The causes of hypersomnia or excessive daytime sleepiness (EDS) besides volitionalsleep deprivation and obstructive sleep apnea are principally due to primary centralnervous system abnormalities. Most common amongst these is Narcolepsy, a primarydisorder of the neural control of wakefulness and sleep. The recent discovery ofhypocretin/orexin deficiency as the main cause of narcolepsy will lead to importanttherapeutic advances for patients with narcolepsy and further to understanding of thecontrol of sleep and wakefulness in general. Importantly, the excessive daytimesleepiness is not due to psychiatric conditions, but rather is always due to sleepdeprivation or an underlying diagnosable and treatable sleep disorder.Key words : EDS, Sleep, Narcoleps

Srivastav, M V Padma

English

Annals of National Academy of Medical Sciences (India)

Ann Natl Acad Med Sci (India), 49(3&4): 153-160, 2013
Causes of Hypersomnia – Narcolepsy
The causes of hypersomnia or excessive daytime sleepiness (EDS) besides volitional 
sleep deprivation and obstructive sleep apnea are principally due to primary central 
nervous system abnormalities. Most common amongst these is Narcolepsy, a primary 
disorder of the neural control of wakefulness and sleep. The recent discovery of 
hypocretin/orexin deﬁciency as the main cause of narcolepsy will lead to important 
therapeutic advances for patients with narcolepsy and further to understanding of the 
control of sleep and wakefulness in general. Importantly, the excessive daytime 
sleepiness is not due to psychiatric conditions, but rather is always due to sleep 
deprivation or an underlying diagnosable and treatable sleep disorder.
Key words : EDS, Sleep, Narcolepsy
Correspondence : Prof. M.V. Padma Srivastava, Department of Neurology, All-India 
Institute of Medical Sciences, Ansari Nagar, New Delhi – 110029. E-mail: 
vasanthapadma123@gmail.com
M.V. Padma Srivastava
Department of Neurology
All-India Institute of Medical Sciences, New Delhi
ABSTRACT
Volitional sleep deprivation and 
obstructive sleep apnea are the most 
common causes of hypersomnia. The 
remaining causes are primarily due to 
p r imary  cen t r a l  ne rvous  sys t em 
abnormalities, the most common of which 
is narcolepsy, a primary disorder of the 
neural control of wakefulness and sleep.
NARCOLEPSY :
It is the prototypic example of 
dissociated sleep-wake phenomenon in 
which components of one state, ie rapid 
eye movement (REM) sleep, appear in 
another (wakefulness) (1).
Narcolepsy is a relatively frequent 
disorder with a prevalence of 0.09%. A 
clear genetic component is indicated by 
the fact that over 90% of individuals with 
narcolepsy carry the HLA DR15 and HLA 
DQ6 gene, which is found in less than 
30% of the general population. Siblings of 
individuals with narcolepsy have a 60-
fold increased likelihood for developing 
the disease. Narcolepsy if thought to result 
also from abnormal neurotransmitter 
functioning and sensitivity and abnormal 
immune modulation (1,2,3).
The male to female ratio in 
narcolepsy is 1.64:1. The usual age of 
onset of narcolepsy is adolescence or early 
adulthood, although it ranges from early 
childhood to senescence (3 to 72 years of 
age), with a primary peek in the teens and 
a lesser peak in the early 30s. 
Signs and Symptoms :
Manifestations of narcolepsy are as 
follows: (1,2)
1. EDS
2. Cataplexy
3. Hypnogogic hallucinations
4. Sleep paralysis
Excessive Daytime Somnolence (EDS) :
EDS is the primary symptoms of 
n a r c o l e p s y  w i t h  u n w a n t e d  a n d 
unanticipated sleep episodes lasting 
seconds to minutes and occurring at 
inappropriate times, particularly during 
periods of reduced environmental 
stimulation, such as reading, watching 
television, riding in or driving or attending 
a class or meeting. During periods of 
excessive sleepiness, a brief (10 to 30 
minute) nap is frequently very refreshing, 
if only for a short period of time. The 
symptom of sleepiness is accompanied by 
failing performance due to impairment of 
sustained attention, at times reﬂected in a 
complaint of impaired memory. The 
apparen t  memory  d is turbance  i s 
secondary to impaired attention (1,2,4).
Ancillary symptoms of narcolepsy 
i n c l u d e  c a t a p l e x y,  h y p n o g o g i c 
hallucinations, and sleep paralysis. 
