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15 Narcolepsy andIdiopathic Hypersomnia
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Table 15.2 Diagnostic criteria for idiopathic hypersomnia
Idiopathic hypersomnia
1. At least 3months of EDS
2. Cataplexy is not present
The MSLT should show a sleep latency of ≤8min and less than two sleep onset REM
3.
periods; if the preceding PSG has a sleep onset REM period (i.e., within 15minutes of sleep
onset), then there should not be a SOREMP on the MSLT.
4.
If the mean sleep latency on the MSLT is >8min, then a total sleep time of at least
11hrs/24hr. period should be demonstrated either with a 24hr. polysomnogram or by wrist
actigraphy and sleep log (averaged over at least 7days)
5. Insufcient sleep syndrome should be ruled out
6. Other sleep, medical, or psychiatric disorders or medications/drugs should not better explain
the EDS and/or MSLT ndings
Adapted from American Academy of Sleep Medicine [
3]
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following an overnight polysomnogram to do a MSLT does not allow for the documentation of a prolonged sleep time. Additionally, the mean sleep latency on the
MSLT may not always be diagnostic, and the short naps scheduled every 2h do not
allow for the demonstration of prolonged unrefreshing naps. Therefore, as an alternative to the MSLT showing a mean sleep latency of ≤8min, the typical nocturnal
sleep duration of at least 11hours can be demonstrated with a 24 hr. polysomnographic recording or by wrist actigraphy and sleep logs over at least 7 days.
Insufcient sleep syndrome and other sleep disorders should also be ruled out [3].
Similar to adults, before a diagnosis of idiopathic hypersomnia is made in children, other sleep disorders, especially insufcient sleep syndrome, and use of recreational drugs should be ruled out. If the sleep duration criteria is being used to
diagnose idiopathic hypersomnia in the pediatric population, age appropriate normal values for total sleep time should be taken into account. A repeat MSLT study
should be considered in patients diagnosed with idiopathic hypersomnia after a certain time interval, because SOREMPs may develop overtime in narcolepsy. If 2 or
more SOREMP are present in the repeat PSG/MSLT study, then the patient should
be reclassied as having NT2.
It is evident by many experts that the current diagnostic criteria have its limitations. It relies on ancillary testing such as the MSLT that is not well validated in all
patient populations and is relatively nonspecic. The stability of repeated MSLT
results is also in question with one study showing only 10–20% of patients with a
positive initial MSLT being positive after the test was repeated in 4 years [62].
Additionally, although validated, the method for measurement of CSF hypocretin
levels has some issues [63–65]. Sakai etal. showed that the typical method of hypocretin measurement actually measures hypocretin-1 metabolites believed to be inactive. Therefore, while standard testing would demonstrate deciency of
“hypocretin- 1” in some NT1 patients, an alternative method of testing which measures the true active hypocretin-1 protein can actually demonstrate some degree of
deciency in NT1 and NT2 patients that were found to have no deciency when
tested with standard techniques [64].
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Accordingly, it stands to reason that diagnostic tools utilizing other markers to
aid in the diagnosis of narcolepsy are needed. For instance, Stephansen etal. demonstrated that a combination of a more thorough evaluation of the overnight polysomnogram and HLA testing yielded a high sensitivity and specicity for NT1
diagnosis. A PSG analysis revealing unusual sleep stage overlap alone achieved a
sensitivity of 91% and specicity of 96%, and when combined with testing showing
HLA-DQB1*0602, the specicity increased to 99% [66]. Identication of REM
sleep without atonia (in at least 8% of stage REM sleep epochs) in the pediatric
population has demonstrated high specicity for the diagnosis of narcolepsy [67].
Additionally, Murer etal. veried that sleep stage analysis with better characterization of REM sleep duration and sleep stage sequence during the PSG contributed to
a higher MSLT specicity for narcolepsy [68].
Other features in patients with narcolepsy have been identied, and future tools
utilizing these ndings may aid in diagnosing narcolepsy or differentiating it from
other hypersomnias. For instance, the frequency and distribution of eye movements
during various sleep stages throughout the night as well as while awake was shown
to be signicantly different in NT1 patients compared to clinical controls as well as
NT2 patients [69]. Furthermore, heart rate variability abnormalities during stage
NREM 2 and non-dipping blood pressure patterns were found to be more prevalent
in NT1 patients compared to control groups [70, 71]. Additionally, certain neuroanatomical correlates on neuroimaging studies may also contribute to diagnosing
narcolepsy and other hypersomnias [72].
I. Ahmed and M. Thorpy
Differential Diagnosis
Excessive sleepiness is common to many sleep disorders, besides narcolepsy and
idiopathic hypersomnia, and can also be a normal phenomenon in certain circumstances (e.g., sleep deprivation). Some of these sleep disorders can be differentiated
from narcolepsy or idiopathic hypersomnia by history. For instance, identication
of a disruptive environmental feature during sleep may lead one to the diagnosis of
an environmental sleep disorder. A history of sleeping less than expected from ageadjusted normative data or having a sleep period that is delayed, advanced, or irregular would suggest behaviorally induced, insufcient sleep syndrome or a circadian
rhythm disorder, respectively. A description of normal sleep between episodes of
hypersomnia can suggest a diagnosis of recurrent hypersomnia. Certain psychiatric
disorders (e.g., depression or substance abuse) can also be responsible for excessive
sleepiness and are identiable on history.
