Narcolepsy is a prevalent sleep disorder defined by quick REM sleep onset and sudden sleep or paralysis at times of high emotional or physical arousal. It is the second most common cause of excessive daytime sleepiness after sleep apnea.1 Epidemiological data show an incidence of 0.2 to 1.6 per thousand in European countries, Japan and the United States, a frequency at least as large as that of Multiple Sclerosis.2 By this estimate, as many as 200,000 Americans may be afflicted by narcolepsy, but less than 50,000 are diagnosed.3 It is most commonly mistaken as depression, epilepsy, or the side effects of medication.4
There is no cure, and the exact causes are not fully understood, but research into the causes and mechanisms of narcolepsy promise to shed light on the connections between complex behavior and genetics, and the processes of sleep and REM.
The main symptoms of narcolepsy are excessive daytime sleepiness, abnormal REM sleep exemplified by short latency before the first REM period (SOPREMPS), sleep paralysis, cataplexy, and hypnagogic hallucinations (hallucinations associated with a sleep state). These have been recognized for some time as disorders rooted in the regulation of REM sleep.
All patients experience excessive daytime sleepiness (sleep attacks and persistent daytime drowsiness). Sleep attacks are short periods of sleep that occur many times a day, regardless of the amount or quality of sleep the night before. They are often described as irresistible and may occur with or without warning when a person is driving, working, eating, talking, or engaging in any other activity. The excessive daytime sleepiness experienced by people with narcolepsy has been described as being like trying to stay awake after going 72 hours without sleep.5 Most patients also experience persistent daytime drowsiness.6
Severity, frequency, and order of appearance vary
widely for secondary symptoms of Narcolepsy, but 20-25% of Narcolepsy patients
experience all four.7
Narcolepsy as a Dysfunction of REM Sleep
Sleep consists of several stages, but these can be divided into two higher-level stages: REM and Non REM sleep (NREM). NREM and REM sleep alternate cyclically throughout the night beginning with NREM sleep, which typically lasts about 80 minutes. NREM sleep is followed by REM sleep, which lasts about 10 minutes. This 90-minute cycle is repeated 3-6 times each night. In successive cycles the amount of NREM sleep decreases and the amount of REM sleep increases.8
REM sleep is physiologically similar in arousal levels and electrical activity to a waking state with the exception that stimuli are endogenous (except for the occasional alarm clock, bright outside light or other stimuli that cannot be ignored), and muscular activity (except for eye movement) is inhibited.
The symptoms of narcolepsy are all tied to the functioning of REM sleep
components at inappropriate times.
SOPREMPS:
Although I did not find this information in any resources, it
appears to me that there should be a minimal amount of NREM sleep before
REM sleep can be beneficial. NREM sleep in part functions to “downshift”
brain activity smoothly down, and then back up into REM sleep. It seems
intuitive to me that if these steps are skipped or rushed through that
problems would arise. This is especially the case with the hypothesized
restorative function of sleep believed to occur in NREM sleep. I think
that this would be a partial explanation to the problem of excessive daytime
sleepiness. Although the patient may get the right number of hours of sleep,
it may not be as physiologically restful as it should be.
Cataplexy
Cataplexy is the sudden loss of voluntary muscle
control, usually triggered by emotions such as laughter, surprise, fear,
or anger. It occurs more frequently during times of stress or fatigue.
The cataplectic attack may involve only a slight feeling of weakness and
limp muscles (such as sagging facial muscles, a nodding head, buckling
knees, loss of arm strength, garbled speech); but it may also result in
immediate total body collapse.9 Often the patient will
appear to have fallen completely asleep and unresponsive, despite the fact
that they are alert and conscious.
Obviously, this is a very intrusive problem in a
patient’s life, if every time that there is an emotionally charged event,
they start to fall asleep, or collapse. Studies have shown that even treated
narcoleptic patients are often markedly psychosocially impaired in the
area of work, leisure, interpersonal relations, and are more prone to accidents.10
I imagine that this is due in large part to the cataplectic attacks. Excessive
daytime sleepiness may be very disruptive, but these attacks, to me, have
a more intense and immediate upsetting effect on one’s life and those around
you.
As for what would explain this cataplexy, in the
most severe cases where the person collapses suddenly into sleep, the inhibitory
signals that accompany REM sleep have been fully activated. The patient’s
voluntary musculature is completely paralyzed, but this is not go together
with a mental sleep state. The Penn School of Nursing
draws the following parallel which is interesting but may be impossible
to test: “Just as night-time REM sleep is normally accompanied by skeletal
muscle paralysis and strong emotions (dreaming); an intense emotion during
the waking period can trigger instantaneous muscle weakness or paralysis.”
