---start---- bbd 9/11/98 Kubin: narcolepsy/cataplexy question: what other diseases or disorders may have certain symptoms in common with narcolepsy-cataplexy? give examples of such disorders and the corresponding symptoms, and describe appropriate tests/questions through which you could differentially diagnose narcolepsy/cataplexy. review the evidence linking narcolepsy/cataplexy to other autoimmune disorders Narcolepsy/cataplexy: a syndrome of unknown origin characterized by excessive daytime sleepiness and pathological manifestations of REM sleep. major symptoms: 1. daytime sleepiness (falling asleep any time/any place) 2. cataplexy (sudden spells of muscular atonia) 3. sleep onset REM sleep 4. sleep paralysis (at REM sleep termination) 5. hypnagogic hallucinations the disorder is characterized by overwhelming sleepiness slides of a cat of some kind and some polar bears with cataplexy the individual is aware but muscles are totally relaxed. how to tell narcolepsy from other sleep disorders - depending on the question you come up with different percentages. everyone says they are sleepy. but only a few people have sudden sleep attacks which are irresistible. also few people report falling asleep at work. why narcolepsy/cataplexy? it's interesting from the point of view of understanding why we sleep, and understanding REM sleep. it gives a unique perspective on REM sleep. also has major social consequences (accidents) (and our society is intolerant of sleepiness, so he says) and is associated with HLA (human leukocyte antigen). HLA is part of the genome responsible for various autoimmune disorders, and this is another reason why knowing more about narcolepsy can help us. video: manifestations of narcolepsy/cataplexy in humans and dogs, and tests administered in dogs to dx the disorder. narcolepsy tetrad: 1. excessive daytime sleepiness - relentless tendency to be sleepy all the time typical patient has difficulty reading, sustaining any activity, motivation problems. 2. cataplexy - attacks of paralysis precipitated by strong emotion 3. hypnagoguic hallucinations 4. sleep paralysis. man flops over when someone tells him a joke... this muscle paralysis is the same thing seen in REM sleep. poodles flopping over dogs - joy of eating causes them to flop over in man and animals there is genetic predisposition in dogs, autosomal recessive gene humans- more complex in both, there is delayed onset - humans, peak risk is puberty/adolescence, dogs, 6-12 wks old. paralysis is flaccid, once an attack is over animal/person is normal these are attacks of REM sleep - brain is active, having vivid hallucinations/dreams, and at the same time, it is paralyzing the body attack of drowsiness - microsleeps. Food elicited cataplexy test in dogs 10 yummy bites of dog food placed ina circle. time how long it takes dog to eat it. takes narcoleptic dog a long time b/c eating is interrupted by attacks of paralysis and/or full on REM sleep. there is then spontaneous termination and resumption of eating. severely affected dogs may take 5-10 minutes. regular dog snarfs it down. people are tested with multiple sleep latency tests - individuals are put in bed and we measure how long it takes them to fall asleep. usually these people fall asleep within a minute every time, over and over. other diagnostic tests: Epworth Sleepiness test - in handout, table 38-2. another important test used. (I got a 12!) does this occur in the wild? well, animals with this problem would be eaten or would die b/c they couldn't catch prey, so the gene wouldn't be passed on. for diagnosis, patient must have at least 3 of the 5 major symptoms. some signs are more obvious or more complicated. those include sleep-onset REM sleep. sleep paralysis means that when sleep is ending, and patient is awakening, patient is paralyzed. many people experience this once in a while, but only for a few seconds. narcoleptics may experience it for 30-40 min after being awakened. hypnagogic hallucinations are sort of dreams we experience during normal REM sleep but occuring during sleep onset while we are still partly aware of the world and not unconscious. normal REM sleep - how does this relate? we recognize, score and observe changes in sleep with electrophysiological recordings of EEG, muscular tone, etc. we define REM this way...signs of REM are low amplitude, rapid, chaotic cortical waves similar to waking state; accompanied by rapid eye movements occuring repeatedly and chaotically; accompanied by absence of muscle tone (flat EMG). one important in relatoin to narcolepsy feature of REM sleep is timing of REM sleep during sleep cycle - normally, it occurs with cyclic pattern, with initial transition from wakefulness to slow wave sleep - then, an episode of REM- then, slow wave sleep or transient wakefulness, the repeat the cycle. in normal person, this would repeat 5-6 times. narcolepsy doesn't obey this rule. we see instead sleep-onset REM sleep - patient immediately enters REM sleep, and the whole night includes random episodes of REM sleep with no periodicity. the other feature for narcolepsy that's very different from normal sleep is it ignores the circadian clock. this diagram (that he is standing in front of so I can't see) shows two variables - the circadian variable that oscillates with 24 hr periods, which is why sleep is consolidated in night periods, and the sleepiness variable,w hich goes gradually up during 24 hrs until we fall asleep. superimposing these, we see that we sleep during night. with narcolepsy, these sleepiness signals are not occuring in synchrony with circadian clock. sleep signal is always high. there are animals like elephants that have two periods of sleep during 24 hr period- they are nappers. they nap in the middle of the day. speaking of naps, and also about ways of eh, eh,improving the condition of narcolepsy, naps are one of the eh best remedies to help a narcoleptic person. just let them nap and after that is a period of refractoriness during which another attack of sleep or cataplexy is unlikely. now what eh is wrong and what eh may be responsible for this disorder? we ultimately concentrate on certain mechanisms and aspects of brain neurochemistry that we knonw are important for the sleep/wake cycle. this