATION: The study is registered at Clinicaltrials.gov (trial registration number NCT05023460, registration date 07-27-2023).

Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments-a consensus article.

AIM: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. FINDINGS: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium. CONCLUSION: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache.

Treatment of chronic cluster headache with burst and tonic occipital nerve stimulation: A case series.

OBJECTIVES AND BACKGROUND: Chronic cluster headache (CCH) is a rare but severely debilitating primary headache condition. A growing amount of evidence suggests that occipital nerve stimulation (ONS) can offer effective treatment in patients with severe CCH for whom conventional medical therapy does not have a sufficient effect. The paresthesia evoked by conventional (tonic) stimulation can be bothersome and may thus limit therapy. Burst ONS produces paresthesia-free stimulation, but the amount of evidence on the efficacy of burst ONS as a treatment for intractable CCH is scarce. METHODS: In this case series, we report 15 patients with CCH treated with ONS at Aarhus University Hospital, Denmark, from 2013 to 2020. Nine of these received burst stimulation either as primary treatment or as a supplement to tonic stimulation. The results were assessed in terms of the frequency of headache attacks per week and their intensity on the Numeric Rating Scale, as well as the Patient Global Impression of Change (PGIC) with ONS treatment. RESULTS: At a median (range) follow-up of 38 (16-96) months, 12 of the 15 patients (80%) reported a reduction in attack frequency of ≥50% (a reduction from a median of 35 to 1 attack/week, p < 0.001). Seven of these patients were treated with burst ONS. A significant reduction was also seen in maximum pain intensity. Overall, 10 patients stated a clinically important improvement in their headache condition following ONS treatment, rated on the PGIC scale. A total of 16 adverse events (nine of which were in the same patient) were registered. CONCLUSION: Occipital nerve stimulation significantly reduced the number of weekly headache attacks and their intensity. Burst ONS seems to function well alone or as a supplement to conventional tonic ONS as a preventive treatment for CCH; however, larger prospective studies are needed to determine whether the effect can be confirmed and whether the efficacy of the two stimulation paradigms is even.

Glucocorticoids modify intracranial pressure in freely moving rats.

BACKGROUND: Glucocorticoids (GCs) are widely prescribed for a variety of inflammatory diseases, but they are also used to treat raised intracranial pressure (ICP) caused by trauma or oedema. However, it is unclear if GCs independently modulate ICP and if GCs are involved in normal ICP regulation. In this study, we aimed to assess the ICP modulatory effects of GCs and their molecular consequences on choroid plexus (CP). METHODS: Adult female rats were implanted with telemetric ICP probes for physiological, continuous ICP recordings in a freely moving setup. Rats received prednisolone or vehicle via oral gavage in a randomized acute (24 h) ICP study. In a subsequent study rats received corticosterone or vehicle in drinking water for a 4-week chronic ICP study. CP were removed, and the expression of genes associated with cerebrospinal fluid secretion were assessed. RESULTS: A single prednisolone dose reduced ICP by up to 48% (P < 0.0001), where ICP was reduced within 7 h and was maintained for at least 14 h. Prednisolone increases ICP spiking (P = 0.0075) while not altering ICP waveforms. Chronic corticosterone reduces ICP by up to 44%, where ICP was lower for the entirety of the 4-week ICP recording period (P = 0.0064). ICP daily periodicity was not altered by corticosterone. Corticosterone ICP reduction was not accompanied by ICP spike differences or alteration in ICP spike periodicity. Chronic corticosterone treatment had modest effects on CP gene expression, lowering the expression of Car2 at CP (P = 0.047). CONCLUSIONS: GCs reduce ICP in both the acute and chronic setting to a similar degree. Moreover, GCs did not modify the diurnal rhythm of ICP, suggesting the diurnal variation of ICP periodicity is not under explicit control of GCs. ICP disturbances should be considered a consequence of GC therapy. Based on these experiments, GCs may have broader ICP therapeutic uses, but side effects must be taken into consideration.

Functional brainstem representations of the human trigeminal cervical complex.

