The development of a health-related quality-of-life instrument for young people with narcolepsy: NARQoL-21.

BACKGROUND: Narcolepsy is a lifelong sleep disorder with a prevalence of between 0.03% and 0.06% and onset at around puberty. It is associated with psychiatric comorbidities and cognitive difficulties. No valid and reliable condition-specific health-related quality-of-life (HrQoL) instrument has been developed for this population. METHODS: A questionnaire based on four mixed-gender age-defined focus group discussions and a patient panel analysis was administered to young people with narcolepsy and a control group. External reliability was measured by a test-retest procedure and internal reliability was measured using Cronbach's alpha. Convergent validity with the KIDSCREEN-10 index was assessed using with intraclass correlation coefficients (ICC) and receiver operating characteristic (ROC) curves. Factor analysis techniques were used to identify suitable items and confirm the factor structure. Baseline values were assessed for convergent validity, ceiling effects, agreement and sensitivity. Comparison with KIDSCREEN-10 was made on the basis of area under the curve (AUC). RESULTS: One hundred young people with narcolepsy and 95 control subjects returned questionnaires. The factor structure revealed two main factors with five domains and 21 questions, which was confirmed with confirmatory factor analysis. The domains of the NARQoL-21 showed good independence while the floor and ceiling effects were acceptable. The external reliability (0.928), convergent validity (rs = 0.769) and internal consistency (Cronbach's alpha = 0.886) were excellent. A Bland-Altman plot revealed some proportional bias. Good discriminant validity was detected for control/patient (Cohen's d = 2.114). ROC analysis showed significantly better AUC for NARQoL-21 (0.939) than KIDSCREEN (0.877). A cut-off score equivalent to KIDSCREEN-10 for suboptimal HrQoL which maximized sensitivity (84%) and specificity (92%) was found at NARQoL-21 score below 42. CONCLUSIONS: Establishing the validity of a disease-specific HrQoL instrument in a population of people with a rare condition poses significant challenges. The mixed-methods approach adopted here has resulted in a questionnaire of 21 items with good discrimination and convergent validity, and excellent internal and external reliability, allowing precise and stable measurements. The cut-off score can be useful to identify patients with very poor HrQoL and thus improve the design of treatment options. Further testing in a longitudinal cohort is recommended in order to establish responsiveness.

Endocrine and metabolic aspects of narcolepsy type 1 in children.

STUDY OBJECTIVES: To study whether the onset of narcolepsy type 1 (NT1) in children and adolescents affects BMI, specific metabolic risk factors, the onset of puberty, longitudinal growth or other endocrine functions. METHODS: A population-based study, comprising 34 patients, was performed with a clinical evaluation, an assessment of puberty and growth, actigraphy and blood samples at fasting, from patients and controls, to evaluate pituitary function, growth factors, thyroid gland, gonads, insulin sensitivity, appetite regulation and blood lipids. RESULTS: In the post-H1N1 vaccination (PHV) narcolepsy group, the median BMI SDS was higher 6-12 months after the onset of narcolepsy (p < 0.01), but it was no different 10 years after the onset of narcolepsy (p = 0.91), compared with 12-24 months before the onset of narcolepsy. There was a correlation between an increase in BMI and a decrease in total energy expenditure (R = -0.74). In the nPHV group, weight and BMI changes were smaller and no significant changes were recorded. Early puberty was more common in patients with puberty onset after narcolepsy onset (n = 16/19) compared with patients with puberty onset before narcolepsy onset (n = 3/11, p = 0.02). There was no significant change in height SDS during the studied period. Although they were within normal ranges, both median HDL and median TSH levels were significantly lower in NT1 patients, compared with controls. CONCLUSIONS: We found a high prevalence of large BMI gain in the period immediately after the onset of narcolepsy, which had almost normalized at the long-term follow-up. The onset of narcolepsy led to early puberty in both sexes. Linear growth was not affected. We did not find any strong indicators of metabolic disturbances.

