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SLEEP (M THORPY AND M BILLIARD, SECTION EDITORS)
Narcolepsy Associated with Pandemrix Vaccine
Tomi Sarkanen
1,2
&Anniina Alakuijala
2,3
&Ilkka Julkunen
4
&Markku Partinen
2,5
#Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Purpose of Review After the connection between AS03-adjuvanted pandemic H1N1 vaccine Pandemrix and narcolepsy was
recognized in2010, research on narcolepsy has been more intensive than ever before. The purpose of this review is to provide the
reader with current concepts and recent findings on the Pandemrix-associated narcolepsy.
Recent Findings After the Pandemrix vaccination campaign in 2009–2010, the risk of narcolepsy was increased 5- to 14-fold in
children and adolescents and 2- to 7-fold in adults. According to observational studies, the risk of narcolepsy was elevated for
2 years after the Pandemrix vaccination. Some confounding factors and potential diagnostic biases may influence the observed
narcolepsyrisk in some studies, but it is unlikely that they would explain the clearly increased incidence in all the countries where
Pandemrix was used. An increased risk of narcolepsy after natural H1N1 infection was reported from China, where pandemic
influenza vaccination was not used. There is more and more evidence that narcolepsy is an autoimmune disease. All Pandemrix-
associated narcolepsy cases have been positive for HLA class II DQB1*06:02 and novel predisposing genetic factors directly
linking to the immune system have been identified. Even though recent studies have identified autoantibodies against multiple
neuronal structures and other host proteins and peptides, no specific autoantigens that would explain the disease mechanism in
narcolepsy have been identified thus far.
Summary There was a marked increase in the incidence of narcolepsy after Pandemrix vaccination, especially in adolescents,but
also in young adults and younger children. All vaccine-related cases were of narcolepsy type 1 characterized by hypocretin
deficiency in the central nervous system. The disease phenotype and the severity of symptoms varied considerably in children
and adolescents suffering from Pandemrix-associated narcolepsy, but they were indistinguishable from the symptoms of idio-
pathic narcolepsy. Narcolepsy type 1 is most likely an autoimmune disease, but the mechanisms have remained elusive.
Keywords Narcolepsy .H1N1 vaccination .Va c c i n es .Pandemrix .Hypocretin .Orexin
Introduction
Narcolepsy is a chronic hypersomnia syndrome characterized
by excessive daytime sleepiness, disturbed sleep pattern, and
REM sleep parasomnias such as hypnagogic hallucinations
and sleep paralyzes. In the most recent (3rd version)
International Classification of Sleep Disorders (ICSD-3), the
disease is divided into two different subcategories, narcolepsy
type 1 and type 2 (Table 1)[1]. Narcolepsy type 1 (NT1) is
likely an immune-mediated disease caused by the destruction
of hypocretin-producing neurons in the lateral hypothalamus
resulting in hypocretin deficiency in the central nervous
This article is part of the Topical Collection on Sleep
*Markku Partinen
markpart@me.com; markku.partinen@helsinki.fi
Tomi Sarkanen
tsarkane@gmail.com
Anniina Alakuijala
anniina.alakuijala@hus.fi
Ilkka Julkunen
ilkka.julkunen@utu.fi
1
Department of Neurology, Tampere University Hospital,
Tampere, Finland
2
Department of Clinical Neurosciences, University of Helsinki,
Helsinki, Finland
3
HUS Medical Imaging Center, Department of Clinical
Neurophysiology, Helsinki University Central Hospital,
Helsinki, Finland
4
Institute of Biomedicine, University of Turku, Turku, Finland
5
Helsinki Sleep Clinic, Vitalmed Research Center, Helsinki, Finland
Current Neurology and Neuroscience Reports (2018) 18:43
https://doi.org/10.1007/s11910-018-0851-5
system (CNS). Over 98% of the NT1 patients have a predis-
posing genetic background, positivity for HLA DQB1*06:02
allele. Cataplexy, sudden loss of muscle tone triggered by
emotions, is a common symptom in these patients. In narco-
lepsy type 2 (NT2), hypocretin levels are normal and cata-
plexy is absent. The etiology of NT2 is presently not known.
Narcolepsy is a rare disease. A remarkable increase in the
incidence of NT1 was seen after the H1N1 vaccination cam-
paign in the countries where the Pandemrix vaccine was used
[2••,3]. Pandemrix-related narcolepsy with a clearly recog-
nized environmental trigger increased global research activi-
ties on the pathophysiological mechanism of narcolepsy but
crucial observations explaining the underlying disease mech-
anisms have so far not been identified.
