Title: Sodium oxybate resolves cataplexy in narcolepsy and lowers IL-2 receptor levels in a 12-

year-old boy: Case Report

Dr. William S Baek, MD

Parkside Medical Group

1310 San Bernardino Rd, Suite 102

Upland, CA 91786

Tel: 909 608 2008

Fax: 909 608 7705

E-mail: [email protected]

Abstract word count:

Manuscript word count:

This was a non-funded study.

The author has no financial relationships to disclose.

Introduction

Objective

Abstract

Keywords:

Case Presentation

A 12 year-old boy, accompanied by his parents, presented with excessive daytime sleepiness

(EDS) and cataplexy.

Two years ago his father noticed that he would take frequent naps, and fall asleep every time at a

baseball game. However he was unable to sleep at night.

For the past 2 months he first noticed that his legs would become heavy when excited. While

checking for pressure points with a chiropractor he lost all body tone. Then while arguing with

his father and running after him he fell flat on his face. These attacks would occur 1-2 times

every day, hence they went to a tertiary academic hospital 1 month ago. There he had a normal

EEG, video EEG, and brain/cervical spine MRIs. He was diagnosed with narcolepsy based on

his MSLT, demonstrating sleep onset REM periods during naps 2, 3 and 5. His polysomnogram

was normal with an AHI of 0.8 events/hr.

His baseline Epworth Sleepiness Scale (ESS) score was 13.

On his initial visit he was having on average ten attacks of cataplexy per day, with two already

having occurred that morning, and had to lie down on the exam table.
These were triggered by emotions, especially when laughing, and were very disabling; he was on

home bed rest. His father had to be close by at all times to prevent falls. Prior to the episodes he

would report a pulsating sensation throughout his body.

There was no family history of narcolepsy; his paternal grandfather had epilepsy.

He was 67 inches tall and weighed 135 lbs. His neurological exam revealed a teenage boy who

was awake, alert and mildly anxious. No episodes of cataplexy were observed.

His HLA type II DQB allele 1 was 0402 SPC class II DQB, and allele 2 was 0602 ABXZV.

Baseline IL-2 receptor levels were 399, and both IL-6 and TNF-alpha levels were less than 5.0.

He was started on modafinil 200mg daily and sodium oxybate(SXB, Xyrem®) 4.5 g/day as two

equally divided doses, 4 hours apart. His symptoms did not improve after being on SXB 4.5

g/day for one week, therefore his dose was increased to a total of 6 g/day, resulting in a dramatic

improvement of 2-3 attacks of cataplexy per day. He would still sleep 2-4 hours during the day,

spread out as naps and 3 hours at night, and scared to sleep at night due to vivid dreams.

Modafinil 200mg caused palpitations/anxiety hence the dose was decreased to 100mg/day, but

did not help hence was discontinued. Two months after his initial visit his SXB was increased to

a total of 7 g/day(as 3g and 4g), which resulted in complete resolution of his cataplexy without

an falling, and he was able to sleeping longer during night with less naps. His ESS score on the

7g/day dose was 11, which had significantly improved from his baseline of 13. His IL-2 receptor

levels decreased to 350(L, 406-1100, SHOULD COME DOWN AND DID), with both IL-6

levels and TNF-alpha levels being less than 5.0. His dose was further increased to a total of 7.5

g/day (3.75g/3.75g) with the goal of returning back to school. At this dose was able to sleep 5

hours at night. He also had social phobia, hence was referred to Psychiatry.
Discussion

Narcolepsy is a REM sleep hypocretin which affects worldwide.

The role of cytokines and growth hormone in the regulation of sleep and narcolepsy has been

considered, and data suggest that proinflammatory cytokines may be involved in sleep and

narcoleptic symptoms. (Okun)

Patients with narcolepsy are 2 to 3 times more likely to report a mood disorder, including anxiety

and/or depression, as seen in this case with social phobia.[25]

Cataplexy is an involuntary loss of muscle tone. Classic cataplexy attacks are abrupt, lasting

only seconds to minutes, which are triggered by laughter, anticipation, excitement, anger, and

embarrassment, affecting the knees, head, and jaw, resulting in falls(as seen in our patient), head

bobbing/head drops, and jaw slackening/changes in speech. Atypical cataplexy attacks in

children may manifest as cataplectic facies such as ptosis, jaw opening, or tongue protrusion, and

even positive motor phenomena such as grimacing and repetitive tongue protrusion.[10] Atypical

cataplexy attacks are not emotionally triggered. It is also possible for a broad range of emotional

triggers, including, to cause more classic cataplexy symptoms.

Narcolepsy in children and adolescents poses a challenge as both SXB and Modafinil are not

FDA approved in this age group but have been used off-label (Kauta, Mansukhani).

