Prevalence and neurophysiological correlates of sleep disordered breathing in pediatric type 1 narcolepsy

doi:10.1016/j.sleep.2019.07.004

Sleep Medicine

Volume 65, January 2020, Pages 8-12

https://doi.org/10.1016/j.sleep.2019.07.004 Get rights and content

Highlights

•
SDB correlates were assessed in childhood NT1.
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SDB in drug-naïve pediatric NT1 is rare, and mostly mild.
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SDB in pediatric NT1 is not influenced by overweight/obesity.
•
Since drugs influence SDB, PSG study is needed along course.

Abstract

Study objectives

To investigate the prevalence and neurophysiological correlates of obstructive sleep disordered breathing (OSA) in type 1 narcolepsy (NT1) children and adolescents.

Methods

Thirty-eight, drug-naïve, NT1 children and adolescents and 21 age- and sex-balanced clinical controls underwent nocturnal polysomnography (PSG) and multiple sleep latency test (MSLT). According to the rules for pediatric population, an obstructive apnea-hypopnea index (Obstructive AHI) ≥ 1 (comprising obstructive and mixed events), defined comorbid OSA.

Results

NT1 children showed higher prevalence of overweight/obesity and severe nocturnal sleep disruption (lower sleep efficiency, and increased N1 sleep stage percentage) coupled with higher motor activity (periodic limb movement index [PLMi] and REM atonia index) compared to clinical controls. Sleep-related respiratory variables did not differ between NT1 and clinical controls (OSA prevalence of 13.2% and 4.8%, respectively). NT1 children with OSA were younger and showed lower N2 sleep stage percentage and higher PLMi than NT1 children without comorbid OSA. Overweight/obesity was not associated with OSA in NT1.

Conclusions

Despite higher body mass index (BMI), OSA prevalence did not differ between children with NT1 and clinical controls. OSA in pediatric NT1 patients is a rare and mild comorbidity, further contributing to nocturnal sleep disruption without effects on daytime sleepiness.

Introduction

Type 1 Narcolepsy (NT1) is a chronic central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralyses, hypnagogic hallucinations, and disrupted nocturnal sleep [1]. Disease pathophysiology is linked to the loss of hypothalamic hypocretinergic neurons [2], most likely due to an autoimmune process [3], resulting in low/undetectable cerebrospinal fluid hypocretin-1 levels (CSF hcrt-1) [4].

Symptoms' onset very often occurs during childhood/adolescence and is frequently accompanied by a rapid weight gain resulting in overweight and obesity [5], [6], a factor possibly contributing to misdiagnosis with sleep disordered breathing (SDB) and to diagnostic delay [7]. Moreover, NT1 is associated with a wide range of comorbid conditions including endocrine, metabolic, and psychiatric disorders [8], [9].

Several studies also reported a high prevalence of SDB of both central and obstructive type (obstructive SDB, [obstructive sleep apnea OSA]) in NT1 patients, the latter possibly related to obesity [10], [11].

The presence of OSA has to be addressed in the diagnostic work-up (eg, in patients without clear-cut cataplexy and or when CSF hctr-1 assay is not available), and should be considered before prescribing pharmacological treatments such as Sodium Oxybate that could potentially exacerbate SDB [12], [13]. The few studies on OSA prevalence in NT1 were performed on adult patients, while studies specifically aimed at addressing SDB prevalence, risk factors, and polysomnographic (PSG) features in pediatric NT1 are lacking. We therefore investigated a large cohort of drug-naïve NT1 children and adolescents compared with clinical controls matched for sex and age, aiming specifically at analyzing nocturnal respiratory comorbidity.

Section snippets

Participants and evaluations

Thirty-eight consecutive, drug-naïve, children and adolescents (mean age: 11.66, range: 2–18 y) with a final diagnosis of NT1, fulfilling the current International Classification of Sleep Disorders, third edition (ICSD-3) criteria [14], were recruited at the Center for Narcolepsy of the Department of Biomedical and Neuromotor Sciences of the University of Bologna between January 2017 and December 2018.

