Daytime sleepiness and BMI exhibit gender and age differences in patients with central disorders of hypersomnolence.

The aim of the present study was to examine gender and age-specific effects on subjective daytime sleepiness (as measured by the Epworth Sleepiness Scale), body weight and eating behaviour in patients with central disorders of hypersomnolence. Based on the European Narcolepsy Network database, we compared 1035 patients with narcolepsy type I and 505 patients with other central disorders of hypersomnolence ("narcoleptic borderland"), including narcolepsy type II (N = 308) and idiopathic hypersomnia (N = 174), using logistic regression and general linear models. In the entire study population, the Epworth Sleepiness Scale was higher in women (N = 735, mean age = 30 years, mean Epworth Sleepiness Scale = 16.6 ± SD 3.9) than in men (N = 805, mean age = 32 years, mean Epworth Sleepiness Scale = 15.8 ± SD 4.4). In women with narcolepsy type I (N = 475), both Epworth Sleepiness Scale and body mass index increased in parallel with age. In women of the narcoleptic borderland (N = 260), the Epworth Sleepiness Scale markedly peaked in their early 30s, while body mass index only started to rise at that age. This rise in body mass index following the Epworth Sleepiness Scale peak cannot be explained by sleepiness-induced uncontrolled eating, as self-reported uncontrolled eating was negatively associated with the Epworth Sleepiness Scale in this group. We propose that the narcoleptic borderland harbours a unique cluster of women in their fertile years with an unexplored aetiology requiring further investigation towards tailored interventions.

Recent insights into the pathophysiology of narcolepsy type 1.

Narcolepsy type 1 (NT1) is a sleep-wake disorder in which people typically experience excessive daytime sleepiness, cataplexy and other sleep-wake disturbances impairing daily life activities. NT1 symptoms are due to hypocretin deficiency. The cause for the observed hypocretin deficiency remains unclear, even though the most likely hypothesis is that this is due to an auto-immune process. The search for autoantibodies and autoreactive T-cells has not yet produced conclusive evidence for or against the auto-immune hypothesis. Other mechanisms, such as reduced corticotrophin-releasing hormone production in the paraventricular nucleus have recently been suggested. There is no reversive treatment, and the therapeutic approach is symptomatic. Early diagnosis and appropriate NT1 treatment is essential, especially in children to prevent impaired cognitive, emotional and social development. Hypocretin receptor agonists have been designed to replace the attenuated hypocretin signalling. Pre-clinical and clinical trials have shown encouraging initial results. A better understanding of NT1 pathophysiology may contribute to faster diagnosis or treatments, which may cure or prevent it.

Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache.

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.

Potential immunological triggers for narcolepsy and idiopathic hypersomnia: Real-world insights on infections and influenza vaccinations.

OBJECTIVE: It is hypothesized that narcolepsy type 1 (NT1) develops in genetically susceptible people who encounter environmental triggers leading to immune-mediated hypocretin-1 deficiency. The pathophysiologies of narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) remain unknown. The main aim of this study was to collect all reported immunological events before onset of a central disorder of hypersomnolence. METHODS: Medical records of 290 people with NT1, and 115 with NT2 or IH were retrospectively reviewed to extract infection and influenza vaccination history. Prevalence, distribution of immunological events, and time until hypersomnolence onset were compared between NT1 and the combined group of NT2 and IH. RESULTS: Immunological events were frequently reported before hypersomnolence disorder onset across groups. Flu and H1N1 influenza vaccination were more common in NT1, and Epstein-Barr virus and other respiratory and non-respiratory infections in NT2 and IH. Distributions of events were comparable between NT2 and IH. Rapid symptom onset within one month of infection was frequent across groups, especially after flu infection in NT1. Hypersomnolence disorder progression after an immunological event was reported in ten individuals. CONCLUSIONS: Our findings suggest a variety of immunological triggers potentially related to NT1, including H1N1 influenza infection or vaccination, infection with other flu types, and other respiratory and non-respiratory infections. Frequent reports of immunological events (other than those reported in NT1) immediately prior to the development of NT2 and IH support the specificity of triggers for NT1, and open important new research avenues into possible underlying immunological mechanisms in NT2 and IH.

