A 19-month-old boy with decreased sleep and a distinctive electroencephalogram pattern

Citation:

Baughn J, St. Louis EK. A 19-month-old boy with decreased sleep and a distinctive electroencephalogram pattern. J Clin Sleep Med. 2021;17(7):1507–1511.

INTRODUCTION

A 19-month-old boy with developmental delay presented with an irregular sleep-wake pattern. He was put to bed with a bottle at 11 pm, awakened for variable durations through the night requiring his bottle to reinitiate sleep, and awakened for the day between 4:30 and 5:30 am. An earlier bedtime was attempted but did not result in improved sleep initiation. Daytime napping was brief and irregular, and he did not have evidence of daytime sleepiness.

He was born full term with an unremarkable birth. His parents first noticed a delay in milestones at 6 months of age. He currently requires support to sit and is unable to walk. He is babbling but does not have any words. One week before the evaluation, he had a convulsive seizure associated with fever and received abortive rectal diazepam but no additional antiepileptic medications. General and neurologic examinations were unremarkable.

Polysomnography (PSG) was performed to evaluate for obstructive sleep apnea because of a history of mouth breathing with sleep. He was also reported to be restless. A 16-lead electroencephalogram (EEG) was obtained during PSG because of his recent history of a seizure. PSG showed a total sleep time of 198.2 minutes and decreased sleep efficiency of 51.4%. There was no evidence of snoring on PSG, and the obstructive apnea-hypopnea index was normal at 0 events/h, with an oxygen nadir of 91%. Periodic limb movement index was 16.3/h. PSG and electroencephalography during wakefulness and stage N3 sleep are shown in Figure 1 and Figure 2, respectively.

Figure 1. Polysomnography with full EEG montage during wakefulness in a 19-month-old boy with developmental delay.

(A) Polysomnography shows high-voltage polymorphic delta wave activity, with runs of notched rhythmic delta (red arrows) in a generalized distribution; 30-second epoch. (B) Full longitudinal bipolar EEG montage of the same epoch shown in A; 30-second epoch. (C) Detail, full longitudinal bipolar EEG montage of the same epoch shown in A; 10-second epoch. Sensitivity, 300 μV/mm; high frequency filter = 70 Hz; low frequency filter = 0.3 Hz. EEG = electroencephalography.

Figure 2. Polysomnography with full electroencephalography montage during stage N3 sleep in a 19-month-old boy with developmental delay.

QUESTION 1: What are the EEG findings noted in Figure 1 and Figure 2?

A. Phantom spike and wave

B. Generalized atypical spike and wave

C. Occipital intermittent rhythmic delta activity

D. Notched rhythmic delta activity

E. Delta brush pattern

QUESTION 2: What genetic syndrome is consistent with this EEG finding and supported by the clinical history?

A. Angelman syndrome

B. Brugada syndrome

C. Idiopathic childhood occipital epilepsy (Gastaut type)

D. Lennox Gastaut syndrome

E. Idiopathic childhood occipital epilepsy (Paniyatopoulos type)

ANSWER 1: D. Notched rhythmic delta activity

ANSWER 2: A. Angelman syndrome

ANSWER RATIONALE

Question 1

The correct answer is notched rhythmic delta activity. Phantom spike and wave usually have a slightly faster frequency near 6 Hz, are most often seen in older children and adolescents or adults, and are rare in this age group. Generalized atypical spike and wave have a more consistent spike and wave, with admixed polyspike discharges. Occipital intermittent rhythmic delta activity is more monomorphic and organized and often indicates underlying focal deep midline or generalized cerebral dysfunction (analogous to frontal intermittent rhythmic delta activity in adults, ie, “rhythm ala distance” or “projected rhythm”). Delta brush pattern shows delta with superimposed “brush” (faster spindle like frequency waves) and is seen in premature newborn infants (ie, dysmature pattern). Notched rhythmic delta activity is a rare EEG pattern typically seen in, although not specific for, Angelman syndrome.

Question 2

The correct answer is Angelman syndrome. Brugada syndrome is characterized by syncope and cardiac bradyarrhythmia and is associated with an electrocardiogram pattern of incomplete right bundle branch block with anterior precordial ST segment elevation and underlying calcium channelopathy. Brugada syndrome may predispose to sudden cardiac death, particularly from ventricular arrhythmia during sleep, and obstructive sleep apnea comorbidity is more frequent in patients with Brugada syndrome and may be an additional mediator of autonomic instability and predisposition toward ST segment changes and arrhythmia occurrence.¹ The idiopathic childhood occipital epilepsies are self-limited syndromes characterized by nocturnal seizures with prominent vomiting and typically present later in childhood. In these disorders, preceding development is normal. Lennox Gastaut syndrome presents with multiple medically refractory generalized seizure types (astatic, nocturnal tonic, atypical absence, and generalized tonic-clonic) and features a slow (2-Hz) spike and wave pattern on EEG during wakefulness and sleep.

