A retrospective analysis of clinical characteristics of childhood narcolepsy

Abstract

Aim

Narcolepsy, encompassing excessive daytime sleepiness (EDS), cataplexy, sleep paralysis and hypnogogic hallucinations, was previously considered rare in childhood. Recently, cases of childhood narcolepsy have increased significantly and the reasons for this may include the increasing awareness of narcolepsy as well as the H1N1 vaccination. The aim of this study was to describe the clinical characteristics of childhood narcolepsy, specifically focusing on cataplexy subtypes that may facilitate early recognition of narcolepsy.

Methods

We retrospectively reviewed and analyzed the medical records of 33 children diagnosed with narcolepsy at the Hospital for Sick Children, in Toronto, Ontario. All patients were seen prior to 18 years of age and symptoms were self-reported by parents and/or children themselves.

Results

At presentation, 32 of 33 children reported EDS and 28 of 33 reported cataplexy. Among the 28 patients with cataplexy, 18 of 28 reported cataplexy referred to as ‘cataplectic facies’ (e.g., facial hypotonia and/or tongue protrusion) while 10 of 28 patients reported characteristic cataplexy, defined as bilateral loss of muscle tone. Children with cataplectic facies reported higher BMI z-scores compared to those with characteristic cataplexy, 1.8 and 0.8, respectively. Children with cataplectic facies also tended to be younger than those with characteristic cataplexy, 9.2 and 11.8 years of age, respectively. Cataplectic facies appear to be related to narcolepsy close to disease onset.

Conclusions

Children, especially young, obese children, presenting with a history of EDS with associated facial hypotonia or tongue protrusion raises the index of suspicion of narcolepsy and should prompt a referral to a specialized sleep facility to establish the diagnosis.

Narcolepsy is identified by excessive daytime sleepiness (EDS) and cataplexy, and associated with sleep paralysis and hypnogogic hallucinations (1). The biological cause of narcolepsy is widely thought to be the auto-immune-mediated destruction of hypocretin producing neurons (2) though the precise mechanism is not elucidated (3). Hypocretin is a neuropeptide involved in maintaining wakefulness, a decrease of which explains the tendency to fall asleep unexpectedly (4).

The onset of symptoms associated with narcolepsy peaks between 15 and 35 years of age and is usually delayed by 10 to 15 years (5,6). However, since 2009, the incidence of childhood narcolepsy has grown, especially in children younger than 10 years of age (7,8). Reasons for this increase have been widely debated, with both the adjuvanted H1N1 vaccination and viral infections implicated (9–11).

Diagnosing childhood narcolepsy with cataplexy can be difficult as children typically present with subtle symptoms and few associated features (12). Characteristic cataplexy, the loss of limb muscle tone usually following laughter, is considered a hallmark of narcolepsy yet is not always present in children. Rather, children may present with cataplectic facies, a loss of facial muscle tone resulting in facial droop, tongue protrusion, ptosis and/or head rolling (13,14). These features are specific to narcolepsy and may help in avoiding common misdiagnoses such as epilepsy, tics or myasthenia gravis (12).

Since childhood narcolepsy impacts quality of life and academic achievement, early recognition and management of this condition is vital. The aim of this study is to review a cohort of children diagnosed with narcolepsy and describe characteristics and symptom at presentations. This study is the first to compare children with cataplectic facies and children with characteristic cataplexy in a Canadian cohort and provides useful insight for real-life clinical practice.

METHODS

We retrospectively reviewed the charts of 33 patients who were diagnosed with narcolepsy at The Hospital for Sick Children in Toronto, Ontario. We included all patients who were consecutively referred to our facility for suspected narcolepsy from 2009 to 2015 and were subsequently diagnosed. Symptoms were self-reported by parents and/or children themselves. A validated paediatric version of the of the Epworth sleepiness scale (ESS) was administered to all patients and their families to assess EDS (15,16) at presentation when no patients were receiving stimulant or anticataplectic medications. A diagnosis of EDS was made for any individual who scored 10 of 24 or higher on the ESS.

All children underwent a full clinical examination. As we rarely saw childhood narcolepsy with cataplexy prior to 2009, we routinely performed additional investigations to rule out other causes of EDS including: 1) An overnight polysomnography (PSG) followed by a daytime multiple sleep latency test (MSLT) with five 20-minute nap periods, 2) A brain magnetic resonance imaging (MRI), 3) A sleep deprived electroencephalography (EEG), 4) Human leukocyte antigen (HLA) typing and 5) Blood work for total blood count, thyroid stimulating hormone and ferritin. Adherence to prescribed medications was obtained through clinical interviews.