Sleep in the intensive and intermediate care units: Exploring related factors of delirium, benzodiazepine use and mortality.

AIM OF THE STUDY: The primary purpose was to examine sleep difficulties and delirium in the Intensive and Intermediate Care Unit. Secondarily, factors impacting night-time sleep duration and quality, mortality, and the impact of benzodiazepine use on sleep outcomes were investigated. MATERIALS AND METHODS: This retrospective study encompassed data from 323 intensive and intermediate care unit admissions collected in the Netherlands, spanning from November 2018 to May 2020. Sleep quality was measured using the Richards-Campbell Sleep Questionnaire. Night-time sleep duration was nurse-reported. We investigated associations of these sleep outcomes with age, sex, length-of-stay, natural daylight, disease severity, mechanical ventilation, benzodiazepine use, and delirium using Generalized Estimating Equations models. Associations with one-year post-discharge mortality were analyzed using Cox regression. RESULTS: Night-time sleep duration was short (median 4.5 hours) and sleep quality poor (mean score 4.9/10). Benzodiazepine use was common (24 % of included nights) and was negatively associated with night-time sleep duration and quality (B = -0.558 and -0.533, p <.001). Delirium and overnight transfers were negatively associated with sleep quality (B = -0.716 and -1.831, p <.05). The day-to-night sleep ratio was higher in the three days before delirium onset than in non-delirious individuals (p <.05). Age, disease severity and female sex were associated with increased one-year mortality. Sleep quality was negatively, but not-significantly, associated with mortality (p =.070). CONCLUSIONS: Night-time sleep in the critical care environment has a short duration and poor quality. Benzodiazepine use was not associated with improved sleep. Sleep patterns change ahead of delirium onset. IMPLICATIONS FOR CLINICAL PRACTICE: Consistent sleep monitoring should be part of routine nursing practice, using a validated instrument like the Richards-Campbell Sleep Questionnaire. Given the lack of proven efficacy of benzodiazepines in promoting sleep in critical care settings, it is vital to develop more effective sleep treatments that include non-benzodiazepine medication and sleep hygiene strategies.

Translating the Cluster Headache Quality of Life Questionnaire (CHQ) from English to Dutch with the TRAPD method.

OBJECTIVE: Cluster headache is associated with a decreased quality of life (QoL). The increased focus on patient-reported outcome measures (PROMS) has led to the creation of a tailored Cluster Headache Quality of Life scale (CHQ). Our objective was to create and authenticate a Dutch version of the CHQ (CHQ-D). METHODS: The TRAPD model (Translation, Review, Adjudication, Pretesting, Documentation) was used to translate the CHQ from English to Dutch and ensure cross-cultural adaption. Pre-testing was performed in n = 31 participants, and validity was in a new sample of n = 40 participants who completed the CHQ twice at a 2-day interval. Intraclass correlation coefficient (ICC) and Cronbach's alpha were used to assess the validity and reproducibility of the CHQ-D. RESULTS: To produce the CHQ-D, we made five modifications based on pretesting. Participants finished the questionnaire in a median time of 10 min (IQR:10.0, 17.5) and 90% within 20 min. The majority of participants (74.2%) did not find it burdensome at all. The reliability of the CHQ-D was excellent (Cronbach's alpha: 0.94; ICC: 0.94). CONCLUSION: The CHQ-D is a valid and practical instrument for QoL in individuals with cluster headache. We aim to use CHQ-D as PROM in clinical research in the Netherlands to enforce international collaborations and comparisons of studies.

Narcolepsy type 1 and Sydenham chorea - Report of 3 cases and review of the literature.