Sodium oxybate(SXB, Xyrem®)

Side effects include weight loss, sleep disordered breathing and hypoventilation, increased

anxiety, hallucinations, and delusions.

Although SXB is not indicated for use in children, this was used off-label to control both his

cataplexy, which was his most disabling symptom, and his EDS. He could not tolerate

Modafinil. Selective serotonin reuptake inhibitors(SSRIs), serotonin-norepinephrine reuptake

inhibitors(SNRIs), and TCAs all have not shown to be able to control both EDS as well as

cataplexy.

The efficacy and safety of off-label use of SXB in children and adolescents have been

investigated in retrospective studies; Mansukhani et al. reported that sleepiness had improved in

13 out of 15 patients with narcolepsy by adding 5 ± 2 g of SXB, with ESS scores decreasing

from a baseline median of 18 to 12 (n=10, p=0.01) and the number of cataplectic episodes from a

median of 38 to less than 1 per week (n=14, p<0.001). Moreover, improvement in social and

academic spheres were noted in 11 out of 15 patients. Only one patient had to discontinue due to

constipation and dissociative feelings. Mecendreux et al. studied 27 children of ages 6 to 16

years with narcolepsy with cataplexy, who had been treated with off-label SXB and documented

favorable efficacy and tolerability among the majority of the patients through a semi-structured

interview. There was a case of an adolescent girl with SXB-induced psychosis and suicide

attempt(Chien J); further studies are required to demonstrate its safety in this population.

Here we were able to achieve complete resolution of cataplexy at a dose of 7g/day

(0.11g/kg/day), which was somewhat on the higher end, with perhaps a less impressive decrease
in ESS scores from 13 to 11. He did not experience any side-effects, even tolerating the salty

taste of the medication.

Furthermore, we aimed to see if any serum biomarkers would be affected by using SXB in

cataplexy, to provide more of an objective assessment of this condition. High levels of IL-2

receptors (Lecendreux), TNFa and IL-6(Tanaka et al, Okun et al) levels have been reported to be

associated with narcolepsy; we were unable to demonstrate high levels of TNFa or IL-6 at

baseline but interestingly there was a decrease in IL-2 receptor levels after administering SXB,

suggesting a potential role as a serum biomarker for monitoring treatment.

In conclusion, we attempted to establish correlations between the patient’s cataplexy

(symptoms), ESS scores (a scale for EDS) and IL-2 receptor levels (a potential serum biomarker)

while treating a 12 year-old narcoleptic with SXB. We found that there was a decrease in ESS

scores and IL-2 receptor levels with resolution of his cataplexy as we increased his dose of SXB.

https://www.SXB.com/healthcare-professionals/SXB-clinical-trials/#trial-n3

HETEROZYGOTE for HLA-DQB*1 0602

Drug Symptoms Treated

Methylphenidate (immediate EDS

release [IR], extended release [ER])

D- or L-Amphetamine (IR, ER) EDS

Modafinil EDS

Armodafinil EDS

SXB EDS, nocturnal sleep disturbance, and cataplexy

Protriptyline, clomipramine Cataplexy

Fluoxetine, paroxetine (selective Cataplexy

serotonin reuptake

inhibitors [SSRIs])

Venlafaxine (serotonin- Cataplexy

norepinephrine reuptake inhibitor)

Lecendreux M, Libri V, Jaussent I, Mottez E, Lopez R, Lavault S, Regnault A, Arnulf I,

Dauvilliers Y. Impact of cytokine in type 1 narcolepsy: Role of pandemic H1N1 vaccination? J

Autoimmun. 2015; 60: 20-31.

Comparison for sera biomarkers between narcolepsy (n = 84, 54 males, median age: 15.5 years

old) and healthy controls (n = 41, 13 males, median age: 20 years old) revealed an increased

stimulation of the immune system with high release of several pro- and anti-inflammatory serum

cytokines and growth factors with interferon-γ, CCL11, epidermal growth factor, and

interleukin-2 receptor being independently associated with narcolepsy. Increased levels of

interferon-γ, CCL11, and interleukin-12 were found when close to narcolepsy onset. To

conclude, we highlighted the role of sera cytokine with pro-inflammatory properties and

especially interferon-γ being independently associated with narcolepsy close to disease onset.

Okun ML, Giese S, Lin L, Einen M, Mignot E, Coussons-Read ME. Exploring the cytokine and

endocrine involvement in narcolepsy. Brain Behav Immun. 2004; 18(4): 326-32.

