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Volume 15 No. 01
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Accepted Papers





Scientific Investigations

Polysomnography Findings and Sleep Disorders in Children With Alternating Hemiplegia of Childhood

Sujay Kansagra, MD1; Ryan Ghusayni, MD1; Bassil Kherallah, MD1; Talha Gunduz, MD1; Melissa McLean, BS1; Lyndsey Prange, MSN, APRN, CPNP-PC1; Richard M. Kravitz, MD2; Mohamad A. Mikati, MD1
1Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina; 2Division of Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina

ABSTRACT

Study Objectives:

Patients with alternating hemiplegia of childhood (AHC) experience bouts of hemiplegia and other paroxysmal spells that resolve during sleep. Patients often have multiple comorbidities that could negatively affect sleep, yet sleep quality and sleep pathology in AHC are not well characterized. This study aimed to report sleep data from both polysomnography (PSG) and clinical evaluations in children with AHC.

Methods:

We analyzed nocturnal PSG and clinical sleep evaluation results of a cohort of 22 consecutive pediatric patients with AHC who were seen in our AHC multidisciplinary clinic and who underwent evaluations according to our comprehensive AHC clinical pathway. This pathway includes, regardless of presenting symptoms, baseline PSG and evaluation by a board-certified pediatric sleep specialist.

Results:

Out of 22 patients, 20 had at least one type of sleep problem. Six had obstructive sleep apnea as documented on polysomnogram, of whom two had no prior report of sleep-disordered breathing symptoms. Patients had abnormal mean overall apnea-hypopnea index of 5.8 (range 0–38.7) events/h and an abnormal mean arousal index of 15.0 (range 4.8–46.6) events/h. Based on sleep history, 16 patients had difficulty falling asleep, staying asleep, or both; 9 had behavioral insomnia of childhood; and 2 had delayed sleep-wake phase syndrome.

Conclusions:

Sleep dysfunction is common among children with AHC. Physicians should routinely screen for sleep pathology, with a low threshold to obtain a nocturnal PSG.

Citation:

Kansagra S, Ghusayni R, Kherallah B, Gunduz T, McLean M, Prange L, Kravitz RM, Mikati MA. Polysomnography findings and sleep disorders in children with alternating hemiplegia of childhood. J Clin Sleep Med. 2019;15(1):65–70.


BRIEF SUMMARY

Current Knowledge/Study Rationale: Alternating hemiplegia of childhood is a rare neurologic disorder with multiple comorbidities that could potentially result in sleep disorders. However, at this time, little is known about sleep pathology in this disease.

Study Impact: Understanding the risks of sleep disordered breathing and other sleep-related clinical disturbances should allow for better screening and comprehensive care of children with alternating hemiplegia of childhood.

INTRODUCTION

Alternating hemiplegia of childhood (AHC) is a rare, clinically unique neurologic disorder affecting an estimated 1 of 1 million live births.1,2 The disorder is diagnosed based on six core clinical criteria: (1) paroxysmal hemiplegia; (2) paroxysmal double hemiplegia or quadriplegia; (3) abnormal eye movements, strabismus, nystagmus, dystonia, autonomic disturbance, choreoathetosis, tonic spells, or other paroxysmal manifestations; (4) chronic neurologic dysfunction such as developmental delay, and/or persistent motor deficits; (5) sleep during a paroxysmal event aborts the symptoms; (6) the first evidence of dysfunction begins prior to 18 months of age.3 Mutations in ATP1A3 are found in most patients meeting diagnostic criteria.4

ATP1A3 codes for the alpha-3 subunit found in the α3 iso-form of the Na+/K+-ATPase enzyme, which plays a role in establishing and maintaining an electrochemical gradient across plasma membranes. Mutations in ATP1A3 have also been found in other neurologic disorders, including rapid-onset parkinsonism. The mechanism by which alteration in enzyme function leads to clinical manifestations is unclear.5

Sleep and AHC have a close link. Sleep leads to resolution of hemiplegia and paroxysmal spells. Although remission of symptoms is noted immediately after awakening, episodes can quickly recur. Although sleep plays a critical role in diagnosis and clinical symptomatology, and even though many patients with AHC report sleep problems, little is known about how often and which types of sleep pathology may exist in this disorder. There are a variety of comorbidities with AHC that could potentially predispose to sleep disorders.6 For example, hypotonia and bulbar dysfunction increase the risk of sleep-disordered breathing.7 Additionally, seizures can disrupt sleep architecture and decrease sleep efficiency.8,9 Finally, children with chronic neurological conditions are more likely to have behavioral insomnias of childhood due to maladaptive sleep practices, parental difficulties in setting limits, and caregiver stress.10 Patients with AHC have many of the aforementioned factors that predispose to sleep disorders, supporting investigation of sleep in AHC.11

