pISSN 2093-9175 / eISSN 2233-8853

REVIEW ARTICLE
https://doi.org/10.17241/smr.2017.00052

Autoimmunity and Immunotherapy in Narcolepsy

Min Jae Seong, MD1, Seung Bong Hong, MD, PhD2
1
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute,
Samsung Advanced Institute for Health Sciences & Technology, Seoul, Korea

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucination, and sleep paraly-
sis. Narcolepsy is caused by damage of hypocretin producing neurons in the lateral hypothalamus. The association of narcolepsy with
HLA DQB1*0602 and high incidence following H1N1 pandemic in china, vaccination with pandemrix and an adjuvanted H1N1 vaccine
suggests that pathophysiology of narcolepsy is involved in the immune system. This review focused on immunological associations and
immunotherapy in narcolepsy. Sleep Med Res 2017;8(1):1-7

Key WordsaaNarcolepsy, Autoimmune, Immunoglobulin.

INTRODUCTION

Narcolepsy is a sleep disorder that affects approximately 0.02 percent to 0.05 percent of popu-
lations worldwide.1,2 Narcolepsy usually begins with abrupt excessive daytime sleepiness (EDS).
Approximately 95 percent of cases of narcolepsy are sporadic, and occur in familial environ-
ments. Therefore, it has been suggested that susceptibility to environment is involved.3 Age of
onset was varied from early childhood to age 50 by bi-modal distribution, with the main peak
at age 15 and the secondary peak at age 36.4 The incidence is rare in patients older than 50. The
reason for the delay in diagnosis is that many clinicians do not know much about narcolepsy.
Narcolepsy is often mistaken for depression or psychiatric illness. Symptoms are usually diag-
nosed 5–15 years after onset of symptoms, or after serious issues in daily life occur.5
Narcolepsy is characterized by decreased cerebrospinal fluid (CSF) hypocretin concentration
associated with arousal, wakefulness and sleep regulation.6,7 Narcolepsy patients exhibit EDS,
cataplexy (decreased muscle tone triggered by emotions) and abnormal transition to rapid eye
movement (REM) sleep.8 Symptomatic fluctuations may appear in the clinical course and in
general, EDS is the initial symptom and cataplexy occurs slowly over several months after onset
and persists for life.9 Cataplexy may disappear spontaneously in some patients and it is pre-
Received: June 20, 2017 sumed the patient adapts to his or her illness and avoids situations in which cataplexy can occur.
Accepted: June 22, 2017 Hypnagogic hallucinations or sleep paralysis are mostly transient.10-12 In many patients with
Correspondence narcolepsy, sleepiness is severe, resulting in difficulty focusing and staying awake at school, work
Seung Bong Hong, MD, PhD
Department of Neurology, and during periods of inactivity.13 Quality of life studies suggest the impact of narcolepsy is
Samsung Medical Center, equal to Parkinson’s disease.14
Sungkyunkwan University
School of Medicine, Samsung Biomedical Hypocretin is synthesized in the lateral hypothalamus and is derived from a protein precursor
Research Institute, called prepro-hypocretin. Prepro-hypocretin is enzymatically cleaved into two peptides, divided
Samsung Advanced Institute
for Health Sciences & Technology, into hypocretin 1 and 2, and consists of 33 and 28 amino acids, respectively. There are two coned
81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea hypocretin receptors, HCRTR1 and HCRTR2, that are serpentine G-protein-coupled receptors.15
Tel +82-2-3410-3599
Fax +82-2-3410-0052 Hypocretin producing neuron is active during wakefulness and stimulates cortex, basal fore-
E-mail sbhong@skku.edu brain, brain stem and hypothalamus producing norepinephrine, serotonin, dopamine, and his-