For a diagnosis of narcolepsy, the following criteria were used (adapted from the International Classification of Sleep Disorders Version 2, which was current during data collection): 1) History consistent with narcolepsy (EDS, falling asleep unexpectedly), 2) MSLT consistent with narcolepsy; defined as two or more sleep onset REM Periods (SOREMPs) and a mean sleep latency less than 8 minutes. In situations where MSLT could not be completed, a PSG with at least one SOREMP was used, 3) Symptoms not explained by another medical disorder. Characteristic cataplexy was defined as conscious awareness of bilateral muscle weakness and possible association with emotional triggers (i.e., laughter). Cataplectic facies was defined as tongue protrusion, facial droop, facial grimacing and/or head rolling. Cataplectic events, whether through observation or self-reporting, were recorded in all medical charts at presentation. These data were collected retrospectively during chart review. Additionally, the presence of comorbidities (i.e., attention deficit hyperactivity disorder) was also made on the basis of clinical notes and dictations.

Children were subdivided into those with cataplexy and without cataplexy in relation to symptoms at presentation. The presence or absence of HLA DQB1*0601 and/or HLA DQA1*0102 was recorded for all subjects that undertook this testing.

Baseline characteristics and PSG data were reported as mean ± standard deviation (SD) and frequencies for categorical variables. Student t-tests were conducted to compare variables between cataplexy subgroups. Chi-square tests were used to compare ethnicity, gender and frequency of associated features between subgroups. Statistical analysis was performed using SAS version 9.3 (SAS statistical software, Cary NC). Statistical significance was set at P<0.05.

ETHICS

This study was approved by the research ethics board at the Hospital for Sick Children, Toronto, Canada (REB#1000033866).

RESULTS

Of the 33 children with narcolepsy, 21 of 33 (64%) were male. The mean age (±SD) at diagnosis was 10.4 (±3.4) years of age; the youngest patient was 3.9 years of age. The patient group was predominately Caucasian (58%). In this cohort, 11 of 33 (33%) patients presented with comorbidities such as attention deficit hyperactivity disorder and asthma. All patients had a normal neurological examination.

Demographic details are summarized in Table 1. In this cohort, 32 of 33 (97%) patients presented with EDS, with a mean ESS score (±SD) of 17.0 (±3.6). While one patient scored less than 10 on the ESS, she demonstrated EDS during clinical presentation. Cataplexy was also a common symptom at presentation, appearing in 28 of 33 (85%) patients. Of these patients, 18 of 28 (64%) had cataplectic facies and 10 of 28 (36%) had characteristic cataplexy. The mean age (±SD) for those presenting with cataplectic facies was 9.2 (±3.9) years of age while those presenting with characteristic cataplexy was 11.8 (±3.8) years of age (P=0.05). Patients with cataplectic facies had a higher mean BMI z-score (±SD) compared to children with characteristic cataplexy, 1.8 (±0.7) and 0.8 (±1.1), respectively (P=0.002) and increased prevalence of obesity, 14 of 18 (78%) and 4 of 10 (40%), respectively (P=0.05). Triggers for cataplexy were described in 8 of 28 (29%) patients; 20 of 28 (71%) reported that cataplexy occurred spontaneously.

Table 1.

Demographic data, PSG and MSLT in children diagnosed with narcolepsy

Variable	N=33
Age	10.4 ± 3.4
Gender, M:F	21:12
Height (cm)	142.7 ± 17.5
Weight (kg)	46.9 ± 21.9
BMI (kg/m2)	22.0 ± 5.6
BMI z-score	1.3 ± 1.2
Obese children (z-score > 1.65), number (%)	18 (55%)
Ethnicity, number (%)
Caucasian	19 (58%)
African	11 (33%)
Asian	3 (9%)
Excessive Daytime Sleepiness, number (%)	32 (97%)
Cataplexy, number (%)	28 (85%) Cataplectic Facies = 18 (64%) Characteristic cataplexy = 10 (36%)
Hypnogogic Hallucinations, number (%)	7 (21%)
Sleep Paralysis, number (%)	3 (9%)
H1N1 Vaccination, number (%)	10 (30%)
HLA subtype (n=22)	19 (86%)
DQA1*0102	19 (86%)
DQB1*0601	3 (14%)
Epworth Sleepiness Scale Score	17.0 ± 3.6
PSG, number (%)	33 (100%)
Sleep Efficiency (%)	86.5 ± 6.8
Sleep Latency (minutes)	11.1 ± 16.3
REM Latency from Sleep Onset (minutes)	56.4 ± 69.5
SOREMPs, number (%)	18 (55%)
N1 % TST	9.6 ± 6.2
N2 % TST	45.1 ± 11.1
N3 % TST	23.7 ± 8.2
REM % TST	20.6 ± 5.6
Arousal + Awakenings Index (events/hour)	17.1 ± 7.9
CAI (events/hour)	0.9 ± 0.9
OAHI (events/hour)	1.0 ± 1.7
Minimum SaO2, %	90.7 ± 3.5
PLM Index (events/hour)	5.3 ± 11.8
MSLT, number performed (%)	29 (88%)
Sleep Onset Latency (minutes)	3.8 ± 3.9
REM Latency from SO (minutes)	3.3 ± 4.2
SOREMPs	4.0 ± 1.0

