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research-article2014

CPJXXX10.1177/0009922814526301Clinical PediatricsCom et al

Commentary

Narcolepsy With Cataplexy: Diagnostic Challenge in Children

Clinical Pediatrics 2015, Vol. 54(1) 5­–14 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922814526301 cpj.sagepub.com

Gulnur Com, MD1, Mali A. Einen2, and Supriya Jambhekar, MD1

Introduction Narcolepsy is a disabling sleep disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic and hypnopompic hallucinations, and abnormal sleep–wake patterns.1-3 Cataplexy is described as sudden and transient loss of muscle tone, often triggered by intense emotion or excitement. Hallucinations and sleep paralysis occur during sleep–wakefulness transitions and are associated with rapid eye movement (REM) sleep.1-4 Although presence of all characteristics of narcolepsy is common in adult patients, the initial presentation of narcolepsy in children maybe subtle, and concomitant cataplexy, sleep paralysis, and hallucinations may not always present. In addition, symptoms may be difficult to recognize leading to delay in the diagnosis.3 We present the case history of a child with narcolepsy and cataplexy who was challenging to diagnose in the primary care setting. Our patient’s presentation points out the difficulty in arriving at the diagnosis of narcolepsy with cataplexy due to the clinical picture that can resemble other conditions. In this article, we review the clinical presentation of narcolepsy with or without cataplexy in childhood and discuss the disease pathogenesis, diagnostic tools, and treatment.

Case Presentation A previously healthy 8-year-old boy was brought to the emergency room due to new onset seizure episodes since 3 months. The family described that attacks would occur suddenly without any warning and the patient would drop to the floor. He did not display incontinence of stool and urine, or tonic–clonic movements associated with the events. Attacks would be brief and the child would continue his usual activities after the event. He would have no recollection of events or postictal periods. Attacks became more frequent over the month prior to presentation and sometimes occurred more than once a day. The family also described involuntary tongue movements including licking and lip smacking. He also became less energetic and had mood swings. He had previously been an active child playing outside, but

recently, he preferred staying home, watching TV. He used to be an easy going child, but recently he became suddenly angry and/or irritated. He started being disrespectful to his parents and fighting with his friends. The child was in good health until 3 months ago when parents observed a sudden onset of daytime sleepiness. He started staying sleepy despite 2 to 3 naps a day. He would fall asleep in unusual circumstances including while playing with his friends or in the bathtub. School teachers noticed constant napping during classes. The parents denied problems with sleep initiation during his nighttime sleep; however, the child would wake up frequently, sometimes he would jump out of the bed, kicking and moving his arms and legs. Several times the child reported that monsters would come from the ceiling to kill him. He was previously an honors student but recently, his grades declined from As to Ds. Meanwhile, his appetite increased associated with abrupt weight gain (30 pounds) within the past 3 months; the only positive past medical history was that of a clavicle fracture during football practice 2 weeks prior to presentation. His immunization was up to date. Family medical history was noncontributory. The patient was admitted to the hospital for further evaluation. The electroencephalogram did not show any epileptiform discharges, and central nervous system (CNS) magnetic resonance imaging (MRI) was normal. Chest imaging and spirometry were normal. Comprehensive metabolic workup and thyroid function tests were normal. Anti-DNASE and antistreptolysine O titers were 268 (0-170) and >600, respectively. A sleep specialist consultation was requested and diagnostic procedures were performed: An overnight polysomnograpgy (OPSG) demonstrated decreased sleep efficiency (74%) and normal REM sleep latency. The 1

University of Arkansas Medical Sciences, Little Rock, AR, USA Stanford University Center for Narcolepsy, Redwood City, CA, USA 2

Corresponding Author: Gulnur Com, University of Arkansas for Medical Sciences, Pediatric Pulmonary and Sleep Medicine, 100 Children’s Way, Slot 512-17, Little Rock, AR 72202-3591, USA. Email: [email protected]

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Clinical Pediatrics 54(1)

Table 1.  Multiple Sleep Latency Test Results of the Case.

Sleep latency  Measured   Normal reference value, SD REM sleep latency

Nap 1

Nap 2

2 minutes 39 seconds 19.5 ± 1.5 minutes 3 minutes

2 minutes 15 seconds 19.2 ± 2.1 minutes 30 seconds

Nap 3

Nap 4

  1 minute 27 seconds 1 minute 55 seconds 18.6 ± 4.4 minutes 18.4 ± 4.1 minutes 2 minutes 2 minutes

Abbreviation: REM, rapid eye movement.

sleep architecture was abnormal including increased N1 sleep (light sleep) to 19% (N 2-5% of total sleep time) and decreased N3 sleep (deep sleep) to 8% (N 15-25%). There were numerous stage shifts and frequent awakenings, but no evidence of sleep disordered breathing. The multiple sleep latency test (MSLT), performed on the day following the OPSG, showed a mean sleep latency of 2.04 minutes with REM episodes during each nap (Table 1). Due to very abnormal MSLT associated with the clinical presentation, the child was diagnosed with narcolepsy + cataplexy. Further investigation revealed that the patient’s HLA typing was positive for DQB1*0602, and his cerebrospinal fluid (CSF) hypocretin (HCRT) level was (performed at Stanford University Narcolepsy Research Lab) 23.8 pg/mL (normal > 200), which confirmed the diagnosis.

