Efficacy of pitolisant in patients with high burden of narcolepsy symptoms: pooled analysis of short-term,placebo-controlled studies

Study objectiveTo evaluate the efficacy of pitolisant, a histamine 3 (H₃)-receptor antagonist/inverse agonist, in adult patients with high burden of narcolepsy symptoms.MethodsData were pooled from two randomized, placebo-controlled, 7- or 8-week studies of pitolisant (titrated to a potential maximum dose of 35.6 mg/day) in adults with narcolepsy. Analyses included three independent patient subgroups: Epworth Sleepiness Scale (ESS) baseline score ≥16, Maintenance of Wakefulness Test (MWT) sleep latency ≤8 min, and ≥15 cataplexy attacks per week.ResultsThe analysis populations included 118 patients for ESS (pitolisant, n = 60; placebo, n = 58), 105 for MWT (pitolisant, n = 59; placebo, n = 46), and 31 for cataplexy (pitolisant, n = 20; placebo, n = 11). On the ESS, least-squares mean change from baseline was significantly greater for pitolisant (−6.1) compared with placebo (−2.3; P < 0.001). Significantly more pitolisant-treated patients were classified as treatment responders: ESS score reduction ≥3, 69.0% in the pitolisant group versus 35.1% in the placebo group (P = 0.001); final ESS score ≤10, 36.2% versus 10.5%, respectively (P = 0.005). On the MWT, mean sleep latency increased from 3.5 min to 10.4 min with pitolisant and from 3.4 min to 6.8 min with placebo (P = 0.017). Least-squares mean change in the weekly rate of cataplexy was significantly greater for pitolisant (−14.5; baseline, 23.9; final, 9.4) compared with placebo (−0.1; baseline, 23.1; final, 23.0; P = 0.004). Headache was the most common adverse event with pitolisant.ConclusionsPitolisant, at once-daily doses up to 35.6 mg, was efficacious for reducing excessive daytime sleepiness and cataplexy in patients with severe narcolepsy symptom burden.     

Effects of pitolisant,a histamine H3 inverse agonist,in drug-resistant idiopathic and symptomatic hypersomnia: a chart review

ObjectiveTo evaluate the benefits and risks of pitolisant (a wake-enhancing drug that increases the histamine release in the brain by blocking presynaptic H3 histamine reuptake) in patients with idiopathic (IH) and symptomatic (SH) hypersomnia plus sleepiness refractory to available stimulants (modafinil, methylphenidate, mazindol, sodium oxybate, and d-amphetamine).MethodsThrough retrospective analyses of patient files, the benefit (the score from the Epworth Sleepiness Scale [ESS], authorization renewal) and tolerance (side-effects) of pitolisant were assessed.ResultsA total of 78 patients with IH (n = 65%, 78% women) and SH (n = 13%, 54% women) received pitolisant 5–50 mg once per day over the course of five days to 37 months. The median (interquartile range) ESS scores of patients with IH decreased from 17 (15.5–18.5) to 14 (12–17). There were 36% responders (ESS fall of ⩾3). The improvement in ESS score (−1.9 ± 2.6) was different from 0 in IH without long sleep time (P < 0.002) and in IH with a long sleep time (P < 0.0001), but not in SH. Forty-four (63%) patients with IH and 12 (77%) patients with SH stopped pitolisant, mostly due to a lack of efficacy. Side-effects included gastrointestinal pain (15.4%), increased appetite and weight gain (14.1%), headache (12.8%), insomnia (11.5%), and anxiety (9%), as well as exceptional reports of depression and persistent genital arousal.ConclusionPitolisant had a long-term favorable benefit/risk ratio in 23–38% of drug-resistant patients with IH and SH, suggesting that histamine neurons can be stimulated in severe idiopathic and symptomatic hypersomnia.     