Cataplexy :
Cataplexy, which occurs in 65% to 
70% of these patients, comprises of 
sudden loss of muscle tone, typically 
triggered by emotion such as laughter, 
154 M.V. Padma Srivastava
anger, excitement, delight or surprise. The 
muscle weakness of cataplexy may be 
complete, resulting in the patients falling 
or being forced to sit, much more 
commonly, the weakness is milder and 
more focal, taking the form of facial 
sagging, slurred speech or localized 
weakness of an extremity.   Cataplexy 
may never occur in 30% of patients with 
narcolepsy or may precede the onset of 
EDS (1,2,4).
 Hence the salient features of 
Cataplexy are:
1. I f  severe  and  genera l ized , 
cataplexy may cause a fall.
2. More subtle forms exist with only 
partial loss of tone (eg., head nod 
and knee bucking)
3. Respiratory and extraocular 
movements are preserved.
4. Cataplexy is usually triggered by 
emotions (especially laughter and 
anger)
Sleep Paralysis :
Sixty percent of individuals with 
narcolepsy experience sleep paralysis 
upon awakening from REM sleep (usually 
from a dream). At times, this frightening 
manifestation consists of total-body 
paralysis, with sparing of respiration and 
of eye movements, lasting from seconds 
to minutes (1,2,4).
The salient features of Sleep paralysis are:
1. Usually the patient is unable to 
move upon awakening.
2. Less commonly, the patient is 
unable to move upon falling 
asleep with consciousness intact.
3. Paralysis is often accompanied by 
hallucinations
4. Respiratory and extraocular 
muscles are spared
5. Paralysis occurs less frequently 
when  the person sleep in an 
uncomfortable position
6. Paralysis can be relieved by 
sensory stimuli (eg. touching or 
speaking to the person)
Hallucinations :
Hypnogogic (at sleep onset) and 
hypnopompic  (upon  awaken ing) 
hallucinations are noted in 12% to 50% of 
cases. The hallucinations are extremely 
vivid and often frightening dreams that 
occur during the transition between 
wakefulness and sleep. They may be 
associated with total body paralysis and 
sensations of oppression and dread. These 
hallucinations are more frightening than 
conventional dreams because the dream 
imagery arises from the real (waking) 
environment, making differentiation 
between reality and dreaming difﬁcult 
(1,2,4,5).
The following are also common features 
of narcolepsy:
1. A tendency to take short and 
refreshing naps during the day; 
these may be accompanied by 
dreams.
2. Trouble sleeping at night
3. Nocturnal compulsive behaviours 
(sleep related eating disorder and 
nocturnal smoking)
4. Obesity
155Causes of Hypersomnia – Narcolepsy
Features of Narcolepsy in children are : 
(6)
1. Restlessness and motor over 
activity may predominate
2. A c a d e m i c  d e t e r i o r a t i o n , 
inattentiveness and emotional 
lability are common
3. At disease onset, children with 
narcolepsy and cataplexy may 
display a wide range of motor 
disturbances that do not meet the 
classic deﬁnition of cataplexy.
4. Motor disturbances may be 
negative (hypotonia) or active.
5. Motor disturbances may resolve 
later in the course of the disorder.
Diagnosis :
The DSM-5 deﬁnes narcolepsy as 
recurrent episodes of irrepressible need to 
sleep, lapsing or napping occurring within 
the same day. These must have been 
occurring at least three times per week 
over the past 3 months. There must also be 
presence of at least one of the following 
(1,2,5).
1. Episodes of cataplexy occurring at 
least a few times per month
2. Hypocretin deﬁciency
3. REM sleep latency < 15 minutes 
or a mean sleep latency < 8 
minutes and two or more sleep-
onset REM periods (SOREMPs).
Narcolepsy can be categorized as 
mild, moderate or severe based on the 
frequency of cataplexy, need for naps, and 
disturbance of nocturnal sleep. In 
addition, the DSM-5 identiﬁes ﬁve 
subtypes as follows:
1. Narcolepsy without cataplexy but 
with hypocretin deﬁciency
2. Narcolepsy with cataplexy but 
without hypocretin deﬁciency
3. Autosomal dominant cerebellar 
ataxia deafness and narcolepsy
4. Atuosomal dominant narcolepsy, 
obesity and type 2 diabetes
5. Narcolepsy secondary to another 
medical condition
Whenever possible, the diagnosis 
of narcolepsy should be conﬁrmed by 
polysomnography (PSG) followed by a 
multiple sleep latency test (MSLT). The 
MSLT should show sleep latency 8 
minutes or less and 2 or more SOREMPs. 
An alternative criterion is a CSF 
hypocretin level of 110 pg/ml or lower. 