Discussion Narcolepsy is a nonprogressive sleep disorder characterized by excessive daytime sleepiness and abnormal REM sleep manifestations including cataplexy, sleep paralysis, hypnagogic (preceding sleep) and hypnopompic (preceding waking) hallucinations, and abnormal sleep–wake patterns.1-4 In contrast to sleepiness and the other symptoms, cataplexy is a very specific symptom of the disease. The selective loss of neurons in the lateral hypothalamus that secrete a neurotransmitter called hypocretin/orexin (awakefulness-associated nurotransmitter) results in narcolepsy with cataplexy.4-6 In 1999, mutations in the HCRT receptor 2 or a selective loss of HCRT producing neurons were shown to produce narcolepsy in dogs and mice.4-6 Afterwards, mutation in the HCRT gene was described in a subject with infancy onset narcolepsy.7 However, most narcoleptics do not have mutations in the gene coding for hypocretin or its receptors. HCRT-1 can be measured in the CSF and has been found to be undetectable or low in most patients diagnosed with narcolepsy with cataplexy.1

Epidemiology/Etiology Narcolepsy is a rare disorder affecting less than 0.05% of the general population1,4 and has been reported to

occur in approximately 1 out of 2000 to 3000 European and North American adults.6 However, incidence and prevalence data for narcolepsy in children are lacking. The onset of narcolepsy with cataplexy is usually during teenage years and young adulthood and the disease persists throughout the lifetime.1-3 Several factors including genetic, environmental, and infectious have been studied in the etiology of narcolepsy.3-9 •• Genetic background: First-degree relatives are 20 to 40 times more likely to develop the disease than the general population. However, familial clustering accounts for only 10% of patients with narcolepsy, and only 25% to 31% of monozygotic twins are reported to be concordant for disease, suggesting that environmental factors are also involved in the etiology of narcolepsy.10 Narcolepsy + cataplexy/hypocretin deficiency has one of the strongest HLA associations known, and more than 99% of patients carry the HLA-DQB1*06:02 haplotype. However, most people with HLADQB1*0602 haplotype do not have and will never develop narcolepsy.1,4,10,11 A study showed that the severity of narcolepsy symptoms correlates in a linear fashion with the number of HLADQB1*0602 alleles, supporting the concept that HLA-DQB1*0602 is a disease modifying gene.12 •• Infection and autoimmune process: Multiple factors contribute to the development of autoimmune diseases including genotypic features and environmental factors. Neurologic disorders with a hypothesized autoimmune etiology such as Sydenham Chorea have been long known to be associated with streptococcal infections.6,13,15 In the late 2000s, cases of childhood narcolepsy that occurred following streptococcal infections were reported.16 Anti-streptococcal antibodies were found in 65% of narcoleptic patients within 1 year of onset of the disease in comparison to 26% of age-matched controls, supporting the involvement of streptococcal infection in the development of narcolepsy.17 Population studies have shown that the risk of narcolepsy is increased 5.4-fold (95% confidence interval = 1.5-19.1) in

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Com et al Table 2.  Diagnostic Challenges of Narcolepsy With Cataplexy in Children1,3,26.

Narcolepsy in young children is very rare and presents with atypical features Narcolepsy with cataplexy can mimic a variety of conditions in children Young children may have difficulty to express themselves Nocturnal sleep disturbances with vivid dreams and nightmares could be misdiagnosed as parasomnias Daytime sleepiness can be easily missed in preschoolers who nap regularly Excessive sleepiness maybe overlooked by parents until it starts adversely impacting mood, behavior, or academic performance Cataplexy may not be present during the initial years of the disease, can be sporadic and missed easily Cataplexy may be mistaken for seizures and, in particular, atonic/absence seizures or syncope In older children, poor attention and concentration due to sleepiness in class may lead to false diagnosis of ADHD and behavioral issues and accusations of drug use Common findings of mood swings and personality changes may result in children being treated with medications for the wrong diagnoses

subjects with a history of a physician-diagnosed streptococcal pharyngitis.14,15 Streptococcal infections can stimulate autoimmunity by crosslinking T cell receptor molecules and major histocompatibility complex molecules independently of antigen presentation.15 In a study from China, Han et al monitored the incidence of narcolepsy and found out that the occurrence of childhood narcolepsy cases was found to increase 3-fold following the winter of 2009-2010, suggesting that H1N1 infections may increase susceptibility to narcolepsy in children.18 A cluster of suddenonset narcolepsy cases following H1N1 vaccination using the pandemrix vaccine (pH1N1) have been published from European countries such as Finland, Norway, and France.19-21 In a recent study, patients with narcolepsy were administered a seasonal influenza vaccine containing pH1N1 and found to have an increased frequency of circulating HCRT reactive T cells. In addition, in vitro stimulation of narcolepsy CD4+ T cells with pH1N1 proteins increased the frequency of HCRT reactive T cells, indicating that 2009 H1N1 influenza virus can trigger autoimmunity via molecular mimicry between HCRT and a similar epitope in pH1N1.16