Burden of disease in pediatric narcolepsy: a claims-based analysis of health care utilization,costs, and comorbidities

BackgroundThis study analyzed a privately insured pediatric population with and without narcolepsy to determine the impact of pediatric narcolepsy on comorbidities, health care utilization, and cost. Additional analyses compared narcolepsy type 1 and type 2.MethodsThis retrospective cross-sectional study identified US patients with narcolepsy <18 years of age with ≥2 claims with a diagnosis code of narcolepsy using Truven MarketScan® data 2011 to 2015. Patients were matched to controls without narcolepsy. Comorbid conditions, health care utilization, and costs were measured by calendar year. P values are nominal, and no adjustments for multiplicity or multiple comparisons were made.ResultsA total of 1427 pediatric patients with narcolepsy were identified and matched with 4281 controls from 2011 to 2015. Patients with narcolepsy had more comorbid conditions (mean 5.8 vs 2.4, nominal P < 0.001). Respiratory diseases and mood disorders were more common in patients with narcolepsy than controls (57% vs 32% and 56% vs 14%, respectively; both nominal P < 0.001). Compared to controls, patients with narcolepsy underwent more diagnostic tests (electroencephalogram, EEG [0.13 vs 0.0053]) and brain computed tomography, CT/magnetic resonance imaging, MRI (0.26 vs 0.022; both nominal P < 0.001). Mean annual inpatient days (0.71 vs 0.15), emergency department visits (0.51 vs 0.15), and outpatient office visits (8.6 vs 2.3) were higher for patients with narcolepsy than controls (all nominal P < 0.001). Annual mean health care costs were higher for patients with narcolepsy versus controls ($15,797 vs $2449, nominal P < 0.001).ConclusionPediatric patients with narcolepsy had greater comorbidity, higher health care utilization, and higher costs than patients without narcolepsy.     

The Burden of Narcolepsy Disease (BOND) study: health-care utilization and cost findings

ObjectivesThe aim of this study was to characterize health-care utilization, costs, and productivity in a large population of patients diagnosed with narcolepsy in the United States.MethodsThis retrospective, observational study using data from the Truven Health Analytics MarketScan® Research Databases assessed 5 years of claims data (2006–2010) to compare health-care utilization patterns, productivity, and associated costs among narcolepsy patients (identified by International Classification of Diseases, Ninth Revision (ICD9) narcolepsy diagnosis codes) versus matched controls. A total of 9312 narcolepsy patients (>18 years of age, continuously insured between 2006 and 2010) and 46,559 matched controls were identified.ResultsCompared with controls, narcolepsy subjects had approximately twofold higher annual rates of inpatient admissions (0.15 vs. 0.08), emergency department (ED) visits w/o admission (0.34 vs. 0.17), hospital outpatient (OP) visits (2.8 vs. 1.4), other OP services (7.0 vs. 3.2), and physician visits (11.1 vs. 5.6; all p < 0.0001). The rate of total annual drug transactions was doubled in narcolepsy versus controls (26.4 vs. 13.3; p < 0.0001), including a 337% and 72% higher usage rate of narcolepsy drugs and non-narcolepsy drugs, respectively (both p < 0.0001). Mean yearly costs were significantly higher in narcolepsy compared with controls for medical services ($8346 vs. $4147; p < 0.0001) and drugs ($3356 vs. $1114; p < 0.0001).ConclusionsNarcolepsy was found to be associated with substantial personal and economic burdens, as indicated by significantly higher rates of health-care utilization and medical costs in this large US group of narcolepsy patients.     

Prevalence of narcolepsy in King County,Washington, USA

BackgroundRelatively few epidemiologic studies have focused on narcolepsy, a disabling sleep disorder with a strong association with HLA-DQB110602.MethodsWe sought to estimate the prevalence of narcolepsy using multiple overlapping techniques to identify residents of King County, WA who were 18 years or older with physician-diagnosed narcolepsy. Patients were entered into a registry and recruited into an epidemiologic study entailing interview and buccal scrapings to determine HLA-DQB110602 status. Missing values were imputed to allow prevalence to be estimated based on all 425 patients entered into the registry between 2001 and 2005, whether they were recruited into the epidemiologic study (n = 279) or not (n = 146).ResultsAs of July 01, 2001, estimated prevalence per 100,000 of physician-diagnosed narcolepsy with cataplexy was 21.8 (95% confidence interval (CI): 18.8–24.8), similar to prior studies. The median age of onset was 14 (interquartile range: 10–18). For narcolepsy with HLA-DQB110602, prevalence was 15.3 (95% CI: 12.8–17.9). Estimated prevalence was higher in women than men and in African-Americans than other racial groups.ConclusionsThese differences could reflect problems in identification and recruitment or may provide etiologic clues about narcolepsy. This study illustrates the challenges in performing population-based studies of narcolepsy.     