As part of their care in our AHC clinic, patients underwent polysomnography (PSG) and sleep evaluations by a board-certified sleep physician regardless of the presenting symptoms. In this study, we present findings from PSG and clinical evaluations in a cohort of children with AHC.

METHODS

In this study, we investigated a cohort of 22 consecutive children with AHC who underwent a comprehensive evaluation according to our AHC clinical pathway. These patients underwent PSG and clinical sleep evaluations in our Duke AHC and Related Disorders Multidisciplinary Clinic.11 The data were entered into our prospective Institutional Review Board-approved AHC database after obtaining informed consent. For this study, children with at least one baseline PSG and one clinical visit with a sleep medicine physician performed at our center during a period of 4 years were included. The PSG monitoring included limited electroencephalogram, submental electromyogram (EMG), electro-oculogram, airflow from nasal/oral pressure transducers and nasal/oral thermocouples, end-tidal PCO2 via a capnograph sampled through a nasal cannula, arm and leg limb surface EMG, chest and abdominal movement belts, oximeter, and electrocardiogram. Somnostar software (CareFusion, San Diego, California, United States) was used for PSG data capture and analysis.

Scoring of respiratory events was based on the American Academy of Sleep Medicine scoring manual.12 An apnea on PSG was defined as cessation of airflow for a minimum of two breath lengths. Central apneas were scored when there was no respiratory effort for over 20 seconds, or if the event lasted a minimal of two breath lengths along with at least a 3% oxygen desaturation or an arousal. Obstructive apneas were scored when there was evidence of persistent respiratory effort based on chest and abdominal belts. Obstructive hypopneas were scored when there was a decrease in airflow of at least 30% based on nasal/oral pressure transducers, evidence of continued respiratory effort, with an arousal on EEG or oxygen desaturation of at least 3%. Central hypopneas were not routinely scored in our sleep laboratory. Severity of sleep apnea was based on the number of apneas and hypopneas per hour of sleep, known as the apnea-hypopnea index (AHI). Based on normative studies, many practitioners consider an AHI of 1.5 to 5 events/h as mild sleep apnea, 5 to 10 events/h as moderate, and > 10 events/h as severe sleep apnea.13 An obstructive AHI was calculated based on number of obstructive apneas and obstructive hypopneas per hour, and a central AHI was calculated based on number of central apneas per hour. The arousal index was calculated by dividing the total number of arousals by hours of sleep. One-sample t tests to compare PSG variables with population means were calculated for arousal index, combined AHI, average sleep oxygen saturation, and oxygen saturation nadir. Clinical sleep disorders were diagnosed in accordance with the International Classification of Sleep Disorders.14

During evaluation in sleep clinic, all patients were asked questions that assessed sleep routines, sleep schedules, sleep hygiene, and screened for sleep disorders such as sleep-disordered breathing, insomnia, restless leg, and parasomnias.

RESULTS

Twenty-two patients underwent PSG and completed a clinical sleep evaluation as part of their care. All patients fulfilled all six clinical criteria for the diagnosis of AHC. Twelve of the 22 patients were found to have ATP1A3 mutations, and the others were either not tested or were ATP1A3 negative. Twelve patients also had a diagnosis of epilepsy and were taking antiepileptic medications. Twenty patients were found to have hypotonia on physical examination. Patients were sent for PSG as part of routine care regardless of caregiver report of sleep-disordered breathing symptoms. The average age at the time of evaluation was 5.8 (range 1.1–16.5). Demographic data can be found in Table S1 in the supplemental material.

PSG Data

Patients had a mean overall AHI of 5.8 (range 0–38.7) events/h. Eight of the 22 patients had an AHI less than 1.5 events/h. Eight patients had an AHI between 1.5 and 5 events/h, two patients between 5 and 10 events/h, and four patients had an AHI greater than 10 events/h.