OBJECTIVES/BACKGROUND: Narcolepsy type 1 (NT1) is an immune-mediated disorder characterized by excessive daytime sleepiness, cataplexy, low levels of hypocretin-1 in the cerebrospinal fluid, and a strong association with the HLA DQB1*06:02 allele. There is evidence for streptococcal infections as one pathogenic factor that may lead to NT1 as part of a multifactorial pathogenesis. Elevated titers of Antistreptolysin-O antibodies and increased inflammatory activity in response to streptococci antigens have been described in patients with NT1. Sydenham chorea (SC) results from a post-streptococcal autoimmune process targeting basal ganglia neurons. Despite this common trigger, SC has been interpreted as a misdiagnosis in a few described cases of patients who were first diagnosed with SC and later with NT1. Our goal was to analyze the association between SC and NT1. PATIENTS/METHODS: We reviewed the literature and report three patients from three European sleep centers who were diagnosed with both SC and NT1 within a few months. RESULTS: We describe the cases of one male (age 10) and two female (age 22 and 10) patients. CONCLUSIONS: We argue that in those cases both diagnoses are justified, unlike reports of previous cases in which SC was considered a misdiagnosis in patients with NT1. It remains, however, unclear if the conditions occur independently or if there is an overlap disorder- an SC-like subtype of narcolepsy with a particular sequence of symptoms. Further studies need to clarify the causality of the relationship and the pathophysiology of the reported rare association.

A prospective open label 2-8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache.

BACKGROUND: We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety. METHODS: ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals. FINDINGS: Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8-6.3), two (5.1; 3.5-7.6) and five years (4.1; 3.0-5.5) compared to baseline (16.2; 14.4-18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68-0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70-0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year-1 [0.28-0.41]). We didn't find predictive factors for effectiveness. INTERPRETATION: ONS is a safe, well-tolerated and long-term effective treatment for MICCH. FUNDING: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

Vigilance and circadian function in daytime and nocturnal epilepsy compared to controls.

BACKGROUND: People with epilepsy often experience daytime vigilance problems and fatigue. This may be related to disturbed sleep due to nocturnal seizures. AIM: To compare subjective and objective markers of vigilance and circadian function in adults with epilepsy with nocturnal seizures to those with daytime seizures and healthy controls and to identify determinants of impaired daytime vigilance in epilepsy in an explorative study. METHODS: We included 30 adults with epilepsy (15 with daytime seizures and 15 with nocturnal seizures), and 15 healthy controls. All participants filled out the Epworth sleepiness scale (ESS), fatigue severity scale (FSS), Pittsburgh sleep quality index (PSQI) and the Munich chronotype questionnaire (MCTQ). Each participant performed two trials of the sustained attention to response task (SART) as a measure of vigilance, and had a post-illumination pupil response (PIPR) assessment as a marker for the circadian function. RESULTS: Both epilepsy groups reported more fatigue on the FSS than healthy controls (p < .001) and had higher SART error scores (p = .026). The poorer FSS and SART scores were most prominent among those with nocturnal seizures. The ESS, PSQI, MCTQ and the primary PIPR outcome did not differ between groups. Having nocturnal seizures (p = .010) and using more antiseizure medications (p = .004) were related to increased SART error scores. CONCLUSIONS: Nocturnal epilepsy is associated with poorer vigilance, indicating lower quality of wake time. We could not relate this to circadian dysfunction. Further studies should focus on vigilance problems in people with nocturnal epilepsy and explore interventions to improve the quality of wake time.

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.

Skin temperature as a predictor of on-the-road driving performance in people with central disorders of hypersomnolence.

Excessive daytime sleepiness is the core symptom of central disorders of hypersomnolence (CDH) and can directly impair driving performance. Sleepiness is reflected in relative alterations in distal and proximal skin temperature. Therefore, we examined the predictive value of skin temperature on driving performance. Distal and proximal skin temperature and their gradient (DPG) were continuously measured in 44 participants with narcolepsy type 1, narcolepsy type 2 or idiopathic hypersomnia during a standardised 1-h driving test. Driving performance was defined as the standard deviation of lateral position (SDLP) per 5 km segment (equivalent to 3 min of driving). Distal and proximal skin temperature and DPG measurements were averaged over each segment and changes over segments were calculated. Mixed-effect model analyses showed a strong, quadratic association between proximal skin temperature and SDLP (p < 0.001) and a linear association between DPG and SDLP (p < 0.021). Proximal skin temperature changes over 3 to 15 min were predictive for SDLP. Moreover, SDLP increased over time (0.34 cm/segment, p < 0.001) and was higher in men than in women (3.50 cm, p = 0.012). We conclude that proximal skin temperature is a promising predictor for real-time assessment of driving performance in people with CDH.