Epidemiology—How Big Was the Risk
of Pandemrix-Related Narcolepsy?
The most recent pandemic, called “swine flu,”was caused by
a new reassortant H1N1-type influenza A virus, which ap-
peared first in Mexico and the USA in March 2009. The num-
ber of laboratory-confirmed cases increased rapidly and the
new pandemic virus spread to many other countries via people
traveling. By June 2009, the WHO had already declared that a
new pandemic had started. The previous H1N1 pandemic in
1918–1919 (“Spanish flu”) was a devastating disease with a
high mortality rate resulting in 50 to even 100 million deaths
worldwide. In 2009, an early observational study from
Mexico indicated that ca. 6.5% of 900 hospitalized H1N1
infection patients were critically ill and, of those, 41% died
[4]. The mortality seemed to be high especially in children,
young adults, and pregnant women, in contrast to the seasonal
influenza epidemics. Therefore, initially, the first influenza
pandemic of the twenty-first century appeared to be very se-
vere and there was a substantial need for the rapid develop-
ment of an efficient pandemic vaccine.
Eight different pandemic vaccines were used in Europe,
with a coverage of at least 46 million people. Five of these
vaccines had no adjuvant, while two vaccines included MF59
as an adjuvant and one vaccine, namely Pandemrix, had AS03
as an adjuvant. Adjuvants increase the immunogenicity of
antigens, thus allowing the use of lower amounts of immuno-
gens in vaccines for efficient induction of protective immuni-
ty. Pandemrix was the most widely used vaccine in Europe
with more than 30.5 million administered doses [5]. Another
AS03-adjuvanted vaccine, Arepanrix, was used particularly in
Canada. Globally, over 90 million doses of AS03-adjuvanted
H1N1 vaccines were given in different countries [6]. In the
USA, over 90 million doses of pandemic H1N1 vaccines were
administered in 2009–2010, but they were all non-adjuvant
vaccines.
The first signals of the increased number of narcolepsy
cases after H1N1 vaccination campaigns came from Finland,
Sweden, and France [7••,8,9]. Increased incidence of narco-
lepsy was later found in Norway, the UK, Ireland, and
Germany. The vaccination coverage with Pandemrix was high
in all of these countries [10–13]. The risk was first noted in
children and adolescents, and later also in young adults
[13–16]. The time period for increased risk is still unclear.
Finnish and Swedish epidemiological (observational) studies
have reported that the time window of an increased risk ex-
tends to 2 years after the vaccination with Pandemrix [15,17].
The reported relative risk of narcolepsy during the first year
after the vaccination varied from 2 to 25 in children and
Table 1 Diagnostic criteria of types 1 and 2 narcolepsy (ICSD-3) [1]
NARCOLEPSY TYPE 1
Criteria A and B must be met
A. The patient has daily periods of irrepressible need to sleep or daytime
lapses into sleep occurring for at least three months.
1
B. The presence of one or both of the following:
1. Cataplexy (as defined under Essential Features) and ameansleep
latency of ≤8 minutes and two or more sleep onset REM periods
(SOREMPs) on an MSLT performed according to standard techniques.
A SOREMP (within 15 minutes of sleep onset) on the preceding
nocturnal polysomnogram may replace one of the SOREMPs on the
MSLT.
2
2. CSF hypocretin-1 concentration, measured by immunoreactivity, is
either ≤110 pg/mL or <1/3 of mean values obtained in normal subjects
with the same standardized assay.
NARCOLEPSY TYPE 2
Criteria A-E must be met
A. The patient has daily periods of irrepressible need to sleep or daytime
lapses into sleep occurring for at least three months.
B. A mean sleep latency of ≤8 minutes and two or more sleep onset
REM periods (SOREMPs) are found on a MSLT performed according
to standard techniques. A SOREMP (within 15 minutes of sleep onset)
on the preceding nocturnal polysomnogram may replace one of the
SOREMPs on the MSLT.
C. Cataplexy is absent.
3
D. Either CSF hypocretin-1 concentration has not been measured or
CSF hypocretin-1 concentration measured by immunoreactivity is
either >110 pg/mL or > 1/3 of mean values obtained in normal subjects
with the same standardized assay.
4
E. The hypersomnolence and/or MSLT findings are not better explained
by other causes, such as insufficient sleep, obstructive sleep apnea,
delayed sleep phase disorder, or the effect of medication or substances
or their withdrawal.
