What we've learned about Narcolepsy so far...
What's wrong? What causes Narcolepsy?
A Hundred Years of Research. Published in the Stanford Publications on their
Narcolepsy website. http://med.stanford.edu/school/Psychiatry/narcolepsy/
In this article it goes through the history in order of what they figured out.
It explains the hypocretin loss and the HLA genetic markers. (They are finally beginning to understand the system
behind the defects in Narcolepsy and what causes the symptoms of this disease.
But as of yet they do not know what triggers the disease to begin. I was
fortunate to be part of the research to make medical history to document that a
particular neurotransmitter [a chemical that transmits a specific set of
information from one area to another] called Hypocretin [or Orexin] is at fault.
Hypocretin is produced by one cell and then received by two different receptors
(receptor 1 on the and receptor two).
In 90+% of people with Narcolepsy they are losing the production cells for this
chemical. When they tested the spinal fluid, the levels were undetectable
(meaning if you are losing the ability to produce the chemical you will not have
any in your system to show up). In the other 10% they are probably losing the
receptors for the chemical. (Either of these receptors could be damaged or
missing). Most of these 10% test with normal levels of hypocretin 1 (meaning
it's produced and received but we cannot test hypocretin 2 because you have to
mash up some brain cells to test how much is in them, and well we can't do that
on living beings! So the theory is they might be losing the receptor 2 cells
much like the dogs with narcolepsy models. Only with dogs, its usually purely
genetic malformation and not an auto-immune or environmental trigger like they
believe most PWN to be). But their
symptoms and other tests were conclusive of Narcolepsy. And in only a few cases so
far (I was told I am one of them) they believe I might be losing the receptor1 for this
chemical. Which means I make it but I do not get it out of the cerebral spinal
fluid and use it. My test results were very high. They have since found that
some people without Narcolepsy can have elevated levels if they are sleep
deprived, but I was relatively rested (as much as one with Narcolepsy can be)
and it was first in the morning. Also both the other person and I have had brain
damage. Mine is only possible damage, I was born with a cyst in my sinuses that
grew back through the right eye socket down the nerve and into the brain. At the
time they took it out I was three, and they told my parents there was no
permanent damage, now I'm not so sure. The cyst cells could have been similar to
the Hypocretin cells and triggered the body to attack them. But, I didn't have
any real symptoms till about 9. See My Story for the rest.
The cells are spread out throughout the lateral hypothalamus, there are only about 1,000 cells and it doesn't damage any other cells. It is not detectable except at a cellular level. They had to dissect and stain the brains to get a good count. http://www.npi.ucla.edu/sleepresearch/xnarcnet.htm is a paper from UCLA also indicating what they have found similarities as well as differences between UCLA and Stanford.
What exactly happens when cataplexy is triggered?
http://www.npi.ucla.edu/sleepresearch/sciam.htm is an old article but has a wonderful understanding the the mechanism of cataplexy. What chemical changes take place and what is affected.
What future treatments will there be?
http://www.sro.org/bin/article.dll?paper&1772&0&0 is an article of the administration of hypocretin into the brains of dogs with narcolepsy. Hopes that they will find a way to either implant stem cells into the lateral hypothalamus where we are missing ours and have them take hold and work to produce hypocretin again. Or, find a way to cross the blood brain barrier to take a pill or liquid or even a small injection like diabetes to give us the hypocretin we are missing, it will be a temporary relief but at least we will be attacking the problem instead of trying to take care of the symptoms. This will only help those who have lost the production neurons we will have to do more studies on those with normal or high levels to see what will work for us.
When are hypocretin cells active?
An article on C-fos study they determined when the hypocretin cells are most active, physical/mental activity, quiet wakefulness, or REM sleep. 79% of the cells were active during physical activity. REM sleep 34% were active and quiet wakefulness was a mere 2%. ../c-fos.pdf
What is the best treatment for me right now?
XYREM (the best medicine for us so far) Thank you Orphan Medical for going the distance for us!
New look at antihistamines and their effect on EDS...
need adobe it's in pdf
http://www.npi.ucla.edu/sleepresearch/04 narc John neuron.pdf
A good overall article of what we know so far...