Values are presented as mean ± SD unless otherwise indicated.

BMI Body mass index; CAI central apnea index; MSLT multiple sleep latency test; N1 nonrapid eye movement stage 1; N2 nonrapid eye movement stage 2; N3 nonrapid eye movement stage 3; OAHI obstructive apnea-hypopnea index; SaO ₂ oxygen saturation; PSG polysomnogram; REM rapid eye movements; SO sleep onset; SOREMP sleep onset REM period; TST total sleep time

PSG data showed that the mean sleep efficiency (±SD) was 86.5% (±6.8) while the mean sleep (±SD) and REM latencies (±SD) were 11.1 (±16.3) minutes and 56.4 (69.5) minutes, respectively (Table 1). SOREMPs on the PSG were observed in 18 of 33 (55%) patients. Significant OSA was diagnosed in one patient with narcolepsy with cataplexy which was resolved on a follow-up PSG after adenotonsillectomy. MSLT data were available in 29 of 33 (88%) patients. MSLTs were not performed in four patients due to parental concerns regarding cooperation. The MSLT data showed that the mean sleep onset latency (±SD) was 3.8 (±3.9) minutes while the mean number (±SD) of observed SOREMPs was 4.0 (±1.0).

Mean REM latency (±SD) was 1.9 (±1.5) minutes in children with cataplectic facies and 3.1 (±1.5) minutes (P=0.02) in children with characteristic cataplexy. Patients with cataplectic facies had a higher mean number (±SD) of SOREMPs compared to those with characteristic cataplexy, 4 (±0.8) and 3 (±1.1), respectively (P=0.01). Patients with cataplectic facies exhibited a mean ESS score (±SD) of 16.0 (±4.0) while patients with characteristic cataplexy exhibited a score of 18.0 (±3.0) (P=0.3) (Table 2).

Table 2.

Demographic, PSG and MSLT data of children with narcolepsy and cataplexy

Variable	Cataplectic Facies (N=18)	Characteristic Cataplexy (N=10)	P value
Gender, M:F	11:7	5:5	0.4
Age (years)	9.2 ± 3.1	11.8 ± 3.9	0.05
Height (cm)	137.3 ± 20.1	148.7 ± 13.3	0.1
Weight (kg)	47.4 ± 27.6	44.9 ± 17.2	0.9
BMI (kg/m2)	22.7 ± 6.3	20.6 ± 4.0	0.2
BMI z-score	1.8 ± 0.7	0.8 ± 1.1	0.002
Obesity prevalence, number (%)	14 (78%)	4 (40%)	0.05
Ethnicity, number (%)
Caucasian	8 (44%)	6 (60%)	0.4
African	8 (44%)	3 (30%)
Asian	2 (12%)	1 (10%)
Hypnogogic Hallucinations, number (%)	6 (33%)	1 (10%	0.5
Sleep Paralysis, number (%)	2 (11%)	1 (10%)	0.5
H1N1 Vaccination, number (%)	6 (33%)	2 (20%)	0.2
Epworth Sleepiness Scale Score	16.0 ± 4.0	18.0 ± 3.0	0.3
PSG
Sleep Efficiency (%)	86.7 ± 7.7	85.0 ± 6.5	0.7
Sleep Latency (minutes)	8.5 ± 13.6	18.0 ± 23.2	0.2
REM Latency from Sleep Onset (minutes)	50.0 ± 71.3	48.9 ± 62.3	0.9
SOREMPs	11 (61%)	5 (50%)	0.4
N1 % TST	8.9 ± 4.3	11.5 ± 9.4	0.6
N2 % TST	42.4 ± 12.0	50.3 ± 10.6	0.3
N3 % TST	23.7 ± 8.7	21.5 ± 8.6	0.7
REM % TST	22.2 ± 6.4	17.9 ± 5.9	0.05
Arousal + Awakenings Index (events/hour)	16.5 ± 5.2	16.0 ± 10.0	0.9
CAI (events/hour)	1.1 ± 0.9	0.6 ± 0.9	0.06
OAHI (events/hour)	1.1 ± 2.3	1.9 ± 4.1	0.5
Min. SaO2, Total Sleep %	90.4 ± 3.4	90.7 ± 4.6	0.9
PLM Index (events/hour)	6.3 ± 15.2	2.5 ± 3.9	0.9
MSLT, number (%)	16 (89%)	8 (80%)
Sleep Onset Latency (minutes)	3.0 ± 2.6	3.8 ± 4.9	0.7
REM Latency from SO (minutes)	1.9 ± 1.5	3.1 ± 1.5	0.02
SOREMPs	4 ± 0.8	3 ± 1.1	0.01