To better characterize the nature of the sleep apnea, the AHI was divided into obstructive and central AHI (Table 1). Central apneas were common, with a mean central AHI of 4.4 (range 0–32.6) events/h. Five patients had a central AHI between 1.5 and 5 events/h, three were between 5 and 10 events/h, and three had a central AHI greater than 10 events/h. Four caregivers reported no evidence of snoring or witnessed apneas when screened for sleep-disordered breathing during the clinical evaluation. All four had central AHI > 1.5 events/h. Periodic breathing was noted in 9 of 22 patients. These patients spent an average of 3.3% of the sleep study duration in periodic breathing (range 0.2% to 11.9%).

Polysomnography data for individual patients.

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Table 1

Polysomnography data for individual patients.

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The mean obstructive AHI was 1.4 events/h (range 0–6.6). Of the 22 patients, three had mild obstructive sleep apnea (OSA) with an AHI between 1.5 and 5 events/h, and three patients had moderate OSA with an AHI between 5 and 10 events/h. None had an obstructive AHI > 10 events/h. Fourteen patients had obstructive events noted, but not frequent enough to have a diagnosis of OSA. Two patients had no evidence of obstructive events.

Of the four caregivers who reported no evidence of snoring or witnessed apneas, two were found to have OSA, with an obstructive AHI of 6.1 and 6.6 events/h. Of the 18 patients who reported either snoring or witnessed apneas, 4 were found to have an obstructive AHI > 1.5 events/h. Treatment recommendations for patients with OSA included referral to an ear, nose, and throat specialist, intranasal corticosteroids, or watchful waiting.

Oximetry evaluation revealed a mean oxygen saturation of 97% while asleep (range 94% to 99%). The mean oxygen saturation nadir was 88% (range 59% to 97%). No patients were on supplemental oxygen at the time of the study. The American Academy of Sleep Medicine (AASM) defines hypoventilation as greater than 25% of the total sleep time with a PCO2 measurement over 50 mmHg.12 No patients had evidence of hypoventilation (data not shown).

Other measured sleep characteristics included mean sleep efficiency of 88% (range 65% to 99%) and mean arousal index of 15.0 events/h (range 4.8–46.6). No patients had a periodic limb movement index > 5 events/h. See Table 1 for further PSG data for individual patients.

When compared with the population means for each variable, combined AHI and arousal index were found to be significantly higher in our cohort, whereas average oxygen saturation and oxygen saturation nadir were not different from population means (Table 2).

Comparison of PSG findings in AHC versus normal population data.

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Table 2

Comparison of PSG findings in AHC versus normal population data.

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Clinical Sleep Assessments

Reports of difficulty falling or staying asleep were common (Table S2 in the supplemental material). Among the 22 patients assessed clinically, 16 reported either difficulty falling asleep, staying asleep, or both. Frequency of nighttime awakenings ranged from rare (less than once per week) to very frequent (up to 50 per night). Behavioral insomnias of childhood were common. Nine children met criteria for behavioral insomnia, with a sleep onset association subtype diagnosis in seven of nine and limit-setting subtype in two children. Five children had sleep issues that were thought to be related to poor sleep hygiene. All patients with behavioral insomnia received specific instructions on implementation of behavioral modification techniques. Sleep hygiene recommendations were also given where appropriate.

Non-rapid eye movement sleep parasomnias occurred in three patients, with two families reporting sleep-walking and one reporting confusional arousals. No night terrors or rapid eye movement sleep parasomnias were reported. Finally, two patients in our cohort had delayed sleep-wake phase syndrome. Only 2 patients of 22 had neither sleep apnea on polysomnography nor clinical concerns regarding sleep. Table 3 summarizes the types of sleep abnormalities and the percentages of occurrence for each in our patients.

Number and percentage of clinical sleep disturbances and sleep apnea.

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Table 3

Number and percentage of clinical sleep disturbances and sleep apnea.

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DISCUSSION

This study evaluated PSG and clinical sleep data obtained on 22 consecutive children with AHC. The data demonstrate that obstructive events, central apneas, and insomnia occur frequently in these children.