ICSD-3 International Classification of Sleep Disorders, 3rd edition
1
In young children, narcolepsy may sometimes present as excessively
long night sleep or as resumption of previously discontinued daytime
napping
2
If narcolepsy type I is strongly suspected clinically but the MSLT criteria
of B1 are not met, a possible strategy is to repeat the MSLT
3
If cataplexy develops later, then the disorder should be reclassified as
narcolepsy type 1
4
If the CSF Hcrt-1 concentration is tested at a later stage and found to be
either ≤110 pg/mL or < 1/3 of mean values obtained in normal subjects
with the same assay, then the disorder should be reclassified as narcolepsy
type 1
43 Page 2 of 10 Curr Neurol Neurosci Rep (2018) 18:43
adolescents, and 2 to 9 in adults. In a recent meta-analysis, we
found a 5- to 14-fold increased risk of Pandemrix-related nar-
colepsy in children and adolescents, and a 2- to 7-fold in-
creased risk in adults [2••].
The magnitude of observed risk is partly dependent on the
analytical methods and the criteria concerning how the narco-
lepsy cases were identified. For example, in the Swedish reg-
istry study, where there was no case ascertainment and no
medical record review [15], the risk was lower than in a pre-
vious cohort study [8]. Nonetheless, this study also demon-
strated an increase in the incidence of narcolepsy in young
adults during the second post-vaccination year. It is worth
noting that the 2-year risk window is based on epidemiologi-
cal data. The biologic risk window is not known. In the first
series of patients with Pandemrix-related narcolepsy, the me-
dian delay fromtime of vaccination to onset of narcolepsy was
42 days (0 to 242 days) [18••]. However, it is important to note
that a maximal biologic length of a temporal relationship be-
tween the onset of narcolepsy and a specific immunological
trigger, such as a viral infection or a vaccination, has not been
defined.
Controversies in Epidemiological Studies—Is
the Association True?
The main limitation in the observational studies is that they are
unable to prove a direct causal link between the trigger(s) and
the disease. They are also prone to various biases such as
ascertainment and recall bias and other confounding factors.
It has been speculated that a natural H1N1 influenza infection
per se would have been an important confounding factor con-
tributing to an increased incidence of narcolepsy [19–21]. A
3-fold increased risk was reported in Beijing and Shanghai
areas, where pandemic H1N1 vaccines were not used, during
the post-pandemic period [22•,23,24]. These findings sug-
gest a temporal association between the H1N1 epidemic peak
and a peak in new narcolepsy cases 3 to 6 months after the
influenza epidemic. However, these results have not been rep-
licated in the neighboring countries or in any other popula-
tions [2••,25]. The vaccination campaign and H1N1 influenza
epidemic occurred almost simultaneously, and, for example,
in Norway and Finland, less than 10% of the population had
been vaccinated prior to the peak of the pandemic [26].
Another study proposed that more than 50% of the vaccinated
individuals in Norway could already have been infected with
the H1N1 virus prior to vaccinations [27]. Conversely, practi-
cally, no serological evidence of natural 2009 pandemic H1N1
virus infection was found in Finnish narcolepsy patients [28].
The manufacturer of Pandemrix, GlaxoSmithKline, has criti-
cized the latter study for its low specificity and the long inter-
val between the vaccination or infection and collection of the
serum samples [29].
Diagnostic bias may be involved if vaccinated subjects
were more likely to be diagnosed as narcolepsy cases than
unvaccinated subjects. There is a possibility that primary
health care practitioners referred vaccinated subjects to special
sleep clinics more often than unvaccinated children/adoles-
cents. However, this seems unlikely, since narcolepsy, wheth-
er associated with vaccine or not, is usually an incapacitating
disease clearly affecting the quality of life. The unequivocal
diagnostic criteria also reduce the risk of diagnostic ascertain-
ment bias.
There is also a possibility for recall bias. This could be
caused by a memory bias of the correct onset time of narco-
lepsy symptoms and their relation to the vaccination time.
Memory bias could happen involuntarily but also knowingly
after the increased media and public awareness of the connec-
tion between H1N1 vaccination and narcolepsy in the hope of
a monetary reimbursement. However, many observational
studies used the first health care contact as an index date and
the results were similar between different study groups and
countries. Proven association of Pandemrix vaccination and
narcolepsy in the countries where media attention and aware-
ness of the association were lower (England, France, Ireland,
and Germany) also makes the recall bias more unlikely. Some
controversies and unsolved issues are summarized in Table 2.
Pathophysiology—What Is Narcolepsy
and Why Did H1N1 Vaccination Trigger It?