Olfactory dysfunction in narcolepsy with and without cataplexy

BackgroundNot only patients in whom REM behavior disorder (RBD) is associated with narcolepsy, but also those with narcolepsy alone are reported to have olfactory dysfunction. We investigated if hyposmia is specific to narcolepsy with cataplexy (N–C) or if narcolepsy without cataplexy (NwC) is also associated with olfactory dysfunction.MethodsWe studied olfactory function in two groups of patients: N–C group (n = 66, 26 men and 40 women; mean age 41 ± 18 years), and NwC group (n = 17, 7 men and 10 women; mean age 46 ± 20 years). As a control group we used published normative data for particular smell tests.ResultsBoth patients with N–C and patients suffering from NwC had a significantly higher olfactory threshold (N–C group, p < 0.0001; NwC group, p < 0.0001) and impaired odor identification (N–C group, p < 0.0001; NwC group, p < 0.0001). Our results show for the first time that narcolepsy without cataplexy, where the majority of cases have normal CSF hypocretin levels, is associated with olfactory dysfunction.ConclusionsIt appears that also a partial loss of hypothalamic hypocretin neurons without a clear CSF level decrease can affect smell projection.     

Cardiovascular fitness in narcolepsy is inversely related to sleepiness and the number of cataplexy episodes

ObjectiveCardiopulmonary fitness depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy spent more time being sleepy or asleep than controls; thus we may speculate that they have a lower quantity and quality of physical activity. The aim of the present study was thus to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness.Patients and methodsThe cross-sectional study included 32 patients with narcolepsy with cataplexy, 10 patients with narcolepsy without cataplexy, and 36 age- and gender-matched control subjects, in whom a symptom-limited exercise stress test with expired gas analysis was performed. A linear regression analysis with multivariate models was used with stepwise variable selection.ResultsIn narcolepsy patients, maximal oxygen uptake (VO_2peak) was 30.1 ± 7.5 mL/kg/min, which was lower than 36.0 ± 7.8 mL/kg/min, p = 0.001, in controls and corresponded to 86.4% ± 20.0% of the population norm (VO_2peak%) and to a standard deviation (VO_2peakSD) of −1.08 ± 1.63 mL/kg/min of the population norm. VO_2peak depended primarily on gender (p = 0.007) and on sleepiness (p = 0.046). VO_2peak% depended on sleepiness (p = 0.028) and on age (p = 0.039). VO_2peakSD depended on the number of cataplexy episodes per month (p = 0.015) and on age (p = 0.030).ConclusionsCardiopulmonary fitness in narcolepsy and in narcolepsy without cataplexy is inversely related to the degree of sleepiness and cataplexy episode frequency.     

Endovascular thrombectomy is beneficial for functional nonagenarians – a multicenter cohort analysis

IntroductionThe use of endovascular thrombectomy (EVT) has dramatically increased in recent years. However, most existing studies used an upper age limit of 80 and data regarding the safety and efficacy of EVT among nonagenarians is still lacking.Methods767 consecutive patients undergoing EVT for large vessel occlusion (LVO) in three participating centers were recruited into a prospective ongoing database. Demographic, clinical and imaging characteristics were documented. Statistical analysis was done to evaluate EVT outcome among nonagenarians compared to younger patients.ResultsThe current analysis included 41 (5.4%) patients older than 90 years. Compared to younger patients, nonagenarians were more often female (78% versus 50.3%, p ≤ 0.001), had worse baseline mRS scores (2 [0–3] versus 0 [0–2], p < 0.001), higher rates of hypertension and hyperlipidemia and a higher admission NIHSS (20 [14–23] versus 16 [11–20], p < 0.001). No differences were found between groups regarding the involved vessel, stroke etiology, time from symptoms to door or symptoms to EVT, successful recanalization rates and hemorrhagic transformation rates. Nonagenarians had worse mRS at 90 days (5 [3–6] versus 3 [2–5], p = 0.001), similar discharge NIHSS (5 [1–11] versus 4 [1–11], p = 0.78) and higher mortality rates (36.6% versus 15.8%, p < 0.001). All nonagenarians with baseline mRS 4 have died within 90 days. 36.4% of nonagenarian patients with baseline MRS of 3 or less had favorable outcome.DiscussionThis study demonstrates that nonagenarian stroke patients with baseline mRS of 3 or less benefit from EVT with no significant difference in the rate of favorable outcome compared to octogenarians.     

