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... Show moreExcessive 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. Show less
Gool, J.K.; Fronczek, R.; Bosma, P.; Meer, J.N. van der; Werf, Y.D. van der; Lammers, G.J. 2022
The brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment... Show moreThe brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment often used to assess an individual's ability to resist sleep. It is frequently used in narcolepsy type 1, a disorder characterized by impaired sleep-wake control and the inability to resist daytime sleep. We investigated the neural correlates of active sleep resistance in 12 drug-free people with narcolepsy type 1 and 12 healthy controls. Simultaneous fMRI-EEG measurements were recorded during five cycles of two alternating conditions of active sleep resistance and waking rest. Cleaned EEG signals were used to verify wakefulness and task adherence. Pooling both subject groups, significantly higher fMRI activation when actively resisting sleep was seen in the brainstem, superior cerebellum, bilateral thalamus and visual cortices. In controls the activation clusters were generally smaller compared to patients and no significant activation was seen in the brainstem. Formal comparison between groups only found a significantly higher left primary visual cortex activation in patients during active sleep resistance. The active sleep resistance paradigm is a feasible fMRI task to study sleep resistance and induces evident arousal- and visual-related activity. Significantly higher left primary visual cortical activation in patients could be caused by an enhanced need of visual focus to resist sleep, or reflecting a more rapid descent in their level of alertness when resting. Show less
Study Objectives To review the Maintenance of Wakefulness Test (MWT) as assessment of daytime sleepiness in the evaluation of treatment effects and driving fitness in central disorders of... Show moreStudy Objectives To review the Maintenance of Wakefulness Test (MWT) as assessment of daytime sleepiness in the evaluation of treatment effects and driving fitness in central disorders of hypersomnolence (CDH). Methods We performed a scoping review of studies using the MWT in patients with CDH (i.e. narcolepsy types 1 and 2, and idiopathic hypersomnia). N = 20 articles were included, comprising 683 patients and 129 controls. MWT effect sizes were compared to the Clinical Global Impression (GCI) scale and the Epworth Sleepiness Scale (ESS). MWT sleep latency was correlated to objective driving performances. The role of motivation was evaluated by comparing MWTs of treatment studies (low motivation) to driving fitness studies (high motivation to stay awake). Healthy controls were compared to norm values. Results MWT and CGI were both impacted by the same treatment; however, the MWT has higher effect sizes and was more sensitive to measure these effects. The MWT correlated fairly to moderately (rho = -0.26 to -0.56; p <= .05) to objective driving performance. Motivation played a major role on MWT sleep latencies (d = 0.76 to 1.43; p <= .001). Current norm values may not be valid, as sleep latency may be impacted by age. Conclusions The MWTs applicability to measure treatment effects in CDH was confirmed, but age-adjusted norm values are needed. For a more complete evaluation of EDS it should be combined with subjective measures. Its reliability for driving fitness evaluation is insufficient, and motivation plays a major role. To predict or monitor driving performance in CDH, valid and easy methods should be developed. Show less
Hoeven, A.E. van der; Waaij, K. van; Bijlenga, D.; Roelandse, F.W.C.; Overeem, S.; Bakker, J.A.; ... ; Lammers, G.J. 2022
Study Objectives The most sensitive and specific investigative method for the diagnosis of narcolepsy type 1 (NT1) is the determination of hypocretin-1 (orexin-A) deficiency (<= 110 pg/mL) in... Show moreStudy Objectives The most sensitive and specific investigative method for the diagnosis of narcolepsy type 1 (NT1) is the determination of hypocretin-1 (orexin-A) deficiency (<= 110 pg/mL) in cerebrospinal fluid using a radioimmunoassay (RIA). We aimed to assess the reliability of the Phoenix Pharmaceuticals hypocretin-1 RIA, by determining the lower limit of quantification (LLOQ), the variability around the cutoff of 110 pg/mL, and the inter- and intra-assay variability. Methods: Raw data of 80 consecutive hypocretin-1 RIAs were used to estimate the intra- and inter-assay coefficient of variation (CV). The LLOQ was established and defined as the lowest converted concentration with a CV Results: The mean intra-assay CV was 4.7%, while the unconverted inter-assay CV was 28.3% (18.5% excluding 2 outliers) and 7.5% when converted to international values. The LLOQ was determined as 27.9 pg/mL. The intra-assay CV of RIAs with lower specific radioactive activity showed a median of 5.6% (n = 41, range 1.6%-17.0%), which was significantly higher than in RIAs with higher specific activity (n = 36; median 3.2%, range 0.4%-11.6%, p = .013). The CV around the 110 pg/mL cutoff was <7%. Conclusions: Hypocretin-1 RIAs should always be harmonized using standard reference material. The specific activity of an RIA has a significant impact on its reliability, because of the decay of I-125 radioactivity. Values around the hypocretin-1 cut-off can reliably be measured. Hypocretin-1 concentrations below 28 pg/mL should be reported as "undetectable" when measured with the Phoenix Pharmaceuticals RIA. Show less
Background and purpose Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines... Show moreBackground and purpose Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. Methods The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. Results A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. Conclusion The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail. Show less