The hallmark of NT1 is hypocretin deficiency. Hypocretin, also
called orexin, is a neuropeptide independently discovered by
two separate research groups, hence the two different names
[33,34]. Soon after these findings, the lack of a functional
hypocretin system as an etiological factor in narcolepsy in
humans was recognized in immunohistochemical studies [35].
All Pandemrix-related, verified, and true narcolepsy cases
have been of NT1. Although some people may have devel-
oped excessive daytime sleepiness along with a NT2 pheno-
type without hypocretin loss after Pandemrix vaccination, the
correlation is currently considered only coincidental.
Biological plausibility between immunological triggers such
as vaccination and NT2 is lacking.
The pathophysiological events leading to the destruction of
hypothalamic hypocretin-producing cells in NT1 are presently
unclear. It has been speculated that especially cell-mediated
autoimmunity, but also autoantibodies against neuronal struc-
tures, or cytotoxicity caused by cytokines and inflammatory
cells in CNS could lead to the destruction of hypocretin-
producing neurons [3,36]. In addition to immune-mediated
destruction of hypocretin neurons, secondary narcolepsy has
been described, for instance, in patients with rare inherited
disorders, brain tumors, traumatic brain injury, and demyelin-
ating disorders which lie outside the scope of this review [37].
Curr Neurol Neurosci Rep (2018) 18:43 Page 3 of 10 43
NT1 is tightly associated with HLA class II allele
DQB1*06:02. More than 98% of NT1 patients are positive
for this allele, making it almost a prerequisite for the disease.
However, this allele is very common in Western countries and
20–30% of the general population is positive for this allele.
The relative risk among individuals positive for DQB1*06:02
is ca. 250 times higher than among those individuals who do
not have this allele [38•]. The DQB1*06:02 HLA molecule
forms homodimers or heterodimers with another HLA class II
molecule, DQA1*01:02, which also contributes to the relative
risk of NT1 susceptibility [39,40].
HLA class II molecules play a pivotal role in antigen pre-
sentation and cell-mediated immunity. The link between HLA
DQB1*06:02 allele and NT1 is highly indicative of an autoim-
mune background in the disease pathogenesis. Also, HLA class
I alleles and HLA-DP molecules seem to have an independent
role in susceptibility for narcolepsy [41•,42•]. There are also
multiple protective alleles that reduce the risk of NT1. In the
study by Ollila and coworkers, the most protective heterodimer
was HLA-DPA1*01:03-DPB1*04:02 [41•]. HLA-DP loci are
known to have a role in autoimmune diseases such as multiple
sclerosis and type 1 diabetes. Association with HLA class I
alleles also implicates the possibility of the involvement of
cell-mediated cytotoxicity in narcolepsy.
An association with triggering environmental factors such
as H1N1 vaccination, H1N1 virus infection, and streptococcal
infections further strengthens the autoimmune hypothesis in
the pathogenesis of NT1 [3,43]. Nevertheless, no peptides
associated with DQB1*06:02 have been identified; thus, there
is no identification of cross-reactive peptides between micro-
bial pathogens (such as influenza virus or Streptococcus
pyogenes) and human autoantigens, especially those that
could be specific for hypocretin-producing neurons.
In addition, gene polymorphisms in several genes such as
carnitine palmitoyl transferase 1B (CPT1B) and choline kinase
B (CHKB) have been linked to narcolepsy. In some studies, an
increased narcolepsy risk was associated with T cell receptor α
chain gene (TCRA), cathepsin H (CTSH), and purinergic re-
ceptor subtype 2Y11 (P2RY11) (reviewed in [3]). However, the
contribution of gene polymorphisms and other genes apart
from HLA class II genes in narcolepsy susceptibility is rela-
tively low. It is noteworthy that most of the genes associated
with increased narcolepsy risk are involved in the regulation of
the immune system. Thus, these findings further support the
immune-mediated disease mechanisms of NT1.
Moreover, a link between narcolepsy and H1N1 infection
has been seen in immunocompromised mice. Kristensson and
coworkers infected recombinant activating gene 1-deficient
Table 2 Controversies and
unsolved issues in Pandemrix-
related narcolepsy
Factors proving a link between Pandemrix vaccine and narcolepsy
Strong and consistent epidemiological
connection
Increased incidence of narcolepsy shown separately
by different study groups and authorities in all the
countries where the Pandemrix vaccine was used
on a large scale [2••,7••,8–17].