Copyright © 2017 The Korean Society of Sleep Medicine 1

Immunotherapy in Narcolepsy

tamine.16-18 Hypocretin has a long-lasting effect on the target arthritis and type 1 diabetes.29-32
neuron, that helps to maintain daytime wakefulness, suppres- HLA DQB1*0602 is found in 90 percent of patients with nar-
sion of REM sleep, and therefore paralysis or dream-like hallu- colepsy, and presence of this gene is known to increase the risk of
cination, that is a REM sleep characteristic manifested during the narcolepsy by 200 times.25,33 The pathogenic mechanism of
day when it is deficient. The association between hypocretin and DQB1*06:02 in narcolepsy is the destruction of hypocretin-pro-
narcolepsy has been validated by the reduction of hypocretin ducing neurons by interaction between specific TCR subtypes.
peptide in CSF and hypothalamus in narcolepsy patients.7,9,19 The autoimmune basis of narcolepsy, that was initiated by its
Decreased hypocretin in CSF suggests that more than 90 per- association with HLA, has also revealed other mechanisms
cent of hypocretin producing neurons are lost, and this process through research.
has begun at narcolepsy onset.20 Hypocretin-producing cell dam- Second, there is a polymorphism of TCR alpha locus.34-36 TCR
age is selective and the melanin-concentrating neuron is not im- is expressed on the T cell surface and plays a key role in recog-
paired in narcolepsy patients. Specific deletion is a basis for the nizing antigen by binding to HLA molecules on the surface of
autoimmune process.19,21 antigen presenting cells (APCs).37 Among them, alpha locus J re-
Diagnosis can be made in definite clinical history but is limit- gion segment plays a crucial immunological role, and certain
ed, and polysomnography (PSG) and multiple sleep latency test mutations of J region increase risk of developing narcolepsy.35
(MSLT) are essential. PSG is needed to differentiate other sleep The third mechanism is bystander activation of autoreactive
disorders such as obstructive sleep apnea syndrome that exhibit T cells. During viral infection, cytotoxic T cells are polyclonally
EDS, and MSLT is necessary to identify abnormal REM sleep stimulated. The cytokines secreted from antigen-responsive cells
transition during daytime naps. Narcolepsy was strongly suspect- around the infected site directly stimulate surrounding T cells.31
ed when MSLT revealed positive findings without other sleep In this pro-inflammatory micro-environment, normal T cells, not
disorders found in overnight PSG. pathogen-specific T cells, are stimulated and therefore damage
Main treatment strategy of narcolepsy is a symptomatic treat- hypocretin cells.38
ment. EDS is controled by wakefulness-promoting drugs such as The fourth mechanism is molecular mimicry, that is charac-
modafinil or methylphenidate and these medications are associ- terized by structural similarity of pathogen and antigenic deter-
ated with neurotransmitters of dopamine, serotonin and norepi- minants of the host.37 This mechanism may occur at the cross reac-
nephrine.22,23 Cataplexy is prevented by antidepressants (venla- tive by helper T cells and MHC II/TCR synapse level.39 Activation
faxine, floxetine, clomipramine and etc.) that inhibit re-uptake of the cross-reactive TH1 of the microbial epitope and auto-antigen
of norepinephrine and serotonin. In addition, sodium oxybate releases cytokines and chemokines and recruit activated mono-
(sodium salt of gamma-hydroxybutyrate) that activates gamma- cytes and macrophages, leading to self-tissue damage. Subse-
aminobutyric acid type B receptor, is also used, but it is not known quently, autoimmune disease persists from uptake by self-tissue
how this activation modulates sleepiness and cataplexy.24 antigen and APC. At MHC/TCR synapse level, this is caused by
However, these treatments are focused on the control of nar- structural similarities between infectious agents (e.g., H1N1 and/
colepsy symptoms. Many researchers are conducting ongoing or Streptococcus pyogenes) and hypocretin neuron autoantigen.
researches into treatment focusing on hypocretin depletion and MHC class II binding groove selects peptide fragments with spe-
hypocretin-producing neuron destruction. cific amino acids in the context of DQ1A*01:02–DQB1*06:02.
Therefore, in this paper, we reviewed the autoimmune patho- The TCR recognizes the presented peptide with specific amino
physiology of narcolepsy and immunotherapy. acid sequence and activates CD4 + T cells. However, the struc-
ture binding to MHC class II binding groove is similar to pep-
tide fragments from infectious agents and hypocretin cell auto-
The immune system and antigens, therefore the host binds and cross-reacts with CD4 +
narcolepsy T cells instead of infectious agents, resulting in autoimmune re-
sponse to hypocretin neurons.19,40
Researchers have focused on the significance of the potential Clinical cases that support this are large-scale narcolepsy out-
role of the immune system in narcolepsy onset for many years.25-27 breaks after influenza infection or H1N1 influenza vaccination
A study of the relationship between the immune system and in China and Northern Europe. In China, after the pandemic
narcolepsy began with the discovery of strong association be- H1N1 influenza in 2009, diagnosis of narcolepsy tripled but has
tween human leukocyte antigen (HLA) and narcolepsy. HLA since declined. Most patients were not vaccinated, and natural
encodes various subtypes of major histocompatibility complex occurring influenza. An infection is associated with occurrence of
(MHC) class I and II proteins, and MHC triggers immune re- narcolepsy.41 Therefore, onset of symptoms of narcolepsy usually
sponse by T cell receptor (TCR) activation through presenting begins in late spring and is presumed to occur in spring through
foreign peptide to T cells during infection.28 HLA is associated bacterial (Streptococcus pyogenes) or viral infection during win-
with autoimmune diseases such as Graves’ disease, rheumatoid ter.41 The titer of antibody to antistreptolysin O is high immedi-