Depressive feelings in children with narcolepsy

ObjectivesWe aimed to evaluate depressive feelings and their correlations in children and adolescents with narcolepsy collected in national reference centers for narcolepsy.MethodsWe compared clinical and sleep characteristics of patients with and without depressive symptoms evaluated on the Children’s Depression Inventory (CDI).ResultsOur study sample included 88 children (44 boys; 44 de novo patients) with a mean age of 11.9 ± 3.1 years at diagnosis (37.5% were aged ⩽10 years). Obesity was found in 59% of the sample and cataplexy was present in 80.7%. The DQB1*0602 allele was positive in 93.5% of our sample. There were 25% of children who had clinically depressive feelings (CDI > 16), especially girls older than the age of 10 years. Bivariate associations indicated that depressive feelings were associated with fatigue (48%), hyperactivity (31%), insomnia (16%), and excessive daytime sleepiness (EDS) (14–24%). In the multivariate model adjusted for gender and age, only fatigue explained the variability of the depression score.ConclusionIn our large cohort, high levels of depressive symptoms essentially expressed by fatigue affected 25% of children with narcolepsy. The girls older than 10 years of age were especially vulnerable. The similar prevalence of depressive feelings in treated vs never-treated patients suggests a specific need for diagnosing and managing this symptom in young patients with narcolepsy.     

The Nexus Narcolepsy Registry: methodology,study population characteristics,and patterns and predictors of narcolepsy diagnosis

Objective/backgroundThe real-world experience of people with narcolepsy is not well understood.Patients/methodsThe Nexus Narcolepsy Registry (NCT02769780) is a longitudinal, web-based patient registry of self-reported data from adults with physician-diagnosed narcolepsy. Surveys were electronically distributed every 6 months; the current analysis reports registry population demographics, narcolepsy diagnosis journey, and predictors of diagnostic delays.ResultsThe registry population included in this analysis (N = 1024) was predominantly female (85%) and White (92%), with a mean age of 37.7 years. Most participants had education/training beyond high school (93%). Mean (median) reported ages at narcolepsy symptom onset, first consultation for symptoms, and narcolepsy diagnosis were 18.1 (16), 26.4 (24), and 30.1 (28) years, respectively. A majority (59%) of participants reported ≥1 misdiagnosis, and 29% reported consulting ≥5 physicians before narcolepsy diagnosis. More than half (56%) of participants’ first consultations for narcolepsy symptoms were with a general practitioner, whereas the diagnosing clinician was usually a sleep specialist (64%) or neurologist (27%). Pediatric symptom onset was associated with a longer mean interval to first consultation than adult symptom onset (10.7 and 4.6 years, respectively; P < 0.001) and a longer mean interval between first consultation and diagnosis (4.5 and 2.2 years, respectively; P < 0.001). Overall, mean (95% CI) time from symptom onset to diagnosis was 11.8 (11.1–12.5) years.ConclusionsThe Nexus Narcolepsy Registry data indicate that onset of narcolepsy symptoms frequently occurs in childhood or adolescence. In many individuals, the diagnostic process is long and involves multiple physicians and frequent misdiagnosis.     

Parkinson's disease patients first treated at age 75 years or older: A comparative study

BackgroundParkinson's disease (PD) first diagnosed at older age reportedly has different clinical characteristics and survival rates than when it is first diagnosed at younger age. We compared these features among PD patients who initiated anti-parkinsonian drugs at age 75–85 years (elderly) with those who started treatment at age 50–74 years (younger).MethodsWe used a population-based cohort of 4449 incident cases of PD patients aged 50–85 at treatment initiation, based on a pharmacy registry of Maccabi Health Maintenance Organization, with definite/probable/possible certainty of having PD. Mean follow-up was 3.9 ± 2.6 years. The two age groups were compared for time/risk to levodopa and to death, using Kaplan–Meier curves and Cox regression. Gender-specific standardized mortality rates (SMRs) accounting for Israeli death rates were also compared.ResultsOne-half of the entire cohort (n = 2148) were elderly (>75 years) and more likely to be given levodopa (Hazard Rate (HR) = 1.48, P < 0.05), had a significantly higher frequency of comorbidities (e.g., heart disease, hypertension and cancer), and had a 3-fold increased risk to die (HR = 2.97, P < 0.05) within the same follow-up time as the youngers. Accounting for the general Israeli population death rates, female PD patients had a significantly lower risk to die compared to males especially females who were elderly at treatment initiation (SMR = 1.53 for females vs. 1.73 for males, P < 0.05).ConclusionsPD patients first diagnosed and treated at >74 years of age comprise a unique cluster for inclusion into drugs studies, mortality risk analyses and for projection of disease burden.     