slide (that he is standing inf ront of) gives an overview of the major players we think about - ACH, Norepi, and serotonin. ACH is important b/c it is responsible for producing REM under normal conditions. some cells containing ACH in brainstem have to be very active during REM sleep and they are largely responsible for initiating andmaintaining REM. in contrast, norepi and serotonin are quiet at this time, but active at other times, keeping ACH in check. so in narcolepsy it is possible that these neurons somehow escape from control of adrenergic neurons and start getting overactive at innapropriate times, triggering inappropriate REM sleep or cataplexy. b/c of the importance of these transmitters, a lot of studies hae been done. one such study - looks at receptors for these NTs in various parts of the brain, changes in release, reuptake mechanisms. some observations consistent with this idea were made - probably there is some abnormal activity of these ACH neurons. part of brain of most importance is the rostral brainstem- midbrain and caudal pons - contains these cholinergic neurons that produce this postural atonia and REM. what normally keeps these in check are preoptic and hypothalamic neurons, esp those responsible for circadian regulation of expression of sleep, and also norepi and serotonin containing neurons in brainstem. in fact it turns out that in normal experimental animals you can produce cataplexy/REM like episodes by putting small amts of ACH or ACH agonists into a certain area of the pons. in ACH induced REM waveforms are similar to natural REM those neurons which we excite by drugs put into the brainstem normally are excited by ACH producing neurons, and normally they are suppressed by activity of cells in the locus ceoerulus which contain serotonin.so it is a system of checks and balances, and when something goes wrong there is no sleep or too much sleep at the wrong time. what's wrong with these systems? what we've looked at are type II muscarinic receptors, bc they seem most effective in eliciting cataplexy. those receptors are upregulated in brains of humans with cataplexy and in those dogs with narcolepsy. there is also evidence for increased #s of cholinergic neurons in the pons. noradrenergic neurons normally through two mechanisms keep cholinergic neurons in check so they do not trigger REM- but if we interfere with the system of inhibition, we can expect REM or cataplexy to occur at abnormal times or in some abnormal way. diagram that he is standing in front of shows how we can interfere - with alpha2 receptors, which when stimulated inhibit noradrenergic neurons, getting rid of inhibition. or we can block the activity in this connection by blocking alpha1 receptors. then it will change the level of inhibition acting on cholinergic neurons and will also produce increase firing. these receptors are normally inhibisomething eh so there is a lot of sites where we can interfere with the system, but ... what changes are seen in narcolepsy? there is increased binding to alpha1 receptors in the amygdala (not in the pons) why in the amygdala? maybe b/c this is the origin of emotion? remember emotions trigger the cataplexy. no changes in alpha2 receptors, but alpha1 agonists and alph2 antagonists are suppressed in narcolepsy. serotonin - not much evidence for its involvement in narcolepsy. but still, antidepressants are themost frequently used drugs to control signs of narcolepsy, perhaps b/c the system is easy to manipulate and gives that extra inhibition by increasing serotonergic activity. serotonin receptor agonists suppress narcolepsy/cataplexy. there is a lot of other sites where changes occur but we have no clues why and whether that is because eh they contribute to expressionn of disorder, or b/c disorder has changed the brain around and these changes are secondary. disorder is often dxd quite late- eh begins to show up at puberty in people, and most data we have are either postmortem or obtained later in life one way or another, so there is ample time for secondary changes to occur. graph showing efficacy of drugs the far right shows 100% sleepiness in normal individuals. when under 100%, individual is more sleepy. 20% sleepy is extremely narcoleptic. so when treated with certain drugs, - they get closer to the 100% level. so dextroamphetamine looks like the most effective one I see on here. most effective ones are some kind of amphetamine. there is a lot of improvement after dextroamphetamine treatment. this is most common treatment in this country. problem - amphetamines have a lot of side effects and they suppress sleepiness but leave a sleep debt - so patients have to take them all the time, more and more, and get addicted and tolerant and have rebound sleepiness if they stop... with this in mind, consider another drug widely used in france at present - soon to be approved by FDA - modafinil. a far relative of amphetamines, keeps you awake without the aftereffect or the high. no sleep debt. neurochemically, it was looked at where it binds in brain and what changes occur after dosing - it is more selective. it hits much better those areas that are involved, and it turnsout one of most important bindings of this drug in brain is the hypothalamic area that we think causes the feelingn of sleepiness to accumulate in the form of some chemical we do not know about. downside of the drug is that produces a feelign of overconfidence - performance does nnot match up to how well person thinks they are performing. read article in handout for more info. genetic aspects - in humans there is quite large evidence that the disorder is aggregated in certain communes (?) and there is a site on chromosome 6 that contains several alleles that correlate strongly with narcolepsy. if you look for peop;le who express this combination, and have cataplexy, 90% of them will have this both the allele and cataplexy. on the other hand, about 5% of people with cataplexy do not have this allele. it isn't a gene and we do not know what gene there is but this combination is usually present. from other end if you take all people with this trait and ask how many are narcoleptic that is a low % - 20-30% gotta go. he didn't mention much about autoimmunity...uhoh. ----end-----