2 Sleep Med Res 2017;8(1):1-7

 Seong MJ and Hong SB

ately after narcolepsy onset, that is the basis for the streptococ- Norepinephrine and serotonin are related neurotransmitters for
cal infection to trigger the disease.42 REM sleep suppression. Tricyclic antidepressants (TCA) include
In addition to influenza infection, vaccination also induces imipramine and clomipramine, and selective serotonin-reuptake
molecular mimicry. After the H1N1 vaccination of pandemic, inhibitors include venlafaxine and fluoxetine, that are more effec-
AS03 (squalene, alpha-tocopherol) in Europe in 2009, narcolepsy tive than TCA, acting more selectively on the serotonergic trans-
occurred in considerable numbers of children and young adults porter than TCA.
in Finland.43 Finnish studies reported that narcolepsy diagnoses Sodium oxybate has a mechanism to activate GABAB recep-
in children and young adults with DQB1*06:02 for eight months tors and is effective in treating cataplexy and EDS.24
after vaccination were 12.7-fold higher when compared to those These treatments have focused on each symptom control, and
not vaccinated. In Sweden, Finland, Ireland, and the U.K., the many studies have been conducted in recent advanced treatment
incidence has increased in most cases between the age 5 and 19, focusing on autoimmunity that causes hypocretin production,
that is seen as a genetically susceptible person.43,44 neuron damaging or reduction of hypocretin.
Other HLA-DQ alleles, HLA-DP and HLA class I also affect Hypocretin replacement/supplement treatment is theoretical-
genetic susceptibility. Gene polymorphisms such as TCRA, ly a viable method and various approaches have been studied.
TCRB, P2RY11, EIF3G, ZNF365, IL10RB-IFNAR1, cathepsin H The method of administering hypocretin-1 that is more stable
and TNFSF4 that influence immune function, are associated with than hypocretin-2 to blood and CSF has an issue in that it is dif-
autoimmunity of narcolepsy.28 ficult to pass the blood-brain barrier. Another method of admin-
However, evidence of autoimmunity is related to cellular im- istering hypocretin to the brain is intranasal administration.50
munity, and humoral immunity is lesser known. Hypocretin However, this is an animal-based experiment and human-based
specific antibodies have been studied, but only negative or in- studies will be needed.
conclusive results have been reported.27 Recent studies have re- In addition, gene therapy/cell transplantation has been stud-
ported increased total IgG and hypocretin-specific IgM in narco- ied. Gene therapy via hypocretin genes overexpressing was effec-
lepsy patients, but this finding was not specific in narcolepsy tive in mice.51 To transplant hypocretin-producing cells, trans-
patients with low hypocretin levels.45,46 planting of hypothalamus of a neo-natal rat into brainstem of an
In summary, the association of HLA DQB1*06:02, TCR al- adult rat was conducted. However, the issue of graft survival, like
pha locus polymorphism, Streptococcus pyogenes, or influenza A Parkinson’s disease, must be solved.3
or H1N1 vaccination is a unique autoimmune feature of narco- Immunomodulation treatment based on autoimmunity has
lepsy.28 also been studied. Steroid, immunoglobulin and plasmapheresis
have been studied and immunoglobulin and plasmapheresis are
effective.52-57
Narcolepsy treatment option Studies on steroid therapy have been conducted on a dog and
based on autoimmunity human. In dogs, frequency of cataplexy was reduced to 90 per-
cent according to research, but some research reported that it
Narcolepsy is treated with a combination of behavioral and was not effective. In the human study, an eight-year-old child
pharmacologic approaches.47,48 Non-pharmacological treatment was treated with prednisone, but it was ineffective.58-60
is cost efficient with no adverse effects. Non-pharmacological Plasmapheresis was administered in one patient and EDS and
treatment is cirtical considering pharmacological treatment is cataplexy improved, but recurred several weeks later. Symptoms
more effective if combined with non-pharmacological treat- improved after the second plasmapheresis and were successfully
ment. Behavioral treatment for EDS is to improve quality of sleep treated with sodium oxybate.52
at night and take a nap for 15–20 minutes in the afternoon, that The mechanism of autoimmune neurologic disorder of intra-
reduces EDS.49 venous immunoglobulin has the following effects on auto-anti-
The goal of conventional treatment is to reduce EDS and cata- bodies, 1) inhibition of complement binding and prevention of
plexy. Treatment of EDS maintains alertness through central ner- membranolytic attack complex formation, 2) modulation or
vous system stimulants such as dextroamphetamine, methylphe- blockade of Fc receptors on macrophages, 3) suppression of
nidate that act as a mechanism of dopamine re-uptake inhibition pathogenic cytokines and other immunoregulatory molecules.61
and release and modafinil that is a selective dopamine re-uptake The effect of antibiotics is that IgG molecules in IVIg, that ex-
blocker. In the case of mild to moderate daytime sleepiness, hibit wide-range idiotypic and anti-idiotypic specificities, neu-
modafinil is a viable choice. Side effects and abuse are less. Meth- tralize pathogenic auto-antibodies and prevent auto-antigen inter-
ylphenidate, dextroamphetamine, and amphetamine analogues action. These mechanisms are targeted at pathogenesis associated
are more potent than modafinil and side effects are more com- with cellular and humoral immunity. In narcolepsy, a high dose
mon. of IVIg during the disease onset phase down-regulates T cell
Cataplexy can improve through REM sleep suppression. function, pathogenic cytokine and unidentified auto-antibody