Morbidity and mortality of middle-aged and elderly narcoleptics

ObjectivesThe objective of the study was to evaluate the morbidities and mortality in a national group of middle-aged and elderly narcolepsy patients before and after the first diagnosis of the condition.MethodsFrom the Danish National Patient Registry (NPR), 1174 patients (45.1% males) aged 20–59 years and 339 patients (44.8% males) aged 60+ who received a diagnosis of narcolepsy between 1998 and 2014 were compared, respectively, with 4716 and 1353 control citizens matched for age, gender and geography, who were randomly chosen from the Danish Civil Registration System Statistics. In the NPR, all morbidities are grouped into major WHO classes.ResultsMiddle-aged and elderly patients had more health contacts before and after their narcolepsy diagnosis with respect to several disease domains: infections, neoplasm, endocrine/metabolic diseases/diabetes, mental/psychiatric, neurological (including epilepsy), eye, cardiovascular (hypertension, ischemic heart disease), respiratory (upper-airway infections, sleep apnea), gastrointestinal, musculoskeletal (including discopathies) and skin diseases. Narcolepsy patients had lower reproductive rates. Furthermore, patients showed significantly more health contacts due to the evaluation and control contacts for disease and symptoms. Patients suffered from significantly more multiple diseases than did controls.The 17-year hazard ratio mortality rates were 1.35 (95% CI, 0.94–1.95, p = 0.106) among 20–59 year-olds, and 1.38 (1.12–1.69, p = 0.002) among those aged 60+ years.ConclusionThere are higher rates of morbidity in several disease domains before and after a diagnosis of narcolepsy. Elderly narcolepsy patients have higher mortality rates.     

Dopa-decarboxylase gene polymorphisms affect the motor response to l-dopa in Parkinson's disease

BackgroundIn Parkinson's disease (PD), the response to l-dopa is highly variable and unpredictable. The major pathway for dopamine synthesis from l-dopa is decarboxylation by aromatic l-amino acid decarboxylase (AAAD, encoded by the DDC gene).ObjectiveTo determine the motor response to l-dopa in PD patients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDC^T/C) and rs3837091 AGAG del (DDC^AGAG/−)).MethodsThirty-three Caucasian PD patients underwent an acute l-dopa challenge together with the peripheral AAAD inhibitor benserazide and were genotyped for rs921451 and rs3837091. The primary efficacy criterion was the motor response to l-dopa, as estimated by the area under the curve for the change in the Unified Parkinson's Disease Rating Scale part III (UPDRS) score relative to baseline (AUC_ΔUPDRS) in the 4 h following l-dopa administration. Secondary endpoints were pharmacokinetic parameters for plasma levels of l-dopa and dopamine. Investigators and patients were blinded to genotypes data throughout the study.ResultsWhen adjusted for the l-dopa dose, the AUC_ΔUPDRS was significantly lower in DDC^CC/CT patients (n = 14) than in DDC^TT patients (n = 19) and significantly lower in DDC^{−/− or AGAG/−} patients (n = 8) than in DDC^AGAG/AGAG patients (n = 25). There were no significant intergroup differences in plasma pharmacokinetic parameters for l-dopa and dopamine.DiscussionThe rs921451 and rs3837091 polymorphisms of the DDC gene promoter influence the motor response to l-dopa but do not significantly change peripheral pharmacokinetic parameters for l-dopa and dopamine. Our results suggest that DDC may be a genetic modifier of the l-dopa response in Parkinson's disease.     