Values are presented as mean ± SD unless otherwise indicated.

BMI Body mass index; CAI central apnea index; MSLT multiple sleep latency test; N1 nonrapid eye movement stage 1; N2 nonrapid eye movement stage 2; N3 nonrapid eye movement stage 3; OAHI obstructive apnea-hypopnea index; SaO ₂ oxygen saturations; PLM periodic limb movements; PSG polysomnogram; REM rapid eye movements; SO sleep onset; SOREMP sleep onset REM period; TST total sleep time

Genetic testing was available for 26 of 33 (79%) patients; the remaining patients refused consent or refused phlebotomy despite consent. Of the 26 of 33 patients with HLA typing, 22 of 26 (85%) were positive for associated HLA types. Of these 22 patients, 19 of 22 (86%) expressed both HLA DQA1*0102 and HLA DQB1*0601, and the remaining 3 of 22 (14%) patients expressed HLA DQB1*0601 only. A single patient had an Arnold-Chiari malformation and abnormal EEG prior to the narcolepsy diagnosis; no new diagnoses following a brain MRI scan or EEG were made. There were no new diagnoses of anemia or hypothyroidism in this cohort. Less than one-third (30%) of this cohort reported having the H1N1 vaccination.

Following the confirmation of narcolepsy, 25 of 33 (76%) patients were prescribed medications, specifically Modafinil, Ritalin, Dexedrine, Concerta and Biphentin. These medications are targeted at improving EDS and are the first line of medications in children with narcolepsy in Canada. At follow-up, 2 of 25 (8%) of the patients with characteristic cataplexy were also prescribed Venlafaxine, an antidepressant widely used in the treatment of cataplexy. Notably, 8 of 33 (24%) patients refused medication due to concerns regarding side effects and no patient in our cohort was willing to trial sodium oxybate despite provision of literature to suggest it was beneficial against EDS and cataplexy (17). Adherence to medications was self-reported in our sample and was documented in 11 of 25 (44%) patients. All 11 patients reported an improvement in EDS. Of the two patients with characteristic cataplexy who were prescribed Venlafaxine, one reported improvement and the other patient did not adhere and continued to experience characteristic cataplexy. Scheduled naps were adhered to for 12 of 33 (36%) patients, all of whom felt this to be beneficial. Side effects were reported in 8 of 25 (32%) patients and included: palpitations, behavioural changes, loss of appetite, tinnitus, dizziness, chest pain, night terrors and weight loss.

DISCUSSION

In our cohort of children with narcolepsy, the majority of patients had EDS and cataplexy at presentation; associated features occurred less frequently. No patient presented with EDS, cataplexy and associated features (18), suggesting that symptoms of narcolepsy gradually emerge in children. Our study observed that cataplectic facies is more common than characteristic cataplexy, especially in younger children (19).

Children who presented solely with characteristic cataplexy in our cohort were older than Plazzi et al. have previously noted. Of note, cataplectic facies may evolve early and gradually disappear over time (14), giving way to characteristic cataplexy (19). Children with cataplectic facies had a shorter REM latency and increased number of SOREMPs on MSLTs as well as increased total REM sleep time on PSG, possibly related to their younger age. There were no significant differences in the frequency of the EDS and associated features between groups.

Overeem et al. reported that 92% of their patients experienced cataplexy following laughter while 58% of their patients experienced spontaneous cataplexy (20). In contrast, laughter was much less prevalent in our cohort while spontaneous cataplexy was reported by 68% of our patients. These discrepancies may stem from our exclusively paediatric cohort that largely reported cataplectic facies while Overeem et al. reported a mixed cohort that largely reported characteristic cataplexy.