www.sleepmedres.org 3
4
Table 1. Summary of all current narcolepsy cases treated by 1 g/kg/day for two days protocol
Patient Age/gender Disease duration Baseline 1st 2nd 3rd 4th 5th Comments
Our case
Pt 1 13/F 3 mo ESS: 11/24 ESS: 11/24 ESS: 2/24 ESS: 3/24 ESS: 4/24 ESS: 4/24
Cataplexy: > 10/d Cataplexy: > 10/d Cataplexy: > 10/d Cataplexy: 10/d Cataplexy: 3–4/d Cataplexy: 2–3/d
Intravenous immunoglobulin treatment and screening for hypocretin neuron-specific in recent onset childhood narcolepsy with cataplexy
Pt 1 12/M 5.5 mo ESS: 9/24 ESS: 4/24 ESS: 9/24 ESS: 8/24 ESS: 8/24 ESS: 8/24 Clinical improvement
Cataplexy: 3.5/d Cataplexy: 3.5/d Cataplexy: 3.5/d Cataplexy: 3.5/d Cataplexy: 1.5/d Cataplexy: 1.5/d in 4th administration
Immunotherapy in Narcolepsy

Pt 2 10/F 3.5 mo ESS: 21/24 ESS: 10–16/24 ESS: 4–12/24 ESS: 4–12/24 ESS: 4–12/24 ESS: 4–12/24 Clinical improvement