Underutilization of the MSLT in sleepy patients with a short onset REM period (SOREMP) in the sleep clinic

Objective/BackgroundA nocturnal sleep onset REM period (defined as REM onset latency ≤ 15 min; SOREMP) occurs rarely and research has shown that the phenomenon is specific for type 1 and 2 narcolepsy. However, little is known about the meaningfulness of the phenotype in general sleep clinic patients because those that exhibit the phenomenon often present with few traditional narcolepsy symptoms. As such, this study aimed to (1) evaluate the rate of eventual MSLT testing for those with a SOREMP on routine PSG when the phenomenon occurred in the absence of potential explanatory factors and (2) quantify the stability of the SOREMP phenotype.Patients/MethodsThis was a retrospective analysis of a large repository of de-identified PSG and MSLT test results from 2008 to 2015. Patient records were retrieved from a repository of studies completed at a variety of sleep laboratories across the USA. A total of 118,046 baseline polysomnograms were evaluated for a PSG SOREMP (occurred in 0.7% of the sample). Patients were excluded if they indicated working either shift or night work at the time of the SOREMP or if their self-reported habitual weekday time in bed was less than 7 h. A final sample of 391 cases with a SOREMP were sequestered and previous or consecutive studies were searched for each individual.ResultsThe vast majority of patients (n = 347/391; 89%) with a PSG SOREMP never received MSLT testing. Patients that were evaluated by MSLT (n = 44; 11%) were typically very sleepy and 82% ended up with a diagnosis of narcolepsy or had MSLTs consistent with current narcolepsy criteria (ie, including the nocturnal SOREMP). Only seven of the 140 patients (n = 5%) that with OSA that first underwent one or more PAP titrations were subsequently seen for an MSLT. Compared to those that eventually received an MSLT, patients that did not receive MSLT testing were older (52 vs. 41 years, p < 0.001), more likely to have moderate to severe OSA (AHI ≥ 15; 39% vs. 16%, p < 0.001), and were generally less likely to report severe sleepiness (ESS ≥ 16; 25% vs. 55%, p < 0.001) and vehicle or workplace accidents or injuries. However, 12% of those that never received an MSLT reported such extreme sleepiness that they endorsed a near-miss car accident due to sleepiness, almost twice as prevalent than that found in a random sample of matched moderate-to-severe OSA patients (p < 0.01). Overall, the reliability of the SOREMP phenotype was low at 9.8%, but was much higher for those diagnosed with type 2 narcolepsy (31%) compared to those without narcolepsy (IH or normal MSLTs; 0%; p < 0.01) or where narcolepsy status was unknown because an MSLT was not conducted (7%; p < 0.01).ConclusionsThe MSLT has been historically underutilized for those exhibiting a SOREMP on diagnostic PSG, a potential marker of narcolepsy. This is presumably because patients with a PSG SOREMP reported variable levels of sleepiness (although some severe) and many had some degree of OSA, which may either be a partial factor in symptomology or even obscure true narcolepsy. Some patients with a PSG SOREMP were very sleepy and most, when an MSLT was conducted, received a diagnosis of type 2 narcolepsy despite few presenting with some of the associated features of narcolepsy. Well-controlled longitudinal studies with high quality data on cataplexy and hypocretin status are needed to understand where the PSG SOREMP phenomenon falls on the hypersomnolence spectrum and to establish which comorbidities share variance with and/or potentially mask narcolepsy. However because untreated narcolepsy can have high social, functional, and financial burden, until such studies are done, physicians should consider a narcolepsy workup when a SOREMP is observed (especially if multiple are seen) as well as close follow-up for symptom resolution when, for example, a patient is treated for sleep apnea.     

Validation of the geriatric sleep questionnaire

ObjectiveAssessing sleep in later life is essential for diagnosing and treating sleep problems and their consequences. We aimed to test a short questionnaire specifically designed to assess the subjective sleep quality in older people, the Geriatric Sleep Questionnaire (GSQ).MethodThe GSQ was validated in a Portuguese sample of older people (N = 443; 65–100 years; M = 80.02; SD = 6.95). We analyzed reliability, factor validity, convergent validity with other theoretical similar constructs, discriminant validity with a theoretically divergent measure, and predictive power to detect sleep problems (ROC analysis).ResultsA six-item version was obtained with good reliability (Cronbach's α = 0.79), and adequate convergent and divergent validity (p < 0.01). ROC analysis revealed a sensitivity of 80.0% and a specificity of 66.7% in detecting sleep problems with a cutoff point of 16 (AUC = 0.72). Older people in social care, low education, and living in rural areas reported worse sleep quality.ConclusionThe GSQ-6 is a brief instrument with good psychometric characteristics to assess the subjective sleep quality in older people. The GSQ-6 seems to be a valuable tool for future investigations on the relationship of sleep quality with mental health and well-being in older people.     