A population-based and case-controlled study of children and adolescents with narcolepsy: Health-related quality of life, adaptive behavior and parental stress.

OBJECTIVE: To investigate health-related quality of life (HrQoL) and adaptive behavior in young people with narcolepsy and stress among their parents. METHODS: In a cross-sectional exploratory quantitative study design, 37 young people with narcolepsy (8-20 years of age) and their parents were recruited. Thirty-one had post-H1N1 vaccination-related narcolepsy (PHV) and six had narcolepsy not related to PHV (nPHV). In addition, 40 age- and gender-matched controls (aged 5-20 years) were recruited. RESULTS: Thirty-one patients completed the generic HrQoL questionnaire KIDSCREEN and the disease-specific NARQoL-21. HrQoL was found to be significantly diminished in all domains in the PHV group (p = 0.001) and in the School/Concentration domain (p = 0.004) in the nPHV group compared to age- and gender-matched controls. The Adaptive Behavior Assessment System was completed by parents of 32 patients. They rated their children significantly lower in the General adaptive composite (p = 0.026) and the Conceptual (p = 0.050) and Social composite scores (p = 0.001) compared with reference data on healthy Swedish children's and young people's adaptive behavior. Parents of 36 patients filled in the 36-item short form of the Parenting Stress Index questionnaire. They rated significantly higher Total stress, Parent-child dysfunctional interaction, and Difficult child scores compared with parents of controls (p = 0.001, p = 0.005, p < 0.001). CONCLUSIONS: Children with narcolepsy have diminished HrQoL compared with controls. Parents of children with narcolepsy experience impaired adaptive behavior in their children and high levels of parenting stress. Identifying the contributory factors is necessary, and early intervention is crucial in order to improve the HrQoL of these children and their families.

Structural anomaly in the reticular formation in narcolepsy type 1, suggesting lower levels of neuromelanin.

The aim of this study was to investigate structural changes in the brain stem of adolescents with narcolepsy, a disorder characterized by excessive daytime sleepiness, fragmented night-time sleep, and cataplexy. For this purpose, we used quantitative magnetic resonance imaging to obtain R1 and R2 relaxation rates, proton density, and myelin maps in adolescents with narcolepsy (n = 14) and healthy controls (n = 14). We also acquired resting state functional magnetic resonance imaging (fMRI) for brainstem connectivity analysis. We found a significantly lower R2 in the rostral reticular formation near the superior cerebellar peduncle in narcolepsy patients, family wise error corrected p = .010. Narcolepsy patients had a mean R2 value of 1.17 s-1 whereas healthy controls had a mean R2 of 1.31 s-1, which was a large effect size with Cohen d = 4.14. We did not observe any significant differences in R1 relaxation, proton density, or myelin content. The sensitivity of R2 to metal ions in tissue and the transition metal ion chelating property of neuromelanin indicate that the R2 deviant area is one of the neuromelanin containing nuclei of the brain stem. The close proximity and its demonstrated involvement in sleep-maintenance, specifically through orexin projections from the hypothalamus regulating sleep stability, as well as the results from the connectivity analysis, suggest that the observed deviant area could be the locus coeruleus or other neuromelanin containing nuclei in the proximity of the superior cerebellar peduncle. Hypothetically, the R2 differences described in this paper could be due to lower levels of neuromelanin in this area of narcolepsy patients.

Corrigendum: Altered Brain Microstate Dynamics in Adolescents With Narcolepsy.

[This corrects the article DOI: 10.3389/fnhum.2016.00369.].

Evidence for cognitive resource imbalance in adolescents with narcolepsy.