Narcolepsy is a chronic disabling sleep disorder affecting
one in 2000 individuals. Patients with narcolepsy suffer from excessive daytime
sleepiness (EDS), cataplexy (sudden loss of muscle tone with emotional
excitement), sleep paralysis, and hypnagogic hallucinations [Nishino and Mignot
1997]. Patients cannot maintain long bouts of wakefulness or sleep and thus
exhibit EDS and insomnia at night. Cataplexy, sleep paralysis, and hypnagogic
hallucination are often regarded as dissociated manifestations of rapid eye
movement (REM) sleep [Nishino and Mignot 1997].
Narcolepsy has been described in several animal species,
including dogs and recently in mice (Table 1). Canine narcolepsy is a naturally
occurring model, with both sporadic (17 breed) and familial forms (Doberman,
Labrador, and Dachshund). In humans, about 95% of narcolepsy occurs
sporadically, while only 5% is familial [Nishino and Mignot 1997]. Human
narcolepsy has a tight association with the human leukocyte antigen (HLA)
markers HLA-DR2 and HLA-DQB1*0602 [Nishino and Mignot 1997]. A number of
autoimmune diseases, such as multiple sclerosis and type I diabetes mellitus,
are associated with certain HLA haplotypes. An autoimmune basis for narcolepsy
would therefore be expected, but no direct evidence of autoimmunity in
narcolepsy has yet been demonstrated. Narcolepsy was first described in the
medical literature at the end of the 19th century, but its pathophysiology was
only elucidated at the end of the 20th century.
Genetic Narcolepsy in Animals and Hypocretin/orexin Deficiency in Human
Narcolepsy
Using positional cloning and gene targeting, two groups
independently revealed the pathogenesis of narcolepsy in animals. The lack of
the hypothalamic neuropeptide Hypocretin/Orexin ligand (preprohypocretin/prepro-orexin
gene knockout mice) [Chemelli et al 1999] or mutations in one of the two
Hypocretin/Orexin receptor genes (hypocretin receptor 2 [hcrtr 2] gene in
autosomal recessive canine narcolepsy) [Lin et al 1999] was observed to result
in the narcolepsy phenotype ( Table 1). After extensive screening, especially in
familial and early-onset human narcolepsy, it has been demonstrated that
mutations in hypocretin-related genes are rare: only one early-onset (6 months
of age) patient has been described to date, caused by a single point mutation in
the preprohypocretin gene [Peyron et al 2000].
Despite the lack of genetic abnormalities in the
hypocretin system, the large majority (85% to 90%) of patients with
narcolepsy-cataplexy have low or undetectable hypocretin-1 ligand in their
cerebrospinal fluid (CSF) [Nishino et al 2001b]. This hypocretin deficiency is
tightly associated with occurrence of cataplexy and HLA-DQ1*0602 positivity [Mignot
et al 2002]. Postmortem human studies, although using few brains, have confirmed
hypocretin ligand deficiency (both hypocretin 1 and 2) in the narcoleptic brain
[Peyron et al 2000 and Thannickal et al 2000]. Hypocretin deficiency has also
been observed in sporadic cases of canine narcolepsy (seven out of seven
studied; the result of four cases are reported in [Ripley et al 2001],
suggesting that the pathophysiology in these animals mirrors most human cases (
Table 1).
Low CSF hypocretin-1 levels are very specific to
narcolepsy compared to other sleep or neurologic disorders [Mignot et al 2002
and Ripley et al 2001]. The establishment of CSF hypocretin measurement as a new
diagnostic tool for human narcolepsy is therefore encouraging. Previously, no
specific and sensitive diagnostic test for narcolepsy based on the
pathophysiology of the disease was available, and the final diagnosis was often
delayed for several years after the disease onset, typically adolescence. Many
patients with narcolepsy and related EDS disorders are therefore likely to
obtain immediate benefit from this new specific diagnostic test. Also,
hypocretin agonists may be promising in the treatment of narcolepsy. In this
respect, the development of small molecular and centrally penetrant (i.e.,
nonpeptide) hypocretin agonists is likely to be necessary. A consideration is
the possible absence of functional hypocretin receptors many years after the
disease onset. Cell transplantation, using embryonic hypothalamic cells or
neural stem cells, and gene therapy (preprohypocretin/orexin gene transfer using
various vectors) might also be used to cure the disease in the future. The
causes/mechanisms of the ligand deficiency in human narcolepsy remain unknown,
but it is possibly to be due to an acquired cell death of hypocretin neurons
(see [Thannickal et al 2000]. This is likely because 1) the onset of most
sporadic cases of human narcolepsy is in the second decade of life and 2)
postnatal ablation of hypocretin neurons in mice [Hara et al 2001] induces a
phenotype that most resembles human narcolepsy. The mechanisms of the hypocretin
cell death should therefore be determined to prevent and/or rescue the disease.