Sleep and libido in men with obstructive sleep apnea syndrome

ObjectivesThe objectives of this study were to investigate the relationship between a low libido and objective sleep parameters as well as mood disturbances in patients with obstructive sleep apnea syndrome (OSA).MethodsWe enrolled 436 untreated patients who were newly diagnosed with OSA (all male, mean age 42.8 years). Patients completed the Symptom checklist-90-Revised (SCL-90-R), Epworth Sleepiness Scale (ESS), Beck Depression Inventory-II (BDI), and Beck Anxiety Inventory (BAI). Patients were divided into low-libido and normal-libido groups according to their response to the statement “Loss of sexual interest or pleasure” on the SCL-90-R.ResultsApproximately 23% of patients reported a low libido. Patients with a low libido were older (47.5 ± 9.0 vs. 41.4 ± 11.1 years; p < 0.001), had more nocturia (33.3% vs. 16.6%; p < 0.001), higher BDI (9.0 (5.0–14.0) vs. 5.0 (2.0–9.0); p < 0.001) and BAI score (11.0 (6.3–16.8) vs. 5.0 (2.0–10.0); p < 0.001). These patients had a lower non-REM sleep stage 3 (N3) % (0.1 (0–4.0) vs. 2.3 (0.1–7.9); p < 0.001). Multivariate analysis revealed that older age and higher BDI score were independent factors associated with a low libido.ConclusionsMen with untreated OSA suffered from a low libido. Older age and depressed mood were the most important factors of low libido in middle-aged men with OSA.     

Fosphenytoin dosing regimen including optimal timing for the measurement of serum phenytoin concentration in pediatric patients

IntroductionWe aimed to evaluate the pediatric fosphenytoin dosing regimen, including optimal timing for the measurement of total serum phenytoin concentration (C_PHT).MethodsWe retrospectively investigated pediatric patients with status epilepticus or seizure clusters treated with fosphenytoin between April 2013 and March 2018. Two C_PHT measurements were analyzed, one 2–4 h after the loading dose and another before the second dose. Individual pharmacokinetic parameters were estimated using the Bayesian method and were used to simulate C_PHT.ResultsThe present study involved 12 pediatric patients; the loading dose of fosphenytoin was 22.1 (17.2–27.2) mg/kg. The C_PHT was 13.4 (8.6–18.9) μg/mL 2–4 h after the loading dose. The C_PHT estimated from individual pharmacokinetic parameters 12 and 24 h after the loading dose was 9.5 (6.7–14.2) and 5.8 (3.7–10.0) μg/mL, respectively. If fosphenytoin was administered at a loading dose of 22.5 mg/kg and a maintenance dose of 5 or 7.5 mg/kg (administered every 12 h, starting 12 h after the loading dose), then the C_PHT on day 8 was estimated to be 5.74 (2.6–15.4) μg/mL at 5 mg/kg and 13.9 (5.7–31.0) μg/mL at 7.5 mg/kg.ConclusionsIn pediatric patients, a maintenance dose of fosphenytoin should be started 12 h after the loading dose, and a maintenance dose of 5–7.5 mg/kg/dose every 12 h may be better than every 24 h. We recommend measuring C_PHT at 2 and 12 h after the loading dose to simplify and safely adjust the dosage in clinical practice.     