Narcolepsy is commonly comorbid with several medical and psychiatric disorders that can not only cause a misdiagnosis but can complicate narcolepsy treatment. Cardiac, mental, neurologic, gastrointestinal, renal, and pulmonary disorders
are more common in narcolepsy [73]. Cardiac disorders can complicate therapy as
some narcolepsy medications can cause cardiac arrhythmias or exacerbate uid
retention and add to hypertension or heart failure. Of the mental disorders,
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depression and anxiety are particularly prevalent and are common causes of delay
in narcolepsy diagnosis. Anxiety disorders can contribute to stimulant medication
failure due to exacerbating adverse effects [74]. In addition, concurrent sleep disorders, such as obstructive sleep apnea syndrome, sleep deprivation, restless legs syndrome, and circadian rhythm disorders, can contribute to, or mask, a narcolepsy
diagnosis.
Disorders that cause excessive sleepiness cannot always be identied by history
alone; additional studies to differentiate them from narcolepsy and idiopathic hypersomnia are often required. A polysomnogram will help identify sleep disordered
breathing. Imaging studies may discover the presence of a brain tumor or stroke
(although other ndings on exam are also usually present). Blood work or CSF
analysis can help identify metabolic abnormalities or encephalitis as a cause of
sleepiness. There was a case report by Maestri etal. [75] on a patient that was diagnosed with idiopathic hypersomnia but after further evaluation was found to have an
insulinoma. After management of the insulinoma, his symptoms of excessive sleepiness resolved. Another report by Shinno etal. [76] identied a patient with idiopathic hypersomnia who was subsequently found to have subclinical hypothyroidism;
after management with levothyroxine his sleepiness improved.
History and additional laboratory studies are also useful in ruling out disorders
that can mimic cataplexy. Transient weakness episodes can represent transient ischemic attacks (TIAs) if there is no history of an association with emotion or if there
is a history of vascular risk factors and/or stroke. Seizures, syncope, and brainstem
or diencephalic tumors can look like cataplexy; a positive EEG may suggest seizures; imaging studies can help identify tumors; and a history of loss of consciousness may help differentiate syncope or seizures from cataplexy.
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Excessive Sleepiness Due to Head Trauma
Sleep disturbances, including excessive sleepiness, can occur as a result of traumatic brain injury (TBI); accordingly, TBI should be considered in the differential
diagnosis of excessive sleepiness. Some researchers contend that the excessive
sleepiness is due to the increased prevalence of obstructive sleep apnea and periodic
limb movement disorder that is seen in TBI patients [77]. In addition, changes in
nocturnal sleep pattern seen in TBI patients are similar to those of depressed
patients, namely, increased nighttime awakenings and longer sleep onset latency
[78]. It is speculated that the sleepiness is due in part to this disturbed nocturnal
sleep and that treatment of concomitant mood disorders may improve the sleepiness
in the TBI patients; however, further research needs to be done in this area.
Hypothalamic damage, not necessarily visible on imaging studies, may be
responsible for the excessive sleepiness that is seen in many TBI patients. The
ICSD-3 classied this group of TBI patients under several separate subtypes: NT1
or NT2 due to a medical condition and hypersomnia due to a medical condition
(posttraumatic hypersomnia subtype). A 2007 study found that the CSF
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hypocretin- 1 levels were decreased in these TBI patients, and a follow-up study in
2009 demonstrated the number of hypocretin neurons in the hypothalamus was signicantly reduced [79, 80]. The loss of hypocretin is likely the etiology underlying
TBI associated with narcolepsy and possibly post-traumatic hypersomnia.
I. Ahmed and M. Thorpy
Treatment
There is no known cure for either narcolepsy or idiopathic hypersomnia; however,
with respect to idiopathic hypersomnia, there are reports of spontaneous remission
[25]. For those with persistent disease, treatment is targeted at symptom management. Even with optimum management, the EDS in narcolepsy and idiopathic
hypersomnia patients, and the cataplexy in narcolepsy patients, are seldom completely controlled.
Nonpharmacologic Management
Nonpharmacologic management should be initiated in all patients. Patient education is an important component of any treatment plan. Good sleep habits with avoidance of sleep deprivation and/or irregular sleep patterns should be emphasized. In
narcolepsy patients, the scheduling of short naps (15–20min) 2–3 times/day can
help control EDS and improve alertness, but this is impractical in many settings.
Napping, in contrast, is not recommended for management of sleepiness in patients
with idiopathic hypersomnia as it usually does not help and may result in unpleasant
sleep inertia. Patients and family members should also be warned about the potential dangers of sleepiness relative to driving and/or in other hazardous settings.
Typically, lifestyle changes alone are not enough to adequately control the symptoms of either narcolepsy or idiopathic hypersomnia; most patients require lifelong
medication.