BACKGROUND: The human in-vivo functional somatotopy of the three branches of the trigeminal (V1, V2, V3) and greater occipital nerve in brainstem and also in thalamus and insula is still not well understood. METHODS: After preregistration (clinicaltrials.gov: NCT03999060), we mapped the functional representations of this trigemino-cervical complex non-invasively in 87 humans using high-resolution protocols for functional magnetic resonance imaging during painful electrical stimulation in two separate experiments. The imaging protocol and analysis was optimized for the lower brainstem and upper spinal cord, to identify activation of the spinal trigeminal nuclei. The stimulation protocol involved four electrodes which were positioned on the left side according to the three branches of the trigeminal nerve and the greater occipital nerve. The stimulation site was randomized and each site was repeated 10 times per session. The participants partook in three sessions resulting in 30 trials per stimulation site. RESULTS: We show a large overlap of peripheral dermatomes on brainstem representations and a somatotopic arrangement of the three branches of the trigeminal nerve along the perioral-periauricular axis and for the greater occipital nerve in brainstem below pons, as well as in thalamus, insula and cerebellum. The co-localization of greater occipital nerve with V1 along the lower part of brainstem is of particular interest since some headache patients profit from an anesthetic block of the greater occipital nerve. CONCLUSION: Our data provide anatomical evidence for a functional inter-inhibitory network between the trigeminal branches and greater occipital nerve in healthy humans as postulated in animal work. We further show that functional trigeminal representations intermingle perioral and periauricular facial dermatomes with individual branches of the trigeminal nerve in an onion shaped manner and overlap in a typical within-body-part somatotopic arrangement.Trial registration: clinicaltrials.gov: NCT03999060.

Plasma levels of VIP are not elevated during PACAP- and VIP-induced cluster headache attacks: an exploratory study.

Background: Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) provoked cluster headache attacks in individuals with episodic cluster headache during their active phase and individuals with chronic cluster headache. In this study, we investigated whether infusions of PACAP and VIP caused alterations in plasma levels of VIP and their potential contribution to induced cluster headache attacks. Methods: Participants received either PACAP or VIP infusion for 20 min on 2 separate days with an interval of at least 7 days in between. Blood collection was performed at T0, T20, T30, and T90. Plasma levels of VIP were measured using a validated radioimmunoassay method. Results: Blood samples were collected from participants with episodic cluster headache in the active phase (eCHA, n = 14), remission (eCHR, n = 15), and from participants with chronic cluster headache (cCH, n = 15). Baseline levels of VIP did not differ among the three groups (p = 0.1161). During PACAP infusion, mixed-effects analysis revealed a significant increase in plasma levels of VIP in eCHA (p = 0.0300) and eCHR (p = 0.0058) but not in cCH (p = 0.2930). We found no difference in the increase of plasma VIP levels between patients who developed PACAP38- or VIP-induced attacks. Conclusion: Cluster headache attacks induced by PACAP38 or VIP infusion are not associated with changes in plasma levels of VIP. Further studies are needed to investigate the role of VIP and the parasympathetic system in cluster headache. Clinical trial registration: The parent study is registered at ClinicalTrials.gov (NCT03814226).

The Global Campaign Against Headache and its future relation to IHS and WHO.

BACKGROUND: Preparations for the Global Campaign Against Headache done jointly with WHO started almost 25 years ago. It was officially incorporated 18 years ago. It is the story of a few dedicated individuals who, together with the World Health Organization, generated epidemiological data all over the world and made use of these data to gradually increase the position of headache disorders, until migraine became number two among all causes of years lost to disability. It is also the story of impressive development of scientific tools, their validation and use in low-income countries. METHODS: Models of care for headache patients were developed that are adaptable and hence can be implemented in future throughout the world. RESULTS: The last phase of the campaign shall use the impressive data set generated to cause real improvement in the healthcare for people with headache throughout the world. The recent World Health Organization initiative: Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders invites international organizations to collaborate, and headache is mentioned. CONCLUSION: This calls for the International Headache Society and all its national members and all other organizations involved in headache to work together with Lifting the Burden, the organization in charge of the Global Campaign Against Headache.

Fundus imaging and perimetry in patients with idiopathic intracranial hypertension-an intermethod and interrater validity study.

BACKGROUND AND PURPOSE: There is a need to improve the diagnostic process of patients suspected of papilledema. In patients with known or suspected idiopathic intracranial hypertension a fundus imaging and perimetric visual field assessment system (COMPASS) performed at a headache center was validated in comparison to an assessment (Topcon plus OCTOPUS) at a neuroophthalmological clinic. METHODS: For intermethod assessment, blinded fundus images and perimetry from COMPASS versus Topcon plus OCTOPUS were assessed by a neuroophthalmologist. For interrater assessment, fundus images and perimetry obtained by the COMPASS system were assessed by an untrained medical doctor, a trained neurologist and a trained medical student and compared to the neuroophthalmologist's assessments. RESULTS: For the intermethod variation of the presence of papilledema on fundus images, a kappa value of 0.60, sensitivity of 87% and specificity of 73% were found. The interrater variation of the presence of papilledema on fundus images showed kappa values ranging from 0.43 to 0.74, sensitivity values ranging from 70% to 96% and specificity values ranging from 46% to 93% when comparing the assessments made by the headache center staff with neuroophthalmologist's assessments. The COMPASS showed a 59% sensitivity and moderate agreement in detecting visual field defects compared with OCTOPUS. The visual field assessment showed only slight to fair agreement from 0.19 to 0.31 between assessments made by the headache center staff and the neuroophthalmologist. CONCLUSION: The COMPASS system can be used with reasonable sensitivity in the assessment of papilledema in patients suspected of idiopathic intracranial hypertension at a tertiary headache center.