Effectiveness and tolerability of antiepileptic drugs in 104 girls with Rett syndrome

Approximately 60–80% of girls with Rett Syndrome (RTT) have epilepsy, which represents one of the most severe problems clinicians have to deal with, especially when patients are 7–12 years old.The aim of this study was to analyze the antiepileptic drugs (AEDs) prescribed in RTT, and to assess their effectiveness and tolerability in different age groups from early infancy to adulthood.We included in this study 104 girls, aged 2–42 years (mean age 13.9 years): 89 had a mutation in MECP2, 5 in CDKL5, 2 in FOXG1, and the mutational status was unknown in the remaining 8.Epilepsy was present in 82 patients (79%). Mean age at epilepsy onset was 4.1 years.We divided the girls into 5 groups according to age: < 5, 5–9, 10–14, 15–19, 20 years and older.Valproic acid (VPA) was the most prescribed single therapy in young patients (< 15 years), whereas carbamazepine (CBZ) was preferred by clinicians in older patients. The most frequently adopted AED combination in the patients younger than 10 years and older than 15 was VPA and lamotrigine (LTG).Seizures in the group aged 10–14 years were the most difficult to treat, requiring a mean of three different AEDs, often used in combination and mostly including VPA. Seizures in fifteen patients (18%) were considered drug resistant. VPA was reported as the most effective AED in younger girls (in 40% of the patients aged < 5 years, in 19% of the girls aged 5–9 years), and CBZ the most effective in the patients 15 years or older. Adverse reactions did not differ from expected: agitation, drowsiness, and weight loss were the most frequently reported. In our sample, LTG was the least tolerated AED. We did not find correlations with MECP2 mutations in terms of effectiveness or adverse reactions.Conclusion: in this study we observed different effectiveness of AEDs based on age, and suggest that clinicians consider age-dependency when prescribing appropriate AEDs in the RTT population.     

Nightmares in narcolepsy: underinvestigated symptom?

ObjectiveBesides main disease symptoms, disturbing dreams are often found in narcoleptics and may contribute to disturbed sleep. Our main goal was to study different types of oneiric activity in narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (N).MethodsWe have analyzed the medical history of 118 narcoleptics (64 men, 86 with NC, 32 with N, mean age 41.6 ± 15 years). Their most frequent dreams were divided into four groups: (A) low recall/mundane dreams, (B) vivid dreams without disturbing negative emotion, (C) nightmares, (D) reduction of nightmares, possibly by medication. Associations with other features of the disease were statistically analyzed.ResultsNightmares were found in one-third of the patients, proportionally distributed in N and NC groups; not negatively charged vivid dreams appeared more frequently in NC patients (P < 0.005). No/mundane dreams occurred with higher prevalence in men (48%) than in women (20%), (P < 0.005), without any significant influence of age. Occurrence of nightmares was significantly higher in patients with REM sleep behavior (P < 0.05), but lower in patients with obstructive sleep apnea (P < 0.005). Polysomnographic correlation of N and NC nightmare groups showed more wakefulness (P < 0.05) and higher percentage of NREM1 stage (P < 0.05) in NC patients with nightmares.ConclusionCompared with the general population, nightmares seem to be significantly more prevalent in both NC and N, and they are not sufficiently investigated and treated. The neurobiological basis of narcolepsy and patients’ dreaming activities appear to be closely related.     

Tendencia de la hospitalización por ictus isquémico en adultos jóvenes de la Región de Murcia durante el periodo 2006-2014

IntroductionRecent studies conducted in Europe and the United States suggest upward trends in both incidence and hospitalisation rates for ischaemic stroke in young adults; however, data for Spain are scarce. This study analyses the trend in hospitalisation due to ischaemic stroke in adults aged under 50 years in the region of Murcia between 2006 and 2014.MethodWe performed a retrospective study of patients discharged after hospitalisation due to cerebrovascular disease (CVD); data were obtained from the regional registry of the Minimum Basic Data Set. Standardised rates were calculated, disaggregated by age and CVD subtype. Time trends were analysed using joinpoint regression to obtain the annual calculated standardised rate and the annual percentage of change (APC).ResultsA total of 27 064 patients with CVD were discharged during the 9-year study period. Ischaemic stroke was the most frequent subtype (61.0%). In patients aged 18 to 49 years, the annual number of admissions due to ischaemic stroke increased by 26%, and rates by 29.2%; however, the joinpoint regression analysis showed no significant changes in the trend (APC = 2.74%, P≥.05). By contrast, a downward trend was identified in individuals older than 49 (APC = –1.24%, P<.05).ConclusionsNo significant changes were observed in the rate of hospitalisation due to ischaemic stroke among young adults, despite the decline observed in older adults. Identifying the causes of these disparate trends may be beneficial to the development of specific measures targeting younger adults.