Immunological connection Higher immune response against H1N1 virus
nucleoprotein in narcoleptic patients than in
healthy controls [30••].
Cross-reactivity between influenza NP and human
hypocretin receptor 2 [31].
Factors affecting robustness of association
Possible biases in observational studies
Confounding by natural H1N1 infection Increased incidence of narcolepsy in China not
related to vaccination [22•,23].
Data showing H1N1 virus is capable of entering
into the hypothalamus via the olfactory nerve
and causing narcolepsy-like sleep-wake disruption
in immune-compromised rat [32].
Concomitant circulating H1N1 infection during
the vaccination campaign [27].
Ascertainment, information and recall bias Lack of validation of cases in some studies [2••,7••,8–21].
Role of increased media attention unclear [2••,7••,8–21].
Self-reported symptom onset [2••,7••,8–21].
Missing pathophysiological link
Missing autoantibodies Possible autoantibodies against different neuronal
structures have a low specificity for narcolepsy
and they are also found, though to a lesser extent,
in other sleep disorders or healthy controls.
43 Page 4 of 10 Curr Neurol Neurosci Rep (2018) 18:43
mice, which lacked T and B cells, with the H1N1 influenza A
virus and demonstrated that the infection spread to CNS and
targeted hypocretin-producing neurons in the hypothalamus,
which led to a narcolepsy-like syndrome in these animals [32].
However, most Finnish patients with Pandemrix-associated
narcolepsy were shown not to have antibodies against non-
structural protein 1 (NS1) of the pandemic H1N1 influenza
virus, making it unlikely that the 2009 pandemic H1N1 virus
infection was the causative factor in the development of nar-
colepsy in these patients [28]. NS1 is produced in the host
during the infection and it is not present in influenza vaccines;
thus, anti-NS1 antibodies are found only in humans who suf-
fered a natural influenza A virus infection. This does not rule
out the possibility of a microbial infection being able to trigger
the onset of narcolepsy, but at least in our patients with
Pandemrix-associated narcolepsy, we could not identify any
other environmental factors apart from the Pandemrix vaccine
that was associated with narcolepsy [18••,28].
In addition to a genetic link with factors regulating cell-
mediated immunity and potential narcolepsy-triggering infec-
tions, many groups have identified higher frequencies of au-
toantibodies among narcoleptic patients. These antibodies in-
clude anti-Tribbles homolog 2 and anti-ganglioside antibod-
ies, as well as antibodies against various neuronal structures,
neurotransmitters, and neuron-specific molecules such as
neurexin-1 [44,45]. There is also evidence that hypocretin
receptor 2 may be the target for autoantibodies [31].
Newly diagnosed narcolepsy patients have been shown to
have a higher frequency of anti-Tribbles 2 (TRIB2) homolog
antibodies than control individuals [46–49]. The Tribbles fam-
ily of proteins is protein kinase homologs involved in cell
growth regulation, but the precise function of TRIB2 homolog
pseudokinase is not known. Immunoglobulins from narcolep-
sy patients positive for anti-TRIB2 antibodies cause loss of
hypothalamic hypocretin neurons and sleep disturbances
when injected into mice [48]. In addition, TRIB2-
immunized rats displayed autoantibody formation and stain-
ing of hypothalamic structures, including hypocretin neurons.
However, the study failed to demonstrate a direct connection
between anti-TRIB2 antibodies and destruction of hypocretin
neurons, suggesting that the development of anti-TRIB2 anti-
bodies may be a consequence of neuronal damage rather than
the cause [50].
Autoantibodies against neuronal gangliosides have been
linked to some neurological diseases such as the Guillain–
Barré syndrome [51]. Recently, Saariaho and coworkers dem-
onstrated that children and adolescent with Pandemrix-
associated narcolepsy have a higher frequency of anti-
human ganglioside GM3 antibodies [45]. An older study
failed to show an association of anti-ganglioside antibodies
and narcolepsy [52], but in that study, the ganglioside pattern
used for autoantibody detection was limited compared to that
in the more recent study. The role of anti-ganglioside
antibodies in the pathogenesis of narcolepsy remains unclear
as it is not known if they contribute to the destruction of
hypocretin neurons or emerge as a consequence of the neuro-
nal damage.