The hypersomnia must not be explained as 
another sleep, neurologic, mental or 
medical condition, or induced by 
medicine /substance use. 
Pathophysiology :
Narcolepsy is thought to result 
from genetic predisposition, abnormal 
neurotransmit ter  funct ioning and 
sensitivity, and abnormal immune 
modulation. Current data indicate certain 
human leukocyte antigen (HLA) subtypes 
and abnormal hypocretin (orexin) 
neurotransmission, which leads to 
abnormali t ies  in  monoamine and 
actylcholine synaptic transmission, 
particularly in the pontine reticular 
activating system (3,7).
156 M.V. Padma Srivastava
U n d e r s t a n d i n g  o f  t h e 
neurochemistry of narcolepsy began with 
research involving narcoleptic dogs. In 
these animal models, the disorder is 
transmitted in an autosomal recessive 
fashion with full penetrance and is 
characterized mainly by cataplexy. 
Muscarinic cholinergic stimulation 
increases cataplexy in these animals, and 
cholinergic blockade eliminates the 
symptom. Nicotinic agents have no effect 
on the cataplexy (8).
Receptor subtypes such as the 
alpha-1-noradrenergic receptor appear to 
mediate cataplexy. Prazosin, an alpha-1-
antagonist, worsens symptoms in canine 
and human subjects. The pons is not the 
on ly  neu roana tomic  s i t e  t ha t  i s 
responsible for mediating cataplexy. The 
mesocorticolimbic dopaminergic system 
also has been implicated. This connection 
with the limbic system in part explains the 
relationship of cataplexy to emotion.
The centrality of hypocretin 
transmission in the pathophysiology of 
narcolepsy was demonstrated when 
hypocretin knockout mice displayed 
cataplexy and sleepiness. Further 
evidence for impaired hypocretin 
functioning in humans was found with the 
discovery of low levels of hypocretin in 
the CSF of narcoleptic patients (9,10).
Subsequently, abnormal immune 
modulation was associated with the 
clinical development of narcolepsy in 
children in Scandinavia and Finland. After 
vaccination against H1N1 inﬂuenza virus 
with a vaccine using a potent ASO3 
adjuvant, narcolepsy in Finish children 
increased 8 to 12 fold. All affected 
children who underwent HLA typing were 
found to have the HLA DQB*0602 allele 
(3,7).
REM Sleep :
Dysfunction and inappropriate 
regulation of REM sleep are thought to 
exist in narcolepsy. Neuroanatomic 
control of REM sleep appears to be 
localized to the pontine reticular 
activating system. 
The brain contains REM-on cells, 
which ﬁre selectively during REM sleep 
periods, and REM-off cells, for which the 
converse holds true. Most REM-on cells 
function through cholinergic transmission 
whereas REM-off cells are noradrenergic 
o r  s e r o t o n e rg i c .  I n  n a r c o l e p s y, 
monoamine-dependent inhibition of 
REM-on cells may be defective (5,4).
Symptoms can be viewed as REM 
sleep components intruding into wakeful 
states. For example, cataplexy and sleep 
paralysis represent an intrusion of REM 
sleep atonia, whereas hallucinations 
represent an intrusion of dreams.
Hypocretin :
Hypocretin plays an important 
role in the pathophysiology of human 
narcolepsy. Patients with narcolepsy have 
been found to have little or no hypocretin 
in their CSF. Postmortem pathologic 
examination of the brains of people with 
n a r c o l e p s y  w i t h  c a t a p l e x y  h a s 
157Causes of Hypersomnia – Narcolepsy
demonstrated dramatically reduced 
numbers  o f  hypocre t in  neurons . 
Hypocretin deﬁciency is theorized to 
produce instability of sleep and wake 
states, thereby preventing the persons 
from sustaining more continuous sleep or 
wakefulness. A large majority of patients 
with narcolepsy without cataplexy have 
normal CSF hypocretin levels (9,10).
Investigators have also found low 
levels of histamine (that helps maintain 
wakefulness) in the CSF of patients with 
hypocretin-deﬁcient narcolepsy. They are 
also seen in narcolepsy patients with 
normal CSF hypocretin levels and in 
patients with idiopathic hypersomnia. 
Low CSF histamine levels have not been 
found in patients with hypersomnia 
secondary to obstructive sleep apnea 
syndrome. The CSF histamine level may 
serve as a biomarker reﬂecting the degree 
of hypersomnia of central origin (9,10).