Two independent groups discovered the Hypocretin/Orexin
system. One group discovered the hypocretins (1 and 2) by searching for
messenger RNAs (mRNAs) specifically expressed in the hypothalamus using
subtractive polymerase chain reaction [De Lecea et al 1998]. The other group
simultaneously discovered the same peptides by searching the endogenous ligands
for orphan G protein coupled receptors [Sakurai et al 1998]. Orphan receptors
are receptors whose sequence/structure is known, but their endogenous ligands
are unknown. This group named these new peptides Orexin (A and B) after the
Greek word for appetite, since they found that central administration of Orexins
potently increased food intake in rats [Sakurai et al 1998].
Hypocretin-1 and hypocretin-2 are produced by cleavage of a single precursor,
preprohypocretin. Mammalian hypocretin-1 is 33 amino acids long with 2
intrachain disulfide bonds, whereas hypocretin-2 is a linear 28 amino acid
peptide. Both peptides are C-terminally amidated. The amino acid sequences of
both peptides are almost identical among examined mammalian species and likely
to be conserved among vertebrates.
The hypocretins/orexins and hypothalamic feeding
mechanisms
The hypothalamus has long been implicated in the
regulation of food intake, body weight, and energy balance (Schwartz et al 2000;
Willie et al 2001; Taheri et al 2002). The lateral hypothalamus is specifically
responsible for feeding, while basomedial hypothalamic
nuclei are believed to be associated with satiation. The existence of neurons
expressing appetite-stimulating (orexigenic) neuropeptides,
such as melanin concentrating hormone (MCH), galanin, and dynorphin has been
reported in the lateral hypothalamic area [Schwartz et al 2000]. Leptin is
another important molecule for the regulation of food intake; it is
secreted by adipocytes to signal the extent of
body fat stores to the hypothalamus [Schwartz et al 2000]. The hypothalamic
arcuate nucleus is a major site for leptin action to suppress food intake. Both
orexigenic neuropeptide Y/agouti-related protein coexpressing neurons and
anorectic pro- opiomelanocortin/cocaine and amphetamine-regulated transcript
(CART) coexpressing neurons exist in the arcuate nucleus and are
targets for leptin action. Since hypocretin neurons are exclusively located in
the lateral hypothalamic area and central administration
of hypocretin-1 stimulates food intake, many researchers started to study the
role of Hypocretin/Orexin in feeding regulation; however,
when hypocretin and its related genes were discovered to be the genes for the
sleep disorder narcolepsy, many researchers, especially in the pharmaceutical
industry, somehow lost interest in the hypocretins as feeding regulators.
The Hypocretin/Orexin system and sleep regulation
The discovery of narcolepsy genes in 1999 was
revolutionary for basic sleep research, since typical approaches for basic sleep
research were using classical anatomical, physiologic, and pharmacological
techniques [McCarley 1995]. The most current popular
models for the regulation of sleep and wakefulness involve an interplay between
monoaminergic, cholinergic, and excitatory/inhibitory amino acid systems. The
direct involvement of other neuromodulators, such as adenosine, and other
humoral factors or autacoids (cytokines and prostaglandins) has also been
suggested [McCarley 1995]. Using the canine model of narcolepsy, we have also
intensively studied the roles of these neurotransmitter systems, in particular
monoamines and acetylcholine, in narcolepsy [Nishino and
Mignot 1997].
Most molecular, pharmacological, and genetic
studies have also focused on classical neurotransmitter systems. The discovery
of the
role of hypocretins in narcolepsy represented a major shift for sleep research.
Hypocretin neurons project to the most brain structures,
such as the cortex, anterior and posterior hypothalamus, thalamus, and the
brainstem monoaminergic and cholinergic nuclei, thought to be important for the
sleep regulation [Peyron et al 1998 and McCarley 1995]. A series of studies have
now proven that the hypocretin system is the major excitatory neuromodulatory
system that controls activities of monoaminergic (dopamine, norepinephrine,
serotonin, and histamine) and cholinergic systems to control vigilance states [Taheri
et al 2002].