Additional information on the presence of autoantibodies
against neuronal structures in Pandemrix-associated narcolep-
sy was obtained in an immunohistochemical study in rat brain
sections [53•]. This study demonstrated that as many as 27%
of patients had autoantibodies against neuronal structures
compared to ca. 10% of healthy controls. A further analysis
revealed that those patients did not have autoantibodies
against hypocretin, but against hypothalamic glutamic acid–
isoleucine/α-melanocyte-stimulating hormone (NEI/αMSH),
GABAergic cortical interneurons, and globus pallidus neu-
rons [53•]. In the hypothalamus, cells expressing NEI/
αMSH are adjacent to hypocretin neurons. Administration
of NEI/αMSH autoantibody-positive immunoglobulins into
a rat CNS, as in the case of anti-TRIB2 antibodies (see above),
led to neurological symptoms and altered sleep pattern [53•].
It was puzzling that the increased frequency of narcolepsy
was associated with the European Pandemrix vaccine and to a
much lesser extent, if at all, with Arepanrix, which was used in
Canada [2••,54]. Since the AS03 adjuvant used in both vac-
cines was produced in the same European factory, the differ-
ences between Pandemrix and Arepanrix are solely in the
H1N1 influenza virus antigen preparation used in the different
vaccines. Vaarala and coworkers showed that the viral nucle-
oprotein (NP) concentration, including polymeric NP, was
higher in Pandemrix than in Arepanrix [30••]. In addition,
immune response against NP was higher in narcoleptic
Pandemrix-vaccinated children than in healthy, matched con-
trol individuals vaccinated with Pandemrix [30••].
Furthermore, antigen absorption experiments pointed out that
the antigen compositions of Pandemrix and Arepanrix are
immunologically different, but the contribution of these dif-
ferences in the development of narcolepsy remains elusive. A
more recent study also confirmed certain differencesin protein
composition and modifications between viral antigens in
Pandemrix and Arepanrix [55].
Molecular mimicry and cross-reactivity between microbial
components and host proteins/molecules may contribute to
the development of autoimmune diseases. A National Center
for Biotechnology Information search for potential cross-
reactive epitopes between Pandemrix viral antigens and host
components led to the identification of a potentially cross-
reactive epitope between influenza NP and human hypocretin
receptor 2 (HCRTR2) [31]. Antibodies against an NP epitope,
which cross-reacted with a similar epitope from human
HCRTR2, were found in sera collected from children and
adolescents who developed narcolepsy after the vaccination
with Pandemrix. The epitope contained seven identical amino
acids within a 20-amino-acid-long structure. Peptide absorp-
tion experiments confirmed the specificity of autoantibodies
Curr Neurol Neurosci Rep (2018) 18:43 Page 5 of 10 43
against the common epitope between NP and HCRTR2 [31].
Nonetheless, sera collected from non-narcoleptic children pri-
or to the 2009 influenza pandemic also showed some autoim-
munity against the cross-reactive epitopes. This raises some
concern regarding the specificity of this cross-reaction as a
causative mechanism in Pandemrix-associated narcolepsy.
Moreover, recent studies demonstrated no anti-HCRTR2-
specific antibodies or a low titer and a very low frequency of
these antibodies in narcoleptic children, suggesting that this
type of autoantibody formation is likely not a general feature
of childhood narcolepsy [56,57]. The situation has recently
become even more complex with the identification of
neurexin-1, methyltransferase-like 22 (METTL22), 5′-nucle-
otidase cytosolic IA (NT5C1A) proteins, and the prostaglan-
din D2 receptor being potential autoantigens in narcolepsy.
Patient sera from Pandemrix-associated narcolepsy patients
showed a higher frequency of antibodies against various epi-
topes of those proteins [44,58•,59•]. However, control indi-
viduals without narcolepsy also showed some autoimmunity
against these proteins.
Numerous studies suggest that the onset of narcolepsy is
genetically linked to several genes, with the HLA class II
system manifesting the highest impact, which implies a role
for cell-mediated immunity in narcolepsy. In addition, various
types of autoantibodies with specificity to hypothalamic cells
and neuronal proteins and peptides propose that humoral im-
munity, too, may contribute to the pathogenesis of narcolepsy.
However, these findings could also be partly explained by a
consequence or a downstream effect of local neuronal cell
death, followed by autoantibody formation. A general inflam-
matory response leading to enhanced cytotoxicity and neuro-
nal damage in CNS is another potential mechanism assisting
the onset of narcolepsy. Figure 1illustrates the potential im-
mune mechanisms contributing to narcolepsy.
There is no evidence of an association between any other
influenza vaccine and narcolepsy. It is possible that there were
other temporary factors, in addition to vaccination, that could
have impaired self-tolerance at the same time. A concurrent
influenza infection was discussed earlier. A Swedish group
found an increased interferon-gamma production against
beta-hemolytic group A streptococcus [60]. We may speculate
that some other factors, such as streptococcal infections, may
have impaired self-tolerance at the time of vaccination.