Regardless of whether this is the mechanism of cataplexy, during an attack,
the person is awake, and aware, but cannot move. The “I-Function” has not
been disengaged, even as the muscles are inhibited.
Hypnagogic hallucinations and sleep paralysis are
the last two symptoms. They can be quite frightening when they occur together.
Hypnagogic hallucinations are the visual and tactile elements of REM sleep
intruding onto some level of consciousness. The person is essentially
dreaming while at some level of alertness. This may be when the person
has just woken up, fallen asleep, or has been up and alert for hours. Sleep
paralysis occurs either falling asleep or coming out of sleep when the
patient is conscious, but realizes that they can not move any part of their
body (Sleep paralysis is not limited to narcoleptics. The topic of sleep
paralysis is discussed in my previous paper available here).
Again, these are components of REM sleep that are active at inappropriate
times. In hypnagogic hallucination, the person is already conscious, but
the visual (and often tactile and auditory) machinations of REM sleep that
create dreamscapes are turned or left on. Because they are on at the same
time that we are getting “real” sensory stimuli, these hallucinations are
sometimes so vivid and realistic, that they cannot be distinguished from
(an often horrible) reality. In sleep paralysis, the problem can be seen
as the failure of subcortical mechanisms to give way to the “I-Function”
even as the “I-Function” struggles to wrest back control over movement.
Narcolepsy and the “I-Function”
At one level of organization, narcolepsy shows us
that the “I-Function” is not king. The narcoleptic is at the will of their
limbic and subcortical brain, which evolutionarily are more basic and older.
This supremacy of subcortical sleep regions is not limited to just narcoleptics.
Even the strongest willed “I-Function” will succumb to the need to sleep
after several days without sleep. The problem here is that even when they
have had what would usually considered a good quality and amount of sleep,
the narcoleptic is still exhausted and sleepy. And then sometimes, either
when they are caught off guard or become excited about something, their
muscles suddenly will become weak. They become trapped in a body that has
decided to fall asleep without consulting the “I-Function.”
Causes
A lot is not understood about the mechanisms underlying
sleep and its different stages. Therefore, the neurophysiological model
of narcolepsy is a bit sketchy at this point. What follows is how the model
is envisioned by the Stanford Center for Narcolepsy. Neurochemical and
electrophysiological studies have shown that narcolepsy is associated with
an abnormal cholinergic supersensitivity and a monoaminergic (dopamine
and norepinephrine) hypoactivity. Both brainstem regions known to generate
REM sleep and limbic structures are functionally involved. A connection
to the limbic system would explain why REM sleep atonia (cataplexy) is
produced by emotions.11 The cholinoceptive hypersensitivity
in the brainstem and the basal forebrain would explain abnormal REM sleep
in narcolepsy (i.e., these areas are activated too easily) whereas abnormalities
in the mesocorticolimbic dopaminergic systems would explain excessive daytime
sleepiness (i.e. they do not receive enough dopaminergic substance to maintain
arousal). Limbic structures have recently been shown to be activated during
natural REM sleep using functional imaging studies and their role in emotion
may be the key to unlocking to narcolepsy pathophysiology.12
The main body of research at this point is focusing
on treating the symptoms of narcolepsy, and into the genetics of its origins.
It does seem to run in families. Several genes have been identified as
being more frequent in narcoleptics than in the general population. The
human gene most talked about in the literature is HLA-DR2, along with the
role of hypocretins (which are also called orexins).13
It appears that a type of HLA-DR2 codes for aberrant hypocretin receptors
in the central nervous system.
Animal research with narcoleptic pedigrees of Doberman
pinschers has made a lot of progress in just the past few years.14
Lin et al. (1999) found, mapped, and cloned the responsible gene in their
Dobermans. The region of canine chromosome 12 to which the canarc-1 locus
was mapped was found to be analogous to the well-mapped region of human
6p21. They identified the gene that encodes the hypocretin type 2 receptor
(HCRTR2) as a plausible candidate. By genomic sequencing of the HCRTR2
gene of the narcoleptic Doberman, Lin et al. (1999) then identified an
insertion that resulted in aberrant splicing and a truncated transcript.
They identified a different deletion in the HCRTR2 transcript in the narcoleptic
Labrador. Lin et al. (1999) speculated that these changes disrupt the proper
localization or transduction functions of this receptor on the cell membrane.
Chemelli et al. (1999) engineered a mouse model of narcolepsy that independently
pointed to the same genetic pathway. Physiologic and pharmacologic studies
of the Doberman pinschers suggested a close similarity between the canarc-1
phenotype and human narcolepsy (Nishino and Mignot, 1997).