As childhood narcolepsy was rare prior to 2009, we adopted a screening program, which included PSG, MSLT, HLA typing, brain MRI and EEG, in addition to blood work for CBC, thyroid function and ferritin, to rule out other underlying diagnoses. With regards to PSG findings, only one child had OSA, which was resolved. No patient exhibited an abnormal brain MRI or EEG to account for narcolepsy, thus we do not recommend that MRI or EEG be included in standard clinical care but be reserved for unusual presentations of suspected narcolepsy. An overnight PSG and MSLT are essential in confirming a diagnosis of narcolepsy and should be the routine first step in cases of suspected narcolepsy (21). In children under 8 years of age, an MSLT may be of limited use due to lack of normative data as well as an inability to try and nap, though some studies do suggest diagnostic utility (22).

Uptake of therapy was low in our cohort compared to other studies (23,24). Aran et al. report rates of 84% and 79% for modafinil and sodium oxybate, respectively in a cohort of 51 children while only 31% of our patients trialed modafinil and none were willing to trial sodium oxybate. Parents who refused sodium oxybate stated concerns with the side-effect profile and in one study, 18% of patients on sodium oxybate discontinued the treatment due to side effects (22).

The limitations of this study require consideration. Principally, the study was retrospective in design with a small number of patients and thus did not permit control over the collection of key measures in a standardized manner. We also relied on parent and/or patient reported symptoms, which may lack accuracy with regards to onset and symptoms observed. Furthermore, the patient cohort consisted entirely of referrals and is likely to represent a biased sample in which the clinical characteristics/prevalence of narcolepsy differs from a community cohort. Hypocretin testing is considered routine in the diagnosis of narcolepsy with cataplexy but this is not clinically available in our centre. Further, the lack of longitudinal follow-up does not permit us to evaluate the evolution of symptoms in these patients as well as their response to therapies over time. Finally, as only one-third of the cohort reported receiving H1N1 vaccination, we were unable to evaluate the frequency of H1N1 vaccination and childhood narcolepsy.

Narcolepsy has negative consequences for quality of life and long-term academic achievements and untreated narcolepsy has significant implications for social development as well as safety (25). There is no cure for narcolepsy but early recognition and therapeutic treatments for childhood narcolepsy have the potential to minimize the impact of narcolepsy on childhood development.

In summary, with the increase in the incidence of childhood narcolepsy, the early recognition of narcolepsy in childhood by family doctors and paediatricians is important to limit morbidity. This study suggests that narcolepsy must be considered in young, obese children presenting with EDS and associated facial hypotonia. These patients should be referred to a specialized sleep facility for consideration for a PSG and MSLT. A brain MRI and EEG in the context of the above clinical history is unlikely to have a high diagnostic yield for establishing the cause of excessive sleepiness.

Future longitudinal research should focus on the evolution and severity of symptoms of narcolepsy over time from childhood to adulthood as well as responses to treatments and side effects of these treatments. Additional qualitative research is needed to evaluate the barriers to medication adherence by the patients and their families as well as quality of life associated with childhood narcolepsy.

Funding Sources

This study received funding from wakeupnarcolepsy.org.

Financial Disclosure

Nothing to disclose.

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

SD contributed substantially as first co-author by designing the study, undertaking data collection, detailed data review and statistical analysis, undertaking data interpretation, writing and revising the manuscript, approving the final version of the manuscript and agreeing to act as guarantor of the work. SA-S contributed substantially as a first co-author by designing the study, undertaking data collection, detailed data review and statistical analysis, undertaking data interpretation, writing and revising the manuscript, approving the final version of the manuscript and agreeing to act as guarantor of the work. RA contributed substantially as a co-author by assisting in the design of the study, revising the manuscript, approving the final version of the manuscript and agreeing to act as guarantor of the work. AZ contributed substantially as a co-author by assisting in the design of the study, assisting with data collection, revising the manuscript, approving the final version of the manuscript and agreeing to act as guarantor of the work. SW contributed substantially as a co-author by reviewing patient data, revising the manuscript, approving the final version of the manuscript and agreeing to act as guarantor of the work. AT contributed substantially as a co-author by reviewing patient data, revising the manuscript, approving the final version of the manuscript and agreeing to act as guarantor of the work. BM contributed substantially as a co-author by reviewing data analysis, revising the manuscript, approving the final version of the manuscript and agreeing to act as guarantor of the work. IN contributed substantially as senior author by designing the study, providing a critical review of data interpretation, providing a critical review of the manuscript, assisting with writing the manuscript, approving the final version of the manuscript and agreeing to act as guarantor of the work.