All participants underwent our standardized diagnostic assessment encompassing at-home

Results

Demographic, clinical, neurophysiological and biochemical data of the two groups are reported in Table 1. No statistically significant differences were observed regarding sex and age. NT1 patients had higher BMI z-score (t₍₅₇₎ = 2.31, p = <0.05) with more frequent occurrence of overweight and obesity (χ² ₍₁₎ = 8.12, p = <0.05) compared to clinical controls. As expected from inclusion criteria, ESS-CHAD score, MSLT results, CFS hctr-1 levels, and HLA-DQB1*06:02 positivity differentiated NT1

Discussion

In our study, we evaluated the prevalence and neurophysiological correlates of SDB in a large cohort of drug-naïve NT1 children and adolescents versus a group of age- and sex-balanced clinical controls. Overall, OSA prevalence was comparable in NT1 children and clinical controls: only 13.2% of NT1 pediatric patients presented with an obstructive AHI above one, and none had co-morbid central SDB [14].

OSA severity in NT1 was mild, not associated with overweight/obesity or sleepiness severity, but

Acknowledgments

We are indebted to all the children and families participating in this study, most notably the Italian Association of Narcolepsy (AIN onlus) patients. Without their contributions, this study would not have been possible. We also thank Cecilia Baroncini for editing the English text.