Just this year, there was a break through finding that may tie the genetic and neurological explanations for narcolepsy.
Nishino et al. (2000) measured hypocretin in the cerebrospinal fluid of 9 patients with narcolepsy and 8 age-matched controls. All patients were positive for HLA-DR2. HCRT was detectable in all controls. However, in 7 of 9 patients, HCRT concentrations were below the detection limit of testing equipment. The authors proposed that an HLA-associated autoimmune-mediated destruction of HCRT-containing neurons in the lateral hypothalamus might produce narcolepsy in these patients.15 In other words, narcolepsy may be an autoimmune disease.
There is a complication to this research that Nishino et al. addressed as recently as April 2000. They observed that although HLA-DR2 is very highly associated with narcolepsy (95-98% of all Caucasian patients16), a large proportion of the human population a) has this gene and b) does not suffer from narcolepsy. They propose that “this indicates that HLA alone makes a relatively small contribution to the development of narcolepsy and that a non-HLA gene(s) can contribute to the genetic predisposition even in narcoleptic cases with HLA.”17 They seem to have found that chromosome 4p13-q21 contains a second locus for HLA-associated human narcolepsy.
Related to this end of the research, Stanford has
identified a region of the human genome that is more closely and exxclusively
related to narcolepsy (a DQB1 allele, DQB1*0602).
Treatment
If physiological model for narcolepsy states that it is a cholinergic supersensitivity and a monoaminergic (dopamine and norepinephrine) hypoactivity, then it would make sense for something that lowers cholinergic substances and boosts amounts of dopamine and norepinephrine to help treatment. In fact, it seems that the therapeutic effects of various compounds on cataplexy are mediated primarily through the blockade of adrenergic uptake whereas the therapeutic effect on sleepiness involves the stimulation of adrenergic and dopaminergic transmission (blockade of monoamine uptake and stimulation of release).19 In general, Sleepiness is treated with amphetamines (which are anticholinergic), while the symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are treated using antidepressant compounds including selective serotonin reuptake inhibitors (SSRI) such as Prozac.
The physiological model holds well because the medications seem
to work. The only problem is that these drugs are treating the symptoms,
and individually too. No one drug treats the cluster of symptoms If you
have a severe enough case, you would need to take amphetamines for sleepiness,
anti-depressants for cataplexy, and dangerous hypnotics to be able to sleep
through the night.
Conclusion
Large strides are being made in pinning down how to treat best approach narcolepsy from the treatment and research ends. What I think is most important is to look at how narcolepsy works and can be treated as the intersection of genetics, sleep function, brain physiology, and the role of the I-function amidst subcortical mechanisms.
I believe that with the recent discoveries (just
in the past 2 years!) of important parts of the genetics involved, researchers
will be able to step back and approach narcolepsy from a more multi-dimensional
and cross-disciplinary vantage point. This new outlook will lead to a greater
understanding of how all these factors interact as we move from the nucleotide
pair all the way up into complex behavior.
1) Stanford
University Center for Narcolepsy Stanford has one the premier research
program into Narcolepsy. They have a very deep and informative site.
2) Stanford
School of Medicine Center for Narcolepsy
3) Facts About Narcolepsy, NIH Publication No. 96-3649. A NIH published pamphlet about narcolepsy for the general public.
4) Facts about Narcolepsy: University of Illinois at Chicago. UIC is one of 3 major centers for narcolepsy in the US, and a leading research facility.
5) University of Illinois at Chicago College of Nursing
6) School of Nursing, University of Pennsylvania One of three major centers for narcolepsy in the United States
7) National Institute for Neurological Disorders and Stroke A agency under the NIH
8) Basics of Sleep Online Syllabus An online advanced textbook on sleep for "undergraduates, graduate students, medical students, and post-doctoral scholars."
9) The Narcolepsy Network A national Non-profit organization of people who have narcolepsy (or related sleep disorders), their families and friends, and professionals involved in treatment, research, and public education regarding narcolepsy."
10) Stanford School of Medicine Center for Narcolepsy
11) Stanford School of Medicine Center for Narcolepsy
12) Stanford School of Medicine Center for Narcolepsy
13) National
Center for Biotechnology Information: Online Mendelian Inheritance in Man
OMIM is a vast catalog
of human genes and genetic disorders, and ligands with text, pictures,
and links to NCBI's Entrez
database of MEDLINE articles
14) OMIM, Narcolepsy
15) OMIM
Hypocretin
http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602358#TEXT
16) Stanford
School of Medicine Center for Narcolepsy
17) Nishino et al. Linkage of Human Narcolepsy
with HLA Association to Chromosome. Genomics 2000 Apr 1;65(1):84-6.
MEDLINE Abstract available
here.