DISCUSSION

Angelman syndrome is a genetic disorder characterized by developmental delay, ataxia, paroxysmal laughter, seizures, intellectual and speech impairments, and sleep disturbances. Angelman syndrome is a genetic disorder affecting 1:15,000 because of loss of the maternal copy of 15q11.2–13; this genetic change then impacts the UBE3A gene that encodes an E3 ubiquitin ligase. All treatments for Angelman syndrome symptoms including sleep disturbances remain symptomatic, although future antisense oligonucleotide strategies or other targeted gene and epigenetic therapies are envisioned.

Our patient had a microdeletion in the maternal copy of 15q11.2–13 region, and his EEG showed a characteristic Angelman syndrome pattern of high amplitude rhythmic notched delta slow wave activity in both wakefulness and sleep^2–4 (Figure 1; Figure 2). A notched delta wave pattern on EEG is characteristic for Angelman syndrome, although not completely specific for that diagnosis because it may be seen in association with other similar childhood genetic pediatric epilepsy syndromes, such as Rett syndrome and 4p(-) chromosomal deletion (Wolff-Hirschorn) syndrome. Rhythmic, moderate amplitude notched delta activity is thought to represent a unique variant of the more common nonspecific EEG pattern of intermittent rhythmic delta activity, which is usually associated with either diffuse cerebral dysfunction or underlying deep midline structural pathology, with the notches caused by epileptiform spike discharges superimposed over the rising or descending phase of the slow waves.⁴ Notched delta is a rare EEG finding and was seen in only 18 of 1,656 patients (1.1%) in all the epilepsy monitoring EEG recordings at an academic pediatric epilepsy referral center over a 4-year time frame.³ If Angelman syndrome is not present, other neurodevelopmental and genetic diagnoses should be explored. Antiepileptic drug therapy was unnecessary after our patient’s brief, uncomplicated febrile seizure, given the relatively low seizure recurrence risk. He had characteristic abnormal sleep-wake patterns and diminished sleep need seen in Angelman syndrome, and his history was also consistent with behavioral insomnia of childhood, sleep-onset association type (ie, need for a bottle to initiate sleep).⁵

Difficulties initiating and maintaining sleep and shortened sleep duration are the main sleep disturbances in Angelman syndrome and are of utmost concern to caregivers of patients with Angelman syndrome.⁶ First-line interventions include behavioral therapies for insomnia, particularly addressing limit setting and sleep-onset association disorders. Pharmacotherapy should be reserved for failure of behavioral therapies. Evidence for hypnotic pharmacotherapy in Angelman syndrome is limited, with a single small randomized controlled trial of melatonin showing improvements shorter sleep latencies, fewer nocturnal awakenings, earlier sleep-onset times, and longer sleep duration.⁷ Abnormalities in melatonin profiles have been observed in Angelman syndrome,⁸ which may contribute to abnormal sleep patterns. In Angelman syndrome, sleep concerns and epilepsy may improve over time.⁹

Ruling out comorbid sleep disorders is also important. Given frequent periodic limb movements of sleep on PSG, ferritin was checked and was low normal at 31 μg/L. Oral iron therapy was initiated, targeting a goal ferritin level of 50 μg/L.¹⁰ A consistent bedtime routine, removing factors for sleep-onset association (the bottle), and melatonin 1 mg at bedtime were recommended.

SLEEP MEDICINE PEARLS

1. Angelman syndrome is a genetic disorder characterized by developmental delay, ataxia, seizures, and a diminished need for sleep.

2. Characteristic EEG findings of posteriorly dominant notched rhythmic high amplitude delta slowing and occipital spike and wave discharges can be noted during PSG in Angelman syndrome.

3. Recognition and treatment of confounding sleep disorders such as behavioral insomnia of childhood and restless legs syndrome or periodic limb movement disorder is important because treatment may improve sleep duration and/or quality of life.

4. Treatment of insomnia is challenging in Angelman syndrome; symptoms may improve over time.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. Work for this case was performed at the Mayo Center for Sleep Medicine, Departments of Pediatrics, Neurology, and Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota. The authors report no conflicts of interest.