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We aimed to clarify the accuracy of PSG/MSLT testing in diagnosing NT1 versus controls without sleep disorders. Repeatability and reliability of PSG/MSLT testing and temporal changes in clinical findings of patients with NT1 versus patients with hypersomnolence with normal hypocretin-1 were compared.
84 patients with NT1 and 100 patients with non-NT1-hypersomnolence disorders, all with congruent cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) levels, were included. Twenty-five of the 84 NT1 patients and all the hypersomnolence disorder patients underwent a follow-up evaluation consisting of clinical assessment, PSG, and a modified MSLT. An additional 68 controls with no sleep disorders were assessed at baseline.
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Polysomnographic studies have been conducted to explore nighttime sleep features in narcolepsy, but their relationship to narcolepsy is still imperfectly understood. We conducted a systematic review of the literature exploring polysomnographic differences between narcolepsy patients and healthy controls (HCs) in EMBASE, MEDLINE, All EBM databases, CINAHL, and PsycINFO. 108 studies were identified for this review, 105 of which were used for meta-analysis. Meta-analyses revealed significant reductions in sleep latency, sleep efficiency, slow wave sleep percentage, rapid eye movement sleep (REM) latency, cyclic alternating pattern rate, and increases in total sleep time, wake time after sleep onset (WASO), awakening numbers (AWN) per hour, stage shift (SS) per hour, N1 percentage, apnea hypopnea index, and periodic limb movement index in narcolepsy patients compared with HCs. Furthermore, narcolepsy type 1 patients showed more disturbed nighttime sleep compared with narcolepsy type 2 patients. Children and adolescent narcolepsy patients show increased WASO, AWN, and SS compared with adult patients. Macro- and micro-structurally, our study suggests that narcolepsy patients have poor nighttime sleep. Sex, age, body mass index, disease duration, disease type, medication status, and adaptation night are demographic, clinical and methodological factors that contribute to heterogeneity between studies.
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Narcolepsy type 1 (NT1) is a lifelong disorder of sleep-wake dysregulation defined by clinical symptoms, neurophysiological findings, and low hypocretin levels. Besides a role in sleep, hypocretins are also involved in regulation of heart rate and blood pressure. This literature review examines data on the autonomic effects of hypocretin deficiency and evidence about how narcolepsy is associated with multiple cardiovascular risk factors and comorbidities, including cardiovascular disease. An important impact in NT1 is lack of nocturnal blood pressure dipping, which has been associated with mortality in the general population. Hypertension is also prevalent in NT1. Furthermore, disrupted nighttime sleep and excessive daytime sleepiness, which are characteristic of narcolepsy, may increase cardiovascular risk. Patients with narcolepsy also often present with other comorbidities (eg, obesity, diabetes, depression, other sleep disorders) that may contribute to increased cardiovascular risk. Management of multimorbidity in patients with narcolepsy should include regular assessment of cardiovascular health (including ambulatory blood pressure monitoring), mitigation of cardiovascular risk factors (eg, cessation of smoking and other lifestyle changes, sleep hygiene, and pharmacotherapy), and prescription of a regimen of narcolepsy medications that balances symptomatic benefits with cardiovascular safety.
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Narcolepsy, a sleep disorder characterized by loss of hypocretin neurons, has been associated with metabolic disturbances. Although the metabolic alterations in narcolepsy patients are widely investigated in the literature, the results are controversial. We performed a systematic search of literature to identify metabolic profiling studies in narcolepsy patients. A total of 48 studies were included in the meta-analysis. Narcolepsy patients exhibited higher prevalence of obesity (log OR = 0.93 [0.73–1.13], P < 0.001), diabetes mellitus (log OR = 0.64 [0.34, 0.94], P < 0.001), hypertension (log OR = 0.33 [0.11, 0.55], P < 0.001), and dyslipidemia (log OR = 1.19 [0.60, 1.77], P < 0.001) compared with non-narcoleptic controls. Narcolepsy was associated with higher BMI (SMD = 0.50 [0.32–0.68], P < 0.001), waist circumference (MD = 8.61 [2.03–15.19], P = 0.01), and plasma insulin (SMD = 0.61 [0.14–1.09], P = 0.01). Levels of fasting blood glucose (SMD = $-$ 0.25 [ $-$ 0.61,0.10], P = 0.15), BMR-RMR (SMD = $-$ 0.17 [ $-$ 0.52–0.18], P = 0.34), systolic blood pressure (SMD = 0.29 [ $-$ 0.39–0.97], P = 0.40), diastolic blood pressure (SMD = 0.39 [ $-$ 0.62, 1.40], P = 0.45), CSF melanin-concentrating hormone (MD = 5.56 [ $-$ 30.79–41.91], P = 0.76), serum growth hormone (SMD = 7.84 [ $-$ 7.90–23.57], P = 0.33), as well as plasma and CSF leptin (SMD = 0.10 [ $-$ 1.32–1.51], P = 0.89 and MD = 0.01 [ $-$ 0.02–0.04], P = 0.56, respectively) did not significantly differ between narcolepsy patients and controls. These findings necessitate early screening of metabolic alterations and cardiovascular risk factors in narcolepsy patients to reduce the morbidity and mortality rates.
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^☆: Department and Institution where work was performed: Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.

¹: Authors Marco Filardi and Nurhak Demidir contributed equally.

View full text

Original ArticlePrevalence and neurophysiological correlates of sleep disordered breathing in pediatric type 1 narcolepsy☆

Highlights

Abstract

Study objectives

Methods

Results

Conclusions

Introduction

Section snippets

Participants and evaluations

Results

Discussion

Acknowledgments

Sleep Med Rev

Sleep Med

Sleep Med

Lancet Child Adolesc Health

Sleep Med

Psychiatry Res

Paediatr Respir Rev

Exp Neurol

Narcolepsy

Nat Rev Dis Primers

A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains

Nat Med

T cells in patients with narcolepsy target self-antigens of hypocretin neurons

Nature

The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias

Arch Neurol

Physical activity and sleep/wake behavior, anthropometric, and metabolic profile in pediatric narcolepsy type 1

Front Neurol

Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study

Sleep

Sleep apnea in narcolepsy

Sleep

Original Article
Prevalence and neurophysiological correlates of sleep disordered breathing in pediatric type 1 narcolepsy☆