Thus, it is likely that deficiency in hypocretin
neurotransmission induces an imbalance between the classical neurotransmitter
systems. Indeed, dopamine and/or norepinephrine contents have been reported to
be high in several brain structures in narcoleptic Dobermans and in human
narcolepsy postmortem brains [Nishino and Mignot 1997], possibly due to the
compensatory mechanisms. This up-regulation alone is, however, insufficient for
the reversal of sleep abnormalities in narcolepsy, necessitating
pharmacological treatment. Drugs that enhance dopaminergic neurotransmission,
such as amphetamine-like stimulants and Modafinil (for EDS), and norepinephrine
neurotransmission, such as noradrenaline uptake blockers (for cataplexy)
are commonly used [Nishino and Mignot 1997]. Histamine is another monoamine
implicated in the control vigilance, and the histaminergic system is also likely
to mediate the wake-promoting effects of hypocretin [Huang et al 2001]).
Interestingly, brain histamine contents both in hcrtr-2 gene mutated and ligand-deficient
narcoleptic dogs are dramatically reduced [Nishino et al 2001a]. Also,
preliminary results suggest that there is decreased histamine content in the CSF
of human narcolepsy [Nishino et al 2002]. Thus, compounds that enhance central
histaminergic neurotransmission may be a future option for the treatment of
narcolepsy.
Narcolepsy as a model for studying the
physiologic roles of hypocretin/orexin system
The idea that the hypocretins are potent
wake-promoting and REM-suppressing substances and that a lack of these
substances in
narcolepsy abnormally releases sleep and REM sleep-related symptoms might be too
simplistic. From the 1980s, the Stanford research group has intensively aimed to
characterize the narcolepsy phenotype in both familial (hypocretin receptor 2
mutation) and sporadic
(hypocretin ligand-deficient) narcoleptic dogs [Mitler and Dement 1977 and
Nishino et al 2000]. It should be noted that the total daily
sleep and REM time in narcoleptic dogs as well as human patients [Broughton et
al 1987] are not different from control subjects. The
major sleep abnormalities in narcoleptic dogs are sleep/wake fragmentation and
abnormal transition to/from different vigilance states [Mitler and Dement 1977
and Nishino et al 2000]. Patients with narcolepsy become alert after having a
short nap; but this does not
last long, and they become sleepy again within a few hours. This contrasts to
the persistent sleepiness of other primary EDS disorders, such as idiopathic
hypersomnia, where no hypocretin deficiency in the CSF is found to be involved
(see details in [Mignot et al 2002].
To study the physiologic roles of the hypocretin
system in sleep regulation and to study why hypocretin deficiency induces
irresistible (but recoverable) sleepiness during prolonged wakefulness, we have
studied the fluctuation of hypocretin tone by measuring extra cellular hypocretin-1 levels in the hypothalamus and thalamus in the rat over 24 hours
and by various manipulations with sleep recordings [Yoshida et al 2001]. The
results of our micro dialysis experiments demonstrate an involvement of a slower
regulatory pattern of hypocretin neurotransmission, as in the homeostatic and/or
circadian regulation of sleep ( Figure 1). Cerebrospinal fluid hypocretin-1 is
lowest at the end of the inactive period at a time when sleep propensity
and body temperature are the lowest. The hypocretin levels gradually increase
during the active period when animals spend most of their waking time, with the
highest levels occurring at the end of the active period. Although the time
resolution of the hypocretin assay is low and levels can be monitored only in 1-
or 2-hour sampling bins, the hypocretin levels in each sampling bin
correlate with brain temperature during the active period, but do not
significantly correlate with the amount of wakefulness [Yoshida et al 2001].
Hypocretin levels decline with sleep onset, while sleep deprivation increases
hypocretin levels [Yoshida et al 2001] ( Figure 1).
The neuronal activities of hypocretin neurons across
different sleep stages are not yet determined. This is mainly due to the fact
that hypocretin neurons are intermingled with other neurons, such as MCH
neurons. In addition, there is no method to positively identify
hypocretin neurons in vivo. Both wake-active and wake and REM active neurons are
reported to exist in the lateral hypothalamic area [Alam et al 2002], but it is
not known which types (or both) of neurons are hypocretin neurons.