CNS nuclei for wakefulness and the 
relevant neurotransmitters generated in 
those nuclei include the following:
1. Locus ceruleus – Norepinephrine
2. Raphe nucleus – Serotonin
3. Tubomammillary nucleus – 
Histamine
4. Ventral tegmental area – 
Dopamine
5. Basal forebrain – Acetylcholine
These areas also inhibit REM sleep.
Hypocretin neurons thought to be 
autoexcitatory project from the lateral 
hypothalamus into these regions and serve 
to maintain wakefulness. A deﬁciency of 
hypocretin neurons may decrease the 
threshold for transitioning between 
wakefulness and sleep. This is a proposed 
explanation for the sleepiness and REM 
intrusion into wakefulness found in 
narcolepsy (9,10).
Destruct ion of  hypocret in-
producing neurons appears to be an 
au to immune  p roces s .  A spec iﬁc 
autoantigen against Tribbles homolog 2 
(Trib2) have been found to be higher in 
narcolepsy patients with cataplexy than in 
normal controls. The autoimmune model 
o f  na rco lepsy  insp i red  t r i a l s  o f 
intravenous immunoglobulin therapy in 
narcoleptic patients with low levels of 
hypocretin – 1. In these trials, IVIG 
reportedly improved cataplexy and 
sleepiness in many cases, but the effects 
did not last long (11).
Genetic Factors:
The genetics of Narcolepsy are 
complex. The risk is as high as 40% in the 
ﬁrst-degree relatives. 
There is a striking association 
between narcolepsy and the HLA 
haplotype DQA1*01:02-DQB1*06:02. A 
genome wide association study proposed 
a protective variant DQB1*06:03. GWA 
studies in Caucasians with replication in 3 
ethnic groups have revealed associations 
between SNP in the T cell receptor alpha 
locus and narcoplepsy. This association 
further supports the autoimmune basis of 
narcolepsy (3,7).
158 M.V. Padma Srivastava
An SNP in the purinergic receptor 
subtype P2Y11gene also appears to be 
associated with Narcolepsy. A GWA study 
that investigated 202 candidate genes in a 
replication study in 222 narcoleptic 
patients and 380 controls identiﬁed 6 
genes  tha t  were  associa ted  wi th 
narcolepsy: NFATC2, SCP2, CACNA1C, 
TCRA, POLE and FAM3D (3,7).
Management :
Treatment of Narcolepsy has both 
nonpharmacologic and pharmacologic 
components. Sleep hygiene is important. 
Most patients improve if they maintain a 
regular sleep schedule, usually 7.5 to 8 
hours of sleep per night. Scheduled naps 
during the day also may help (1,2,11).
Pharmacologic treatment of 
narcolepsy involves the use of central 
nervous system stimulants such as 
m e t h y p h e n i d a t e ,  m o d a ﬁ n i l , 
d e x t r o a m p h e t a m i n e  s u l p h a t e , 
methamphetamine and amphetamine. 
These medications help reduce daytime 
sleepiness, improving the symptom in 
65% to 85% of patients. In patients for 
whom stimulant treatment is problematic, 
subjective beneﬁt from treatment with 
codeine has been reported (1,2,11).
M e t h y l p h e n i d a t e  w a s  t h e 
stimulant most frequently used for 
treatment of narcolepsy. It improves sleep 
tendency in a dose-related fashion. 
Undesi rable  s ide  effects  include 
h e a d a c h e ,  n e r v o u s n e s s ,  a n d 
gastrointestinal complaints. Nocturnal 
sleep may be impaired with a resulting 
decrease in total sleep time (11).
M o d a ﬁ n i l  i s  n o v e l  w a k e -
promoting agent. The mechanism of 
action is not understood, but it does not 
appear to involve altering levels of 
dopamine or norepinephrine. Unlike 
traditional medications, modaﬁnil does 
not appear to affect total sleep time or 
suppress REM sleep; the most common 
adverse effect is headache. Its safety in 
children has not been established (11).
Armodaﬁnil has fewer side 
effects. It is indicated for the treatment of 
EDS associated with narcolepsy. TH most 
common side effects are headache, 
nausea, dizziness and difﬁculty in 
sleeping (11).
Cataplexy in  pat ients  with 
narcolepsy can be treated with the CNS 
depressant sodium oxybate. Other agents 
that are used off-label for cataplexy are 
tricyclic antidepressants, selective 
serotonin reuptake inhibitors and 
serotonin-norepinephrine reuptake 
inhibitors. The strongest evidence is for 
clomipramine, ﬂuoxetine and sodium 
oxybate (11).
159Causes of Hypersomnia – Narcolepsy
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