Background and purpose: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines... Show moreBackground and purpose: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children.Methods: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.Results: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions.Conclusion: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail. Show less
Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the... Show moreIncreased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009-2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009-2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy. Show less
The classification of the central disorders of hypersomnolence has undergone multiple iterations in an attempt to capture biologically meaningful disease entities in the absence of known... Show moreThe classification of the central disorders of hypersomnolence has undergone multiple iterations in an attempt to capture biologically meaningful disease entities in the absence of known pathophysiology. Accumulating data suggests that further refinements may be necessary. At the 7th International Symposium on Narcolepsy, a group of clinician-scientists evaluated data in support of keeping or changing classifications, and as a result suggest several changes. First, idiopathic hypersomnia with long sleep durations appears to be an identifiable and meaningful disease subtype. Second, idiopathic hypersomnia without long sleep time and narcolepsy without cataplexy share substantial phenotypic overlap and cannot reliably be distinguished with current testing, and so combining them into a single disease entity seems warranted at present. Moving forward, it is critical to phenotype patients across a wide variety of clinical and biological features, to aid in future refinements of disease classification. Show less
Gool, J.K.; Werf, Y.D. van der; Lammers, G.J.; Fronczek, R. 2020
Vigilance complaints often occur in people with narcolepsy type 1 and severely impair effective daytime functioning. We tested the feasibility of a three-level sustained attention to response task ... Show moreVigilance complaints often occur in people with narcolepsy type 1 and severely impair effective daytime functioning. We tested the feasibility of a three-level sustained attention to response task (SART) paradigm within a magnetic resonance imaging (MRI) environment to understand brain architecture underlying vigilance regulation in individuals with narcolepsy type 1. Twelve medication-free people with narcolepsy type 1 and 11 matched controls were included. The SART included four repetitions of a baseline block and two difficulty levels requiring moderate and high vigilance. Outcome measures were between and within-group performance indices on error rates and reaction times, and functional MRI (fMRI) parameters: mean activity during the task and between-group activity differences across the three conditions and related to changes in activation over time (time-on-task) and error-related activity. Patients-but not controls-made significantly more mistakes with increasing difficulty. The modified SART is a feasible MRI vigilance task showing similar task-positive brain activity in both groups within the cingulo-opercular, frontoparietal, arousal, motor, and visual networks. During blocks of higher vigilance demand, patients had significantly lower activation in these regions than controls. Patients had lower error-related activity in the left pre- and postcentral gyrus. The time-on-task activity differences between groups suggest that those with narcolepsy are insufficiently capable of activating attention- and arousal-related regions when transitioning from attention initiation to stable attention, specifically when vigilance demand is high. They also show lower inhibitory motor activity in relation to errors, suggesting impaired executive functioning. Show less
Heide, A. van der; Werth, E.; Donjacour, C.E.H.M.; Reijntjes, R.H.A.M.; Lammers, G.J.; Someren, E.J.W. van; ... ; Fronczek, R. 2016
STUDY OBJECTIVES:Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis.... Show moreSTUDY OBJECTIVES:Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis. Here, we evaluated whether human hypocretin deficiency, or the narcolepsy therapeutic agent sodium oxybate, alter the levels of these hormones. METHODS:Eight male, medication free, hypocretin deficient, narcolepsy with cataplexy patients, and 8 healthy controls matched for age, sex, body mass index (BMI), waisttohip ratio, and body fat percentage were assessed. Blood samples of total ghrelin and leptin were collected over 24 hours at 60 and 20-min intervals, respectively, during 2 study occasions: baseline, and during the last night of 5 consecutive nights of sodium oxybate administration (2 × 3.0 g/night). RESULTS:At baseline, mean 24-h total ghrelin (936 ± 142 vs. 949 ± 175 pg/mL, p = 0.873) and leptin (115 ± 5.0 vs. 79.0 ± 32 mg/L, p = 0.18) levels were not different between hypocretin deficient narcolepsy patients and controls. Furthermore, sodium oxybate did not significantly affect the plasma concentration of either one of these hormones. CONCLUSIONS:The increased BMI of narcolepsy patients is unlikely to be mediated by hypocretin deficiency-mediated alterations in total ghrelin or leptin levels. Thus, the effects of these hormones on hypocretin neurons may be mainly unidirectional. Although sodium oxybate may influence body weight, the underlying mechanism is unlikely to involve changes in total ghrelin or leptin secretion. Show less