Sleep Med Res 2017;8(1):1-7

Cataplexy: 2/d Cataplexy: few attacks/w Cataplexy: 2/d Cataplexy: 2/d Cataplexy: 2/d Cataplexy: 2/d was not shown after
4th administration
Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset
Pt 1 10/M 4 mo ESS: 18/24 ESS: 8.7 ± 5.2 ESS: 5.7 ± 4.4 ESS: 10.2 ± 3.3 Not performed Not performed
Cataplexy: 1/d Cataplexy: < 3/m Cataplexy: < 3/m Cataplexy: < 3/m
Pt 2 21/M 2 mo ESS: 13/24 ESS: 9.8 ± 1.9 ESS: 8.7 ± 1.1 ESS: 8.7 ± 1.6 Not performed Not performed
Cataplexy: 2–3/d Cataplexy: < 5/m Cataplexy: < 5/m Cataplexy: < 5/m
Pt 3 12/F 8 mo ESS: 21/24 ESS: 14.3 ± 2.1 ESS: 7.2 ± 2.3 ESS: 7.1 ± 2.6 Not performed Not performed
Cataplexy: 2/d Cataplexy: 2/d Cataplexy: 2/w Cataplexy: < 1/m
Pt 4 45/M 9 yr ESS: 23/24 ESS: 18.07 ± 4.3 ESS: 10.4 ± 2.9 ESS: 14.6 ± 1.7 Not performed Not performed
Cataplexy: 1–2/m Cataplexy: rare Cataplexy: rare Cataplexy: rare
Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy
Pt 1 10/M 2 mo ESS: not performed ESS: not performed Not performed Not performed Not performed Not performed
Cataplexy: 1/d (subjective EDS was
improved)
Cataplexy: 2/m
Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment
Pt 1 28/F 15 d ESS: 22 ESS/cataplexy was not ESS/cataplexy ESS/cataplexy Not performed Not performed
Cataplexy: > 1/d recorded in paper was not recorded was not recorded
The patient reported in paper in paper
a clear effect on both The patient The patient
frequency and severity reported reported a clear
of cataplexy and a clear effect on effect on both
a moderate effect on both frequency frequency and
sleepiness and severity of severity of
cataplexy and cataplexy and
a moderate effect a moderate effect
on sleepiness on sleepiness
No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy
Pt 1 43/F Unknown ESS: 19 ESS: 19 ESS: 15–19 ESS: 17 ESS: 17
Cataplexy: 2/d Cataplexy: 1/d Cataplexy: 1/d Cataplexy: 2/d Cataplexy: 2/d (f/u)
Pt 2 41/M Unknown ESS: 22 ESS: 12 ESS: 14 ESS: 14 ESS:16
Cataplexy: 3.5/d Cataplexy: 1/d Cataplexy: 0.5/d Cataplexy: 0.5/d Cataplexy: 3.5/d (f/
u)
Pt 3 52/F Unknown ESS: 17 ESS: 17 ESS: 18 ESS: 18 ESS: 18
Cataplexy: 5/d Cataplexy: 6/d Cataplexy: 5/d Cataplexy: 6/d Cataplexy: 5/d (f/u)
ESS: epworth sleepiness, EDS: excessive daytime sleepiness.
 Seong MJ and Hong SB