Furthermore, it has been proposed that at least four other
groups of people are at risk of having autoimmune-like symp-
toms after vaccinations: (a) patients with a history of previous
post-vaccination autoimmune phenomena, (b) patients with a
history of some other autoimmunity, (c) patients with a history
of allergic reactions, and (d) individuals who are prone to
develop autoimmunity (positive family history of autoim-
mune diseases, presence of HLA DQB1*06:02 and/or ab-
sence of HLA DQB1*06:03, etc.) [61]. The latter suggestion
is indirectly supported by findings from our original patient
series, where 17% of patients with Pandemrix-related narco-
lepsy had a history of asthma or atopy, and all patients were
positive for HLA DQB1*06:02 [18••]. A similar connection
was reported in a Spanish study, in which 19% of narcoleptic
patients had one or more associated immune-mediated dis-
eases (odds ratio 3.17 compared to general population) [62].
In contrast, in a French study, only 4.9% of NT1 patients had a
comorbid autoimmune disease, which is an equal prevalence
compared to the general population [63]. In this study, comor-
bid autoimmune diseases were more prevalent in idiopathic
hypersomnia and NT2 than in NT1 [63].
Clinical Description—Are There Any
Differences Between Pandemrix-Related
and Idiopathic Narcolepsy?
Some interesting differences have been reported in the
clinical features of Pandemrix-related narcolepsy and
non-vaccine-associated narcolepsy [64,65•]. In our expe-
rience, Pandemrix-related NT1 was often characterized by
a rapid onset and short delay between the onset of symp-
toms and diagnosis. A more abrupt onset in Pandemrix-
associated narcolepsy has also been reported in other
studies [18••,65•,66–68].
Facial hypotonia and “cataplectic facies”are increasingly
recognized features in childhood cataplexy. Facial hypotonia
andtongueprotrusionwerereportedtobemorecommonin
children with Pandemrix-related narcolepsy than in those with
idiopathic narcolepsy [68]. The incidence of childhood narco-
lepsy peaks among 10–20-year-olds and an early onset in
preschool-aged children is very rare. One striking feature of
vaccine-associated narcolepsy was the emergence of cases
also at preschool age [7••,18••,67,69]. On the other hand,
a few studies have reported a higher mean age at the time of
diagnosis or onset of symptoms in Pandemrix-associated nar-
colepsy [18••,64].
In a comparison between unvaccinated Italian and vacci-
nated Finnish children with narcolepsy, no significant differ-
ences were seen, except for more disturbed sleep character-
istics in Finnish subjects [64]. Even if the onset were more
abrupt, the fully developed clinical picture of Pandemrix-
associated narcolepsy seems to be very similar to idiopathic
narcolepsy [65•]. However, the clinical picture of NT1 is
very heterogeneous. Some subjects with Pandemrix-
associated NT1 may manage even without any medication
and be able to fully continue to work or study, while others
are severely handicapped [65•]. Objective polysomnographic
and actigraphic characteristics seem to be very similar be-
tween vaccine- and non-vaccine-associated narcolepsy [70].
There were some differences in sleep–wake rhythm param-
eters implying an earlier sleep phase in Pandemrix-
associated narcolepsy [70].
43 Page 6 of 10 Curr Neurol Neurosci Rep (2018) 18:43
We have seen some, fortunately only a few, Pandemrix-
associated NT1 subjects developing very severe psychiatric
symptoms. Some of these psychiatric symptoms are so dev-
astating that they resemble psychosis, Klüver–Bucy syn-
drome, or autoimmune encephalitis. We have screened for a
large repertoire of neuronal autoantibodies in these patients
but failed to find any conclusive evidence for a CNS-
specific autoimmunity.
Treatment
Symptomatic treatment of Pandemrix-associated narcolepsy
mirrors the treatment of idiopathic narcolepsy using, for ex-
ample, modafinil, methylphenidate, and sodium oxybate.
Immunomodulatory treatment has not proven to be effective
in the treatment of Pandemrix-related narcolepsy but the evi-
dence is limited. We have experience of five Finnish post-
Pandemrix patients with intravenous immunoglobulin (IVIg)
treatment administered within a few months of the disease
onset. None of the patients benefited from the treatment.
Danish colleagues have reported similar results [71]. One re-
cent report suggested that an early combined immunotherapy
with methylprednisolone and IVIg may have had a positive
effect on relieving symptoms, but the results have to be taken
cautiously since we know that the natural course of narcolepsy
is very heterogeneous [65•,72].