The therapeutic potential of opioids in narcolepsy type 1: A systematic literature review and questionnaire study.

OBJECTIVE: Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study. METHODS: We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported. RESULTS: The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7). CONCLUSIONS: Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy.

Activated Wake Systems in Narcolepsy Type 1.

OBJECTIVE: Narcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co-express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake-systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways. METHODS: In postmortem tissue of people with NT1 and matched controls, we immunohistochemically stained and quantified neuronal populations expressing: CRH and AVP in the PVN, and CRH in the Barrington nucleus; the key neuronal histamine-synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate-limited-synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid-brain and for norepinephrine in the locus coeruleus (LC). RESULTS: In NT1, there was: a 234% increase in the percentage of CRH cells co-expressing AVP, while there was an unchanged integrated optical density of CRH staining in the Barrington nucleus; a 36% increased number of histamine neurons expressing HDC, while the number of typical human TMN neuronal profiles was unchanged; a tendency toward an increased density of TH-positive neurons in the substantia nigra compacta; while the density of TH-positive LC neurons was unchanged. INTERPRETATION: Our findings suggest an upregulation of activity by histamine neurons and remaining CRH neurons in NT1. This may explain earlier reports of normal basal plasma cortisol levels but lower levels after dexamethasone suppression. Alternatively, CRH neurons co-expressing AVP neurons are less vulnerable. ANN NEUROL 2023;94:762-771.

Transient side shift of cluster headache attacks after unilateral greater occipital nerve injection.

Attacks of cluster headache (CH) are usually side-locked in most, but not all, patients. In a few patients, the side may alternate between or, rarely, within cluster episodes. We observed seven cases in whom the side of CH attacks temporarily shifted immediately or shortly after unilateral injection of the greater occipital nerve (GON) with corticosteroids. In five patients with previously side-locked CH attacks and in two patients with previously side-alternating CH attacks, a side shift for several weeks occurred immediately (N = 6) or shortly (N = 1) after GON injection. We concluded that unilateral GON injections might cause a transient side shift of CH attacks through inhibition of the ipsilateral hypothalamic attack generator causing relative overactivity of the contralateral side. The potential benefit of bilateral GON injection in patients who experienced a side shift after unilateral injection should be formally investigated.

Applicability of the Sustained Attention to Response Task (SART) in hypersomnolence: Experience and results from a tertiary referral center.

OBJECTIVE/BACKGROUND: Evaluation of hypersomnolence disorders ideally includes an assessment of vigilance using the short Sustained Attention to Response Task (SART). We evaluated whether this task can differentiate between hypersomnolence disorders, whether it correlates with subjective and objective sleepiness, whether it is affected by the time of day, and symptoms of anxiety and depression. PATIENTS/METHODS: We analyzed diagnostic data of 306 individuals with hypersomnolence complaints diagnosed with narcolepsy type 1 (n=100), narcolepsy type 2 (n=20), idiopathic hypersomnia (n=49), obstructive sleep apnea (n=27) and other causes or without explanatory diagnosis (n=110). We included the Multiple Sleep Latency Test (MSLT), polysomnography, Epworth Sleepiness Scale (ESS), Hospital Anxiety and Depression Scale and SART, which were administered five times during the day (outcomes: reaction time, total, commission and omission errors). RESULTS: The SART outcomes did not differ between groups when adjusted for relevant covariates. Higher ESS scores were associated with longer reaction times and more commission errors (p<.01). The main outcome, total errors, did not differ between times of the day. Reaction times and omission errors were impacted (p<.05). CONCLUSIONS: The SART quantifies disturbed vigilance, an important dimension of disorders of hypersomnolence. Results do not suggest that depressive symptoms influence SART outcomes. A practice session is advised. Testing time should be taken into account when interpreting results. We conclude that the SART does not differentiate between central disorders of hypersomnolence. It may be a helpful addition to the standard diagnostic workup and monitoring of these disorders.

Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy.

Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Intra- and interindividual attack frequency variability of chronic cluster headache.

BACKGROUND: The lack of knowledge about the intra- and interindividual attack frequency variability in chronic cluster headache complicates power and sample size calculations for baseline periods of trials, and consensus on their most optimal duration. METHODS: We analyzed the 12-week baseline of the ICON trial (occipital nerve stimulation in medically intractable chronic cluster headache) for: (i) weekly vs. instantaneous recording of attack frequency; (ii) intra-individual and seasonal variability of attack frequency; and (iii) the smallest number of weeks to obtain a reliable estimate of baseline attack frequency. RESULTS: Weekly median (14.4 [8.2-24.0]) and instantaneous (14.2 [8.0-24.5]) attack frequency recordings were similar (p = 0.20; Bland-Altman plot). Median weekly attack frequency was 15.3 (range 4.2-140) and highest during spring (p = 0.001) compared to the other seasons. Relative attack frequency variability decreased with increasing attack frequency (p = 0.010). We tabulated the weekly attack frequency estimation accuracies compared to, and the associated deviations from, the 12-week gold standard for different lengths of the observation period. CONCLUSION: Weekly retrospective attack frequency recording is as good as instantaneous recording and more convenient. Attack frequency is highest in spring. Participants with ≥3 daily attacks show less attack frequency variability than those with <3 daily attacks. An optimal balance between 90% accuracy and feasibility is achieved at a baseline period of seven weeks.The ICON trial is registered in ClinicalTrials.gov under number NCT01151631.

Clinical outcome in patients with suspected inflammatory neuropsychiatric lupus treated with immunosuppression: an observational cohort study.

BACKGROUND: The short-term and long-term outcome of inflammatory neuropsychiatric SLE (NPSLE) with immunosuppressive treatment is largely unknown. We used clinical data from our tertiary referral centre for NPSLE to investigate the type of inflammatory NPSLE manifestations, type of immunosuppressive treatment prescribed for these manifestations and clinical outcomes. METHODS: All patients with SLE visiting the Leiden University Medical Centre NPSLE clinic between 2007 and 2021 receiving immunosuppressive therapy for neuropsychiatric symptoms were included. Clinical, immunological and radiological information was collected in as standardised way during a 1-day multidisciplinary assessment. In a multidisciplinary consensus meeting, the presence of NPSLE and the type of NPSLE manifestations and treatment were determined. For this study, short-term (0-6 months) and long-term outcomes (7-24 months) of the NP symptoms were assessed by two independent readers and scored on a 7-point Likert scale, ranging from death to resolved. RESULTS: In total, 95 out of 398 (24%) patients visiting the NPSLE clinic between 2007 and 2021 received any form of immunosuppressive treatment for 101 separate NPSLE events. The most common NP manifestation was cognitive dysfunction (50%) as identified by formal cognitive assessment, often present in combination with other NPSLE manifestations. Treatment modalities were induction (24%), induction and maintenance (73%) and other therapy (3%). The treatments mostly consisted of (combinations of) prednisone (97%), methylprednisolone (53%), azathioprine (generally 2 mg/kg daily) (49%) and cyclophosphamide (generally induction 750 mg/m2 every 4 weeks for 24 weeks or 500mg biweekly for 12 weeks) (42%). Short-term outcome showed improvement on the Likert scale in 73% (improved: 22%, much improved: 29%, resolved: 22%), no change in 21% and worsening in 6% of patients. Long-term outcome was available for 78 out of 101 events and showed improvement in 70% (improved: 14%, much improved: 28%, resolved: 28%), no change in 17%, worsening in 10% and death in 3% of patients (none directly NPSLE-related). CONCLUSION: The outcome of inflammatory NPSLE after immunosuppressive treatment is generally good, with improvement of neuropsychiatric symptoms occuring in approximately 70% of events.