The study investigated brain activity changes during performance of a verbal working memory task in a population of adolescents with narcolepsy. Seventeen narcolepsy patients and twenty healthy controls performed a verbal working memory task during simultaneous fMRI and EEG acquisition. All subjects also underwent MRS to measure GABA and Glutamate concentrations in the medial prefrontal cortex. Activation levels in the default mode network and left middle frontal gyrus were examined to investigate whether narcolepsy is characterized by an imbalance in cognitive resources. Significantly increased deactivation within the default mode network during task performance was observed for the narcolepsy patients for both the encoding and recognition phases of the task. No evidence for task performance deficits or reduced activation within the left middle frontal gyrus was noted for the narcolepsy patients. Correlation analyses between the spectroscopy and fMRI data indicated that deactivation of the anterior aspect of the default mode in narcolepsy patients correlated more with increased concentrations of Glutamate and decreased concentrations of GABA. In contrast, deactivation in the default mode was correlated with increased concentrations of GABA and decreased concentrations of Glutamate in controls. The results suggested that narcolepsy is not characterized by a deficit in working memory but rather an imbalance of cognitive resources in favor of monitoring and maintaining attention over actual task performance. This points towards dysregulation within the sustained attention system being the origin behind self-reported cognitive difficulties in narcolepsy.

Altered Brain Microstate Dynamics in Adolescents with Narcolepsy.

Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin-1 producing neurons in the hypothalamus. Previous neuroimaging studies have investigated brain function in narcolepsy during rest using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In addition to hypothalamic and thalamic dysfunction they showed aberrant prefrontal perfusion and glucose metabolism in narcolepsy. Given these findings in brain structure and metabolism in narcolepsy, we anticipated that changes in functional magnetic resonance imaging (fMRI) resting state network (RSN) dynamics might also be apparent in patients with narcolepsy. The objective of this study was to investigate and describe brain microstate activity in adolescents with narcolepsy and correlate these to RSNs using simultaneous fMRI and electroencephalography (EEG). Sixteen adolescents (ages 13-20) with a confirmed diagnosis of narcolepsy were recruited and compared to age-matched healthy controls. Simultaneous EEG and fMRI data were collected during 10 min of wakeful rest. EEG data were analyzed for microstates, which are discrete epochs of stable global brain states obtained from topographical EEG analysis. Functional MRI data were analyzed for RSNs. Data showed that narcolepsy patients were less likely than controls to spend time in a microstate which we found to be related to the default mode network and may suggest a disruption of this network that is disease specific. We concluded that adolescents with narcolepsy have altered resting state brain dynamics.

Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccination.

OBJECTIVES: To evaluate psychiatric comorbidity and the cognitive profile in children and adolescents with narcolepsy in western Sweden and the relationship of these problems to H1N1 vaccination. PATIENTS: Thirty-eight patients were included in the study. DESIGN: We performed a population-based, cross-sectional study to investigate psychiatric comorbidity using a test battery of semistructured interviews generating Diagnostic and Statistical Manual of Mental Disorders, 4th Edition diagnoses, including the Development and Well-Being Assessment and the attention deficit hyperactivity disorder rating scale. The Autism Spectrum Screening Questionnaire and the Positive and Negative Syndrome Scale were used to screen for autistic traits and psychotic symptoms, respectively. The cognitive assessments were made by a clinical psychologist using the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, the Wechsler Intelligence Scale for Children, Fourth Edition, or the Wechsler Adult Intelligence Scale, Fourth Edition. MEASUREMENTS AND RESULTS: In the post-H1N1 vaccination (PHV) narcolepsy group (n = 31), 43% of patients had psychiatric comorbidity, 29% had attention deficit hyperactivity disorder (ADHD) inattentive type, 20% had major depression, 10% had general anxiety disorder, 7% had oppositional defiant disorder (ODD), 3% had pervasive developmental disorder not otherwise specified (i.e., atypical autism), and 3% had eating disorder not otherwise specified (anorectic type). In the non-post-H1N1 vaccination (nPHV) narcolepsy group, one of seven patients had ADHD, inattentive type and ODD. The most frequent psychiatric symptom was temper tantrums, which occurred in 94% of the patients in the PHV group and 71% of the patients in the nPHV narcolepsy group. The cognitive assessment profile was similar in both groups and showed normal results for mean full-scale IQ and perceptual speed but decreased verbal comprehension and working memory. Patients with psychiatric comorbidity had a significantly lower full-scale IQ compared to those without. CONCLUSION: Our study indicates increased psychiatric comorbidity in children and adolescents with narcolepsy. The identified cognitive profile with significantly lower verbal comprehension and working memory compared with the normal mean index could have important implications for social relations and schooling. The small numbers of patients with nPHV narcolepsy make it difficult to draw firm conclusions about the possible differences between the two groups of patients.