Diagnosis Diagnosis of narcolepsy in childhood can be challenging (see Table 2). Although cataplexy is reported in 80.5% of idiopathic narcolepsy cases,1-4 it may not be present during the initial years of the disease, and if it is present, it can be sporadic and missed easily. Clinical symptoms compatible with narcolepsy and cataplexy are the following: •• Excessive daytime sleepiness occurs despite long hours of sleep and naps and is exacerbated when the patient is physically inactive. The sleep

episodes are often irresistible, usually short (the duration can increase with passive activities such as watching television), frequently associated with dreaming, and typically restorative.1-4 Daytime sleepiness can be easily missed in preschoolers since they nap regularly and maybe overlooked by parents until it starts adversely affecting mood, behavior, and/or academic performance. •• Cataplexy is specific and is the best diagnostic marker of narcolepsy.4 It is characterized by a sudden drop of muscle tone triggered most often by positive emotions such as laughter or by anger. Catapleptic episodes can be limited to a few muscles or all striated muscles except the diaphragm can be affected resulting in a state of general atonia.3 The duration of cataplexy varies from a split second to several minutes, and the frequency varies from less than one episode per year to several episodes per day.22-24 Similar to our case, short periods of cataplexy may be mistaken for seizures and, in particular, atonic/absence seizures or syncope. The main distinguishing features include retention of consciousness during cataplectic attacks and a history of episodes triggered by sudden, usually positive emotion. A recent study in which untreated children with cataplexy were observed for 3 years showed that the clinical picture of cataplexy is that of a complex movement disorder with hypotonia and prominent facial involvement that can occur without apparent relation to emotions and it gradually evolves into the classically reported adult phenotype.25 Video analysis of cataplexy demonstrated that clinical characteristics of a cataplexy attack in children involved facial muscle weakness, dropped eyelids and facial grimaces, facial slackening, mouth opening, tongue protrusion, and a droopy look characterized as “cataplectic facies.”26

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Clinical Pediatrics 54(1) •• Associated diagnostic features of narcolepsy include sleep-related hallucinations and sleep paralysis. These symptoms may be present in about 50% of those with the disease, but can also be seen in people who do not have narcolepsy.3,4 Sleep paralysis is an inability to move the limbs or the head or to speak or breathe normally either at sleep onset or on awakening (mainly from REM sleep) despite being mentally awake. •• Narcolepsy, even in its early stages, affects personality.3,24,26 Young children may have difficulty to express themselves, and they can be misdiagnosed as having attention deficit hyperactivity disorder (ADHD)/behavioral problems, or conduct disorder. Older children and adolescents become more introverted, most with features of depression. Poor attention and concentration and disciplinary problems due to sleepiness in class may lead to false diagnosis and accusations of drug use.3 Mood swings are common, and children maybe mistakenly labeled as lazy and frequently become the target of negative comments from their peers. Some of them may be treated with medications for the wrong diagnoses.27,28 •• Over the past 2 decades, there have been anecdotal studies linking narcolepsy of childhood to obesity and becoming overweight.29 Excessive eating and obesity may reflect the hypothalamus dysfunction, although the exact mechanism is not well known. Adult studies showed that patients with narcolepsy have frequent comorbidities including periodic limb movements during sleep (PLMS), REM sleep behavioral disorder (RBD), sleep disordered breathing (SDB), and myoclonus.30,31 In children, nighttime sleep was found to be more disrupted when narcolepsy was associated with PLMS.32

Tests to Diagnose Narcolepsy ± Cataplexy •• OPSG followed by multiple sleep latency test (MSLT) are used to document the quality of nighttime sleep, daytime sleepiness, and sleeponset REM periods. OPSG is a comprehensive recording of the biophysiological changes that occur during sleep.1,4 Typical OPSG findings in narcolepsy include sleep fragmentation and disruption of sleep. Narcoleptic patients display a rapid entry into REM sleep after sleep onset. These so-called sleep-onset REM periods (SOREMs) constitute one of the major diagnostic criteria of narcolepsy. OPSG helps rule out other potential causes of daytime sleepiness such as SDB and/or PLMS. However, presence of these

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conditions does not rule out the diagnosis of narcolepsy since these conditions can coexist in narcoleptic patients.30-32 MSLT measures a tendency toward sleepiness and is performed following an OPSG.1,33 During this test, patients are offered 20-minute nap (4/5 naps, scheduled at 2 hourly intervals) opportunities to measure sleep onset latencies (the length of time that it takes to accomplish the transition from full wakefulness to sleep) and occurrence of SOREMs. Mean sleep latency test

Narcolepsy with cataplexy: diagnostic challenge in children.

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