Narcolepsy is a disabling neurological sleep disorder characterized by excessive daytime

sleepiness and abnormal REM sleep manifestations. Recently, the role of cytokines and growth

hormone in the regulation of sleep and narcolepsy has been considered, and data suggest that
proinflammatory cytokines may be involved in sleep and narcoleptic symptoms. Serum and

clinical data were obtained from the Stanford Center for Narcolepsy Research for 39

Narcoleptics (22 Females, 17 Males, age 39+/-14.9) and 40 controls (13 Females, 27 Males, age

46+/-17.9). Plasma levels of TNF-alpha, IL-6, and human growth hormone (hGH) were

measured by ELISA. TNF-alpha and IL-6 were significantly increased in narcoleptic subjects

compared to controls (p=.001). Interestingly, hGH was significantly increased in narcoleptic

subjects (p <.0001). There was also a significant difference in the epworth sleepiness scale (ESS)

(17.7+/-4.6 vs. 5.5+/-3.2, p <.0001). These data indicate that narcoleptics, relative to controls,

had higher serum levels of TNF-alpha, IL-6, and hGH. These data suggest that the dysregulation

of sleep observed in narcoleptics correlates with the immune and endocrine dysregulation seen in

these subjects, and the observed changes may in fact contribute to the higher likelihood of

disturbed sleep and/or increased incidence of infection. Additional work is required to fully

characterize connections between cytokines and narcoleptic symptomatology

Tanaka S, Honda M, Toyoda H, Kodama T. Increased plasma IL-6, IL-8, TNF-alpha, and G-CSF

in Japanese narcolepsy. Hum Immunol. 2014;75(8):940-4.

Narcolepsy is a chronic hypersomnia involving excessive daytime sleepiness and cataplexy.

Some susceptibility genes and environmental factors suggest that post-infectious immunological

alterations underlie its pathophysiology. To investigate the immunological alterations in

narcolepsy patients, we examined cytokines. Nine healthy controls and twenty-one narcolepsy

patients with cataplexy were studied. All subjects were positive for the HLA-DRB1(∗)1501-

DQB1(∗)0602 allele. Age-, sex-, and body mass index -matched healthy controls were selected.
Plasma samples were separated using EDTA-2K-coated blood collection tubes. Bioplex Pro

Human Cytokine 17-Plex Assays were used to measure plasma cytokines. Elevations of

interleukin (IL)-6, IL-8, granulocyte- colony stimulating factor (G-CSF), and tumor necrosis

factor-alpha were found in the narcolepsy group compared with healthy controls (p<0.05). G-

CSF values were significantly correlated with the disease duration in narcolepsy patients

(r=0.426, p<0.05). IL-8 and G-CSF play major roles in neutrophil activation in respiratory

diseases. Since environmental factors including infection are reportedly associated with

narcolepsy onset, elevated IL-8 and G-CSF may be involved in the pathophysiology of

narcolepsy.

http://archinte.jamanetwork.com/article.aspx?articleid=410853

EFFICACY:

Mansukhani MP, Kotagal S. SXB in the treatment of childhood narcolepsy-cataplexy: a

retrospective study. Sleep Med. 2012 Jun;13(6):606-10

Lecendreux M, Poli F, Oudiette D, Benazzouz F, Donjacour CE, Franceschini C, Finotti E, Pizza

F, Bruni O, Plazzi G. Tolerance and efficacy of SXB in childhood narcolepsy with cataplexy: a

retrospective study. Sleep. 2012 May 1;35(5):709-11.

Kauta SR, Marcus CL. Cases of pediatric narcolepsy after misdiagnoses. Pediatr Neurol.

2012;47(5):362-5.

Author information

Abstract

Narcolepsy is characterized by recurrent brief attacks of irresistible sleepiness. Signs can begin

during childhood. However, diagnoses are frequently delayed by 10-15 years because of

unfamiliarity with pediatric narcolepsy and variable presentations of its associated features

(cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis). Therefore, patients

may remain untreated during their formative years. Three children with narcolepsy who were

initially misdiagnosed are described. Each child's signs were initially related to depression,

hypothyroidism, jaw dysfunction, or conversion disorder. However, after a multiple sleep latency

test, the diagnosis of narcolepsy was established. All three patients were treated appropriately
with stimulant medications, selective serotonin reuptake inhibitors, or SXB, and demonstrated

positive responses. Although no definitive cure exists for narcolepsy, early recognition and

appropriate symptomatic treatment with medications can allow affected children to improve

quality of life and achieve normality, both academically and socially.

ABOUT ITS SAFETY:

Chien J, Ostermann G, Turkel SB. Sodium oxybate-induced psychosis and suicide attempt in an

18-year-old girl. J Child Adolesc Psychopharmacol. 2013 May;23(4):300-1.