Hemorrhagic stomatitis in a natural hybrid of Vipera ammodytes × Vipera berus due to inappropriate substrate in terrarium.

A natural hybrid of Vipera ammodytes × Vipera berus was presented having low body weight, seizures and generalized swelling of the cephalic region. Based on the history of the case and clinical examination, hemorrhagic stomatitis of traumatic origin was diagnosed. The snake was kept in a terrarium with wood chips as a substrate, and the material had induced trauma in the oral mucosa which was further complicated with Salmonella Arizonae and Morganella morganii co-infection, abscessation and osteomyelitis. To the best of the authors' knowledge, this is the first reported case of bacterial infection in European snake hybrids and one of a few case reports in European snakes. Although wood chips are an inexpensive substrate, based on our findings, they should be avoided when keeping and breeding European vipers.

Functional magnetic resonance imaging in narcolepsy and the kleine-levin syndrome.

This work aims at reviewing the present state of the art when it comes to understanding the pathophysiology of narcolepsy and the Kleine-Levin syndrome (KLS) from a neuroimaging point of view. This work also aims at discussing future perspectives of functional neuroimaging in these sleep disorders. We focus on functional magnetic resonance imaging (fMRI), which is a technique for in vivo measurements of brain activation in neuronal circuitries under healthy and pathological conditions. fMRI has significantly increased the knowledge on the affected neuronal circuitries in narcolepsy and the Kleine-Levin syndrome. It has been shown that narcolepsy is accompanied with disturbances of the emotional and the closely related reward systems. In the Kleine Levin syndrome, fMRI has identified hyperactivation of the thalamus as a potential biomarker that could be used in the diagnostic procedure. The fMRI findings in both narcolepsy and the Kleine-Levin syndrome are in line with previous structural and functional imaging studies. We conclude that fMRI in combination with multi-modal imaging can reveal important details about the pathophysiology in narcolepsy and the Kleine-Levin syndrome. In the future, fMRI possibly gives opportunities for diagnostic support and prediction of treatment response in individual patients.

Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination.

OBJECTIVES: To assess the incidence of narcolepsy between January 2000 and December 2010 in children in western Sweden and its relationship to the Pandemrix vaccination, and to compare the clinical and laboratory features of these children. METHODS: The children were identified from all local and regional pediatric hospitals, child rehabilitation centers, outpatient pediatric clinics, and regional departments of neurophysiology. Data collection was performed with the aid of a standardized data collection form, from medical records and telephone interviews with patients and parents. The laboratory and investigational data were carefully scrutinized. RESULTS: We identified 37 children with narcolepsy. Nine of them had onset of symptoms before the H1N1 vaccination and 28 had onset of symptoms in relationship to the vaccination. The median age at onset was 10 years. All patients in the postvaccination group were positive for human leukocyte antigen (HLA)-DQB1*0602. Nineteen patients in the postvaccination group, compared with one in the prevaccination group, had a clinical onset that could be dated within 12 weeks. CONCLUSION: Pandemrix vaccination is a precipitating factor for narcolepsy, especially in combination with HLA-DQB1*0602. The incidence of narcolepsy was 25 times higher after the vaccination compared with the time period before. The children in the postvaccination group had a lower age at onset and a more sudden onset than that generally seen.