and interferes with auto-antigen recognition.54,61 went MSLT and MWT improved the outcome. There was no
Immunoglobulin is the most common immunomodulation correlation between clinical parameters and sleep parameters
study in narcolepsy treatment, but it is inadequate compared to in evaluation of treatment efficacy and this was known in past
immunoglobulin therapy for other diseases. This may be due to reports.57,63
the low prevalence of narcolepsy and high cost of immunoglob- The efficacy of IVIg treatment is related to disease duration
ulin. and onset age.54,55,57 Shorter disease duration and younger age
Knudsen et al.55 reported a case of successful treatment of pa- make for better efficacy but there is no definite criterion for dis-
tients with recent onset childhood narcolepsy and cataplexy ease duration and onset age, and depending on literature, effects
with IVIg and a table summarizing cases treated with IVIg for of treatment, timing and age, on effectiveness are inconsistent. Ef-
narcolepsy was presented. Knudsen was treated with 1 g/kg/day fect of treatment time on efficacy is based on the hypothesis that
for two days and five times at monthly intervals. However, the the shorter the disease duration, the lower the destruction of
dose, duration, frequency, and additional medication of IVIg hypocretin-producing neurons by autoimmune. There is no evi-
were variable for each patient in the table. Although IVIg is pre- dence for normalization of hypocretin after IVIg treatment, but
sumed to be effective, IVIg was not effective in some cases which in patients with narcolepsy, CSF hypocretin level is generally
is the reason for the lack of consensus in the protocol of IVIg low, suggesting that more than 90 percent of hypocretin-produc-
treatment in narcolepsy. ing neurons are damaged.7,40,64,65 Patients with hypocretin levels
Therefore, a systemic review of IVIg dose, treatment dura- in complete deficiency state did not have a positive effect with
tion, and resposnes in narcolepsy patients is needed. IVIg treatment, and hypocretin levels in early-treatment pa-
In 17 patients, the dose and treatment duration of IVIg were tients were higher than those in later course patients.55,56 There-
decided as 1 g/kg/day for two days53-56,62 or 0.4 g/kg/day for five fore, if hypocretin neuron is not completely destructive at time of
days.57,62 According to previous reports, a total of 11 patients treatment, the autoimmune process is reversible with IVIg treat-
were treated with IVIg 1 g/kg/day for two days protocol (Table ment.
1). The disease duration of the patients at the time of IVIg ad- Serious side effects were not specifically reported in the pre-
ministration ranged from 15 days to 9 years. There were six males vious case. Commonly known side effects of IVIg include
and five females. Ages ranged from 10–52 years old. Each patient thromboembolic events, migraine, aseptic meningitis, urticari-
received IVIg 1, 3 or 5 times. One patient received IVIg one al, pruritus, anaphylactic reaction, and renal tubular necrosis,
time, and then took oral prednisolone for six weeks in addition but side effects reported in the case were infrequent flushes
to IVIg administration. A total of eight patients received IVIg and headaches.
three times, and one of them was treated with prednisolone too.
Two patients received only prednisolone therapy five times.
One out of 11 patients was 52 years old and disease duration Conclusion
was not mentioned. IVIg was administered three times, but clin-
ical improvement was not revealed. Ten patients had temporary The association of narcolepsy with HLA, TCR polymorphism,
or sustained improvement in symptoms (10/11, 90.9 percent). In and large-scale development after influenza support autoim-
symptomatic improvement, according to the number of admin- mune. TCR polymorphism and vaccination are unique autoim-
istration, eight patients improved after the first administration, mune features of narcolepsy. Narcolepsy caused by this mecha-
one patient had improved symptoms after the second adminis- nism triggers severe daily disability due to EDS and cataplexy.
tration, no patient improved in the third administration and one However, most treatments administered in many clinics remain
patient improved in the fourth administration. Six patients had as symptomatic treatment rather than treatment by approach of
sustained clinical improvement during follow up periods (6/10, pathophysiology. Use of long-term stimulants also have side ef-
60 percent) and there were five patients with disease duration fects.
within six months and one patient was nine years (12/m, 10/m, Therefore, treatment based on underlying disease pathology
21/m, 12/f, 45/m, 10/m). Four of the six patients improved and therefore a deeper understanding of the pathophysiology of
symptoms after the first administration (4/6, 66.6 percent) and narcolepsy is needed. Until now, cellular immunity had been
each patient had improved symptoms after the second and fourth clarified, but humoral immunity and antibody are unknown,
administrations. Follow-up test for MSLT or maintenance of therefore research is also needed on these subjects.
wakefulness test (MWT) was conducted in nine patients. Three Although there are a limited number of cases treated by IVIg in
patients underwent MSLT, two patients underwent MWT and narcolepsy, there have been reports of apparent clinical improve-
five patients underwent MSLT and MWT. In patients that per- ment in IVIg treatment. Guidelines and/or protocols including
formed only MSLT, one patient revealed improvement (1/3, 33 indication, dose and treatment duration should be established by
percent). Two patients that underwent MWT revealed im- research in fundamental treatment based on autoimmunity.
provement of MWT findings. None of the patients that under-

www.sleepmedres.org 5
Immunotherapy in Narcolepsy

Acknowledgments lepsy with cataplexy. Sleep 2013;36:147-8.

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