There is a case report that provides a spark of hope for
immune therapy in narcolepsy [73]. The authors demonstrated
the normalization of hypocretin levels and remission of sleep-
iness and cataplexy in a patient treated with IVIg very early
after the symptom onset [73]. Unfortunately, the treatment
effect lasted only for a few months and the subject refused
further treatment. We have reported a patient with a dramatic,
but again unfortunately temporary, improvement of symptoms
after treatment with rituximab [74]. The largest study so far on
the immunomodulatory treatment in pediatric narcolepsy is a
non-randomized controlled open-label trial in France [75]. In
this study, a subset of patients with the highest scores in the
narcolepsy screening questionnaire Ullanlinna Narcolepsy
Scale (UNS) had remission of symptoms sooner than those
who were not treated with IVIg.
Fig. 1 A hypothetical model of autoimmunity in narcolepsy induced by
influenza A virus infection or vaccination or streptococcal infection.
Influenza A virus infection (or S. pyogenes infection) or vaccination
with AS03-adjuvanted pandemic influenza vaccine leads to an infection
or an uptake of viral antigens by dendritic cells (DCs) in peripheral
tissues. This leads to the maturation and migration of infected or
antigen-loaded DCs to local lymph nodes. In the lymph nodes, DCs
present influenza-specific epitopes to CD4- and CD8-positive T cells.
CD4 helper T cells provide help and activation of B cells that have also
taken up soluble viral antigens. Activated T cells and matured IgG-
producing B cells migrate via blood into the central nervous system. In
the brain, in the event that cross-reactive cell-mediated and humoral
immunity has developed, autoimmunity is involved in the destruction
of hypocretin-producing neurons in the hypothalamus. Potentially, three
mechanisms may be involved: (1) activated CD8 T cells destroy neurons
via cytotoxic mechanisms; (2) inflammatory cytokines, produced by
activated T cells, induce cellular cytotoxicity; or (3) autoantibodies,
which recognize cross-reactive epitopes on neurons, induce antibody-
dependent cytotoxicity
Curr Neurol Neurosci Rep (2018) 18:43 Page 7 of 10 43
Taken together, the attempts to utilize immunomodulatory
treatment in narcolepsy have provided controversial results. It
is possible that immune therapies should be administered very
soon after the disease onset, before the permanent damage to
hypocretin system has taken place. The pathogenic cascade
leading to narcolepsy may begin months or even years before
the actual symptoms emerge; thus, in the majority of cases, it
may already be too late when the patient enters the clinic. A
multicenter randomized controlled trial of immunotherapy
near the disease onset might provide an answer to this ques-
tion. In the future, once the autoantigens have been identified
and the disease mechanisms resolved, immune therapy may
become an efficient therapy.
Conclusions
Several studies from different countries using alternative
methods have confirmed the association between narcolepsy
and Pandemrix vaccination. This provides strong evidence of a
true association even if the possible diagnostic biases may some-
what reduce the risk. The classic criteria for an autoimmune
disease are not fully met in the case of narcolepsy, but increasing
evidence suggests an immune-mediated mechanism in the dis-
ease pathogenesis. It is also important to state that seasonal in-
fluenza vaccines, which are given to hundreds of millions of
individuals every year, have not been associated with narcolepsy.
Research on narcolepsy was remarkably enhanced after
Pandemrix-related narcolepsy was identified in 2010 and the
work, for good reason, continues intensively. A conclusive
explanation for the disease mechanism(s) has still remained
elusive. Hopefully, active research efforts on understanding its
pathogenesis may lead to the revelation of the etiology of
narcolepsy, which provides us with better means to prevent
similar events in the future. There is also a great demand for
novel immunotherapeutic and other treatment modalities.
Acknowledgments We thank Damon Tringham for linguistic advice.
Compliance with Ethical Standards
Conflict of Interest Tomi Sarkanen reports a grant from The Finnish
Medical Council, personal fees from Orion, and travel expenses from
UCB, outside the submitted work.
Anniina Alakuijala reports no conflict of interest.
Ilkka Julkunen reports a research grant from the Academy of Finland,
outside the submitted work.
Markku Partinen reports research grants from the Academy of
Finland, personal fees from UCB-Pharma, GSK, Takeda, MSD, Orion,
and participating in clinical trials by Bioprojet, Jazz Pharmaceuticals, and
MSD, all outside the submitted work.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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