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.

BACKGROUND AND PURPOSE: The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. METHODS: In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. RESULTS: Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. CONCLUSION: The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.

Headache comorbidity in refugees and migrants with post-traumatic stress disorder.

BACKGROUND: Headache is often comorbid with post-traumatic stress disorder yet overlooked in health assessments of refugees. OBJECTIVES: To describe prevalence of severe headache among refugees with post-traumatic stress disorder and compare severity of post-traumatic stress disorder symptoms and treatment outcomes among those with and without severe headache. METHODS: This follow-up study used data from the Danish Database on Refugees with Trauma. Participants were recruited from 2009 to 2015 at a specialized psychiatric clinic. Prevalence of severe headache was computed by age, sex, and history of head injury or torture. Severe headache was defined as maximum headache scores on the Hopkins Symptom Checklist, Symptom Checklist-90 or the Visual Analogue Scale. Groups with and without severe headache were described according to validated questionnaires before and after 12-18 months of multidisciplinary treatment for post-traumatic stress disorder. Regression analyses were used to analyze associations between headache at start of treatment and symptom burden post-treatment, controlled for pre-treatment scores and possible confounders. RESULTS: Among 403 female and 489 male participants, nearly all (97.5%) complained of headaches. Severe headache prevalence was 31.4% to 50.0% (depending on which questionnaire was used) and was significantly more common among females and those aged 30-49 years. There was no clear relationship between headache and head injury or torture. Participants with severe headache had heavier symptom burdens compared to those without severe headache. Post-treatment, headache prevalence by age and sex did not change significantly. Those without severe headache showed a tendency toward improvement in outcome measures; this was not seen among those with severe headache. Pre-treatment headache scores were correlated with all outcome measures. Regression analyses controlled for pre-treatment scores of the outcome variables showed associations between pre-treatment headache scores (Hopkins Symptom Checklist or Symptom Checklist-90) and post-treatment scores for intrusion, numbing, hyperarousal, anxiety, disability, and quality of life (all p < 0.02). CONCLUSION: Headache is a prevalent comorbid condition among refugees with post-traumatic stress disorder. Measures of pre-treatment headache severity appear to predict post-traumatic stress disorder treatment outcomes. Severe headache adversely affects post-traumatic stress disorder prognosis. Assessment and treatment options should be studied further.

Diagnosis of idiopathic intracranial hypertension: A proposal for evidence-based diagnostic criteria.

BACKGROUND: Based on expert opinion, abducens nerve palsy and a neuroimaging criterion (≥3 neuroimaging signs suggestive of elevated intracranial pressure) were added to the diagnostic criteria for idiopathic intracranial hypertension. Our objective was to validate this. METHODS: This prospective study included patients with new-onset idiopathic intracranial hypertension for a standardized work-up: interview, neuro-ophthalmological exam, lumbar puncture, neuroimaging. Neuroimaging was evaluated by a blinded neuroradiologist. RESULTS: We included 157 patients classified as idiopathic intracranial hypertension (56.7%), probable idiopathic intracranial hypertension (1.9%), idiopathic intracranial hypertension without papilledema (idiopathic intracranial hypertension-without papill edema; 0%), suggested idiopathic intracranial hypertension-without papill edema (4.5%), or non-idiopathic intracranial hypertension (36.9%). Moderate suprasellar herniation was more common in idiopathic intracranial hypertension than non-idiopathic intracranial hypertension (71.4% versus 47.4%, p < 0.01), as was perioptic nerve sheath distension (69.8% versus 29.3%, p < 0.001), flattening of the globe (67.1% versus 11.1%, p < 0.001) and transverse sinus stenosis (60.2% versus 18.9%, p < 0.001). Abducens nerve palsy was of no diagnostic significance. Sensitivity of ≥3 neuroimaging signs was 59.5% and specificity was 93.5%. CONCLUSION: Moderate suprasellar herniation, distension of the perioptic nerve sheath, flattening of the globe and transverse sinus stenosis were associated with idiopathic intracranial hypertension. We propose that idiopathic intracranial hypertension can be defined by two out of three objective findings (papilledema, opening pressure ≥25 cm cerebrospinal fluid and ≥3 neuroimaging signs).

DNA-methylation and immunological response in medication overuse headache.