Hypocretin neurons are likely to stimulate REM-off neurons, such as adrenergic
locus coeruleus (LC) and serotonergic raphe neurons [Taheri et al 2002], and
thus some assume that hypocretin neurons are REM-off neurons. In contrast, a
recent micro dialysis study in cats suggests that hypocretin release in the basal
forebrain during REM sleep is as high as during wakefulness [Kiyashchenko et al
2002]. It is however, reported that c-fos expression in hypocretins neurons in
rats is negatively correlated with the preceding amount of REM sleep [Estabrooke
et al 2001]. Furthermore, CSF hypocretin levels in rats are increased
during REM sleep deprivation and reduced after REM sleep rebound (Pedrazzoli et
al, unpublished data). Thus, further experiments are need to determine the
activity of hypocretin neurons across different sleep stages, especially during
REM sleep, and the existence of the heterogeneity of hypocretin neural
populations may also be revealed.
Regardless of the activity pattern of the
hypocretin neurons during REM sleep and sleep/wake cycle, our micro dialysis observations
suggest that basic hypocretin neurotransmission significantly fluctuates across
the 24 hours. Even if the animals had similar amounts of wakefulness in
the selected sample bins in the dark and light periods, hypocretin levels are
much higher during the dark period [Yoshida et al 2001]. Adrenergic LC neurons
are typical wake-active neurons involved in vigilance control [McCarley 1995],
and it has been recently demonstrated that basic firing activity of wake-active
LC neurons also significantly fluctuates at different circadian times
[Aston-Jones et al 2001]. Thus, hypocretin tonus may also contribute to the
slower circadian and homeostatic regulation of sleep, while changes in
short-term activity may also contribute to the sleep state changes.
Several acute manipulations, such as exercise,
low glucose utilization in the brain, and forced wakefulness, increase
hypocretin
levels. We have therefore hypothesized that build-up/acute increase of
hypocretin levels may counteract the sleep propensity that
typically builds up during the daytime and during forced wakefulness (Figure 1).
Interestingly, these patterns in hypocretin tonus mirror
those in presumed sleep propensity, as most typically demonstrated by changes in
delta wave power during slow wave sleep [Franken et al 1991]. Due to the lack of
the build-up of hypocretin tonus that opposes the increasing sleep propensity,
narcoleptic subjects may not be able to stay awake for a prolonged period and do
not respond to various alerting stimuli. Since it was reported that regulatory
processes underlying slow wave sleep homeostasis are operative in narcoleptic
subjects [Tafti et al 1992], narcoleptic subjects can
release any accumulated sleep propensity by having a nap; however, their
threshold of the sleep propensity that the subjects can
counteract is low, resulting in the return of sleepiness in a short period of
time. Conversely, the release of the hypocretin tonus at sleep onset may
contribute to the profound deep sleep that normally inhibits REM sleep at sleep
onset, and the lack of this system in narcolepsy may release REM sleep at sleep
onset.
Cataplexy (another primary symptom of narcolepsy) is
also often regarded as attacks of REM sleep, since cataplexy is very similar to
REM sleep atonia and since narcoleptic subjects have other REM-related symptoms
(e.g., sleep onset REM sleep periods, hypnagogic hallucinations, and sleep
paralysis). We demonstrated that the mechanism for induction of cataplexy in
hcrtr 2 gene-mutated
Dobermans is different from those for REM sleep [Nishino et al 2000].
Furthermore, an extended human study confirmed that cataplexy is very
specific to hypocretin-deficient narcolepsy in contrast to other REM
sleep-related phenomena [Mignot et al 2002]. We therefore propose to separate
cataplexy from other REM-related symptoms and to consider cataplexy as a
hypocretin-deficient pathologic phenomenon. The fact that patients with other
sleep disorders, such as sleep apnea, and even healthy controls often have
sleep-onset REM sleep periods, hypnagogic hallucinations, and sleep paralysis
when their sleep/wake patterns are disturbed but these subjects never develop
cataplexy further supports our proposal. Although cataplexy and REM sleep
atonia have great similarity and possibly share a common executive system, it is
not necessary for the regulatory mechanism of both states to be identical. The
mechanisms of emotional triggering of cataplexy remains undetermined.
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Mali Einen
Clinical Research Coordinator
Stanford University Center for Narcolepsy
401 Quarry Rd., Ste 3301, Stanford, CA 94305
Tel: 650 725-6512
Fax: 650 725-8910
email: einen@stanford.edu
http://www.med.stanford.edu/school/Psychiatry/narcolepsy
Home
My Story
Other's
Stories
Cataplexy
Other
Symptoms
Medications
Recommended
Doctors
Link's
Narcolepsy
Technical Stuff
Disability
Info
What's Up?