Our study demonstrates that children with AHC are at a relatively higher risk of sleep-disordered breathing during sleep, with nearly one-third of our patients having an overall AHI ≥ 1.5 events/h, compared to a population mean AHI of 0.2 events/h.12 The etiology is likely multifactorial. One potential factor is the presence of epilepsy in many patients. Seizures are reported in nearly half of patients with AHC.15 In our study, epilepsy was diagnosed in 12 of our 22 patients. Seizures are associated with a high risk of OSA, as nearly one-third of patients with intractable epilepsy have OSA.16 Another factor is that oropharyngeal dysfunction is a prominently affected motor domain in children with AHC.17 Weakness in facial and upper airway muscles can predispose to sleep-disordered breathing. Also, hypotonia is frequently seen in AHC, with 20 of 22 patients in our cohort with documented hypotonia. During normal sleep, there is a decrease in tone of pharyngeal muscles with an increase in upper airway resistance.18,19 Children with baseline hypotonia are, thus, at a heightened risk for airway collapse during sleep.

Central sleep apnea and periodic breathing were also common among our cohort. Sixteen of 22 patients had a higher central AHI than obstructive AHI. This is important given the increased risk of Sudden Unexpected Death in Epilepsy (SUDEP) and the risk of cardiac arrhythmias in AHC, raising the possibility that not only cardiac but also central respiratory mechanisms may contribute to the risks of SUDEP in AHC.11,2022 The etiology of periodic breathing is unclear. Of note, the mouse model of AHC used in our basic science laboratory (model D801N) also shows periodic breathing (unpublished data). Further study on this mouse model will hopefully help elucidate the relationship between ATP1A3 and respiratory regulation.

Due to the effects of sleep apnea on learning, attention, behavior, seizure control, and various other health measures, providers should be vigilant to screen for and detect sleep-disordered breathing in patients with AHC.23,24 As is evident from our data, ordering a sleep study based on history alone would have missed patients with OSA and central sleep apnea.

Difficulty falling or staying asleep was reported in 73% of our cohort. In comparison, 25% of the general pediatric population reports a problem with some aspect of sleep.25 This may be related to multiple factors. Children with AHC may be more prone to sleep disruption due to the unique role sleep plays in the disorder. Because sleep aborts hemiplegic events, children may be encouraged to sleep during daytime episodes, thereby dissipating the homeostatic sleep drive and disrupting nighttime sleep. Second, children with chronic medical conditions may be more prone to behavioral insomnias due to parental hesitancy in trying behavioral modification approaches.10 Third, seizures disrupt sleep, with excessive sleep fragmentation and rapid eye movement sleep suppression occurring following seizure activity.26 Of the 10 patients reporting both difficulty falling and staying asleep, 6 had epilepsy. Also, medications given for epilepsy and for other AHC spells may disrupt sleep. One limitation of our study is that it was not powered adequately to identify which of these factors may be more important. Another limitation is that referral bias may have directed more severely affected patients to our center who were, thus, more likely to have sleep problems. However, the range of severity of AHC symptoms observed in our patients was not outside the range that has been recognized in other studies of the clinical manifestations of AHC.15,27

The potential mechanisms for sleep disorders in AHC could also be, at least in part, related to the underlying genetic and neurophysiological abnormalities related to sodium-potassium adenosine triphosphatase (ATPase) dysfunction and not necessarily only due to the aforementioned comorbidities. Studies in mice have shown that the sodium-potassium ATPase pump is important in regulation of respiration and in prevention of apnea.28,29 Also, ATP1A3 is strongly expressed in gamma-aminobutyric acid (GABA)ergic interneurons and the suprachiasmatic nucleus and its regulation of circadian rhythms are modulated by GABAergic input.30,31 Additionally, GABAergic input contributes to modulation of brainstem respiratory centers and animal models of ATP1A3 dysfunction also manifest apnea and marked GABAergic interneuron dysfunction.30,3235 Finally, patients with ATP1A3 disease other than AHC have been reported to have apnea indicating predisposition to respiratory center dysregulation,5,11 and patients with AHC are know to have multiple behavioral problems.37 The latter can, thus contribute to behavioral insomnia.

We conclude that sleep-disordered breathing and insomnia are frequent problems in children with AHC. Nocturnal PSG and clinical sleep assessments should be strongly considered as a routine part of care for these patients.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. This study was supported by Duke University Funds and a donation from the CureAHC Foundation (salary support for M. McLean.) The authors report no conflicts of interest.

ABBREVIATIONS

AASM

American Academy of Sleep Medicine

AHC

alternating hemiplegia of childhood

AHI

apnea-hypopnea index

EMG

electromyogram

OSA

obstructive sleep apnea

PSG

polysomnography

SUDEP

sudden unexpected death in epilepsy

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