OBJECTIVE: To investigate whether medication-overuse headache patients have differential DNA-methylation pattern. METHODS: We collected blood samples from 120 medication-overuse headache-patients, 57 controls (29 episodic migraine patients and 28 healthy controls) in a hypothesis-generating cross-sectional case-control pilot study; 100 of the medication-overuse headache-patients were followed for six months and samples were collected at two and six months for the longitudinal methylation analyses. Blood cell proportions of leucocytes (neutrophils, NK-cells, monocytes, CD8+ and CD4+ T-cells, and B-cells) and the neutrophile-lymphocyte ratio were estimated using methylation data as a measure for immunological analysis and a cell type-specific epigenome wide association study was conducted between medication-overuse headache-patients and controls, and longitudinally for reduction in headache days/month among medication-overuse headache-patients. RESULTS: We found a higher neutrophile-lymphocyte ratio in medication-overuse headache-patients compared to controls, indicating a higher immunological response in medication-overuse headache-patients (false discovery rate (adjusted p-value)<0.001). Reduction in headache days/month (9.8; 95% CI 8.1-11.5) was associated with lower neutrophile-lymphocyte ratio (false discovery rate adjusted p-value = 0.041).Three genes (CORIN, CCKBR and CLDN9) were hypermethylated in specific cell types in medication-overuse headache-patients compared to controls. No methylation differences were associated with reduction in headache days in medication-overuse headache-patients after six months. CONCLUSION: This pilot study was consistent with higher immunological response in medication-overuse headache-patients which decreased with a reduction in headache days in longitudinal analysis. medication-overuse headache-patients exhibited differential methylation in innate immune cells but did not exhibit longitudinal differences with alterations in headache days. Our study creates hypotheses for further biomarker searches.ClinicalTrials.gov Identifier: NCT02993289.

Retinal vessel dynamics analysis as a surrogate marker for raised intracranial pressure in patients with suspected idiopathic intracranial hypertension.

INTRODUCTION: Retinal vessel dynamics analysis has proven to be a viable, non-invasive surrogate marker for increased intracranial pressure. We aimed to test this method in patients with suspected idiopathic intracranial hypertension. METHODS: Patients with suspected idiopathic intracranial hypertension were prospectively enrolled for hand-held fundus-videography during diagnostic lumbar puncture. After extracting optic disc images, peripapillary arteriole-to-venule-ratios were measured using machine-learning algorithms with manual identification control. A general linear model was applied to arteriole-to-venule-ratios and corresponding lumbar opening pressures to estimate cerebrospinal fluid pressure. RESULTS: Twenty-five patients were included with a significant difference in arteriole-to-venule-ratio between patients with (n = 17) and without (n = 8) idiopathic intracranial hypertension (0.78 ± 0.10 vs 0.90 ± 0.08, p = 0.006). Arteriole-to-venule-ratio correlated inversely with lumbar opening pressure (slope regression estimate -0.0043 (95% CI -0.0073 to -0.0023), p = 0.002) and the association was stronger when lumbar opening pressure exceeded 15 mm Hg (20 cm H2O) (slope regression estimate -0.0080 (95% CI -0.0123 to -0.0039), p < 0.001). Estimated cerebrospinal fluid pressure predicted increased lumbar opening pressure >20 mm Hg (27 cm H2O) with 78% sensitivity and 92% specificity (AUC 0.81, p = 0.02). A stand-alone arteriole-to-venule-ratio measurement predicting lumbar opening pressure >20 mm Hg (27 cm H2O) was inferior with a 48% sensitivity and 92% specificity (AUC 0.73, p = 0.002). CONCLUSION: Retinal vessel dynamics analysis with the described model for estimating cerebrospinal fluid pressure is a promising non-invasive method with a high sensitivity and specificity for detecting elevated intracranial pressure at follow-up assessments of patients with confirmed idiopathic intracranial hypertension if initial lumbar opening pressure and arteriole-to-venule-ratio data are available.

Transition of cluster headache phenotype: An interview-based study.

Background Cluster headache exists diagnostically in a chronic and episodic variant between which patients can convert. We aimed to describe how many patients change phenotype, elucidate possible factors associated with this transition and identify differences in clinical features between primary and secondary phenotypes.Methods 540 well-defined cluster headache patients according to current ICHD-criteria completed a cross-sectional semi-structured interview.Results Total transition-incidence for the cohort was 20.7%. Conversion from chronic to episodic was reported by 6.3% and transition from episodic to chronic by 14.4% with attack side shift as a possible predictor (p = 0.007). Compared to primary chronic patients, secondary chronic patients had more frequent (60 vs 34 per month, p = 0.0487), but shorter (60 vs 90 minutes, p = 0.041) attacks. Secondary episodic patients experienced shorter remission periods than primary episodic patients (6 vs 11 months, p = 0.010). Treatment response was poor in all groups and only one third had effective prevention.Conclusion Cluster headache is a fluctuating disorder with a fifth of our cohort having experienced at least one phenotype change during course of disease. Apart from attack side shifts, no predictors for transition were identified. Severity differed between primary and secondary subtypes. Overall, there is an urgent need for better understanding of cluster headache.