Pharmacologic Management ofSymptoms Common toBoth
Narcolepsy andIdiopathic Hypersomnia
Pharmacological management of EDS, with a few exceptions, is similar in both
narcolepsy and idiopathic hypersomnia; however, it should be noted that randomized, double-blind, placebo-controlled clinical trials have not been done on idiopathic hypersomnia patients. Stimulants, such as methylphenidate or
dextroamphetamine, have previously been used as rst-line therapy. This transitioned to the use of modanil and armodanil as rst-line treatment for most patients
[81, 82], and more recently a newer agent, solriamfetol, might be the next agent that
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will gain acceptance as initial therapy for EDS treatment. Most clinical studies of
stimulant medications report objective improvements in sleepiness in 65–85% of
subjects.
Common adverse effects associated with stimulants include nervousness, headaches, irritability, tremor, insomnia, anorexia, gastrointestinal upset, and cardiovascular stimulation [83]. The development of drug tolerance or addiction can also
occur; however, this risk is thought to be less than in other patient groups.
Modanil is generally well tolerated, with headache and nausea being the most
common side effects. Rarely, severe rashes and allergic reactions can occur.
Modanil also increases the metabolism of ethinylestradiol which lessens the efcacy of oral contraceptive agents. Armodanil is the long-acting dextro-enantiomer
component of racemic modanil, which has equal amounts of S- and R-modanil.
It has a similar therapeutic and side effect prole to racemic modanil, but with the
advantage of having a longer elimination half-life (t ½) (3–4h for S-modanil vs.
10–15h for armodanil) [84]. Although comparative studies have not been done in
narcolepsy or idiopathic hypersomnia, armodanil has been shown to be effective
and produce longer wakefulness than racemic modanil in patients with sleepiness
due to acute sleep loss [85].
Sodium oxybate, the sodium salt of gamma-hydroxybutyrate (GHB), an endogenous substance in the brain, is an effective medication in the treatment of daytime
sleepiness cataplexy and sleep disruption in narcolepsy [81, 86, 87] and perhaps
also the sleep-related hallucinations and sleep paralysis episodes prominent in this
disorder. It is currently being studied in patients with idiopathic hypersomnia.
Sodium oxybate’s adverse effects include nausea (19%), dizziness (18% incidence),
headache (18%), nasopharyngitis (6%), somnolence (6%), vomiting (8%), and urinary incontinence (6%) with most described as mild or moderate in severity.
Dizziness, nausea, vomiting, and enuresis may be dose related [88].
Pitolisant is a medication that acts as an antagonist/inverse agonist on the histamine 3 receptors which results in increase of brain histamine levels that subsequently
help maintain wakefulness. The more common adverse reactions include headaches,
insomnia, nausea, and anxiety. Caution needs to be taken in patients at cardiac risk
for prolonged QTc. As with modanil, pitolisant also increases the metabolism of
ethinylestradiol and therefore will lessen oral contraceptive efcacy. Although
pitolisant does not currently have an FDA-approved indication to treat cataplexy,
studies have also shown improvement in this symptom in treated NT1 patients [89,
90]. Alternative forms of H3 receptor inverse agonists are in investigation.
Solriamfetol works by inhibiting reuptake of both dopamine and norepinephrine.
It has a similar adverse reaction prole to other medications with headache being
most common followed by nausea, decreased appetite, nasopharyngitis, dry mouth,
and anxiety. With its relatively unique mechanism of action, efcacy, and side effect
prole, it has been increasingly used as rst- or second-line therapy for the treatment of EDS [91]. It has an FDA-approved indication for the treatment of EDS in
patients with narcolepsy.
Currently, sodium oxybate, amphetamines, methylphenidate, modanil,
armodanil, solriamfetol, and pitolisant are the only medications FDA approved in
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the United States for the treatment of EDS in narcolepsy. Alterations of gamma
amino butyric acid (GABA) levels in the brain with GABA-A receptor agonists
(e.g., clarithromycin and umazenil) have shown some efcacy in the treatment of
EDS in narcolepsy patients [92]. Medications targeting the hypocretin receptors for
the treatment of EDS are in development. One such medication currently undergoing clinical trials is TAK-994, which is a hypocretin-2 receptor selective agonist that
has shown promise in preliminary studies. Other medications under investigation
include a low sodium formulation of oxybate, and a new drug application (NDA)
has been submitted for approval by the FDA.A long-acting, once-nightly formulation of sodium oxybate has been studied, and an NDA is about to be submitted.
Reboxetine, a norepinephrine reuptake inhibitor, is currently undergoing evaluation
in narcolepsy. Other medications have been reported to have benecial results, but
little data is available [93]. All medications are used “off-label” for the management
of excessive sleepiness due to idiopathic hypersomnia.
I. Ahmed and M. Thorpy
Pharmacologic Management ofSymptoms Specic
toNarcolepsy
Cataplexy
Although treatment of sleepiness can have a mild benecial effect on cataplexy,
most wake-promoting agents/stimulants do not provide sufcient relief from cataplexy. Pitolisant, as mentioned earlier, has been shown to improve both EDS and
cataplexy symptoms in patients with narcolepsy. Most medications used for the
treatment of cataplexy have REM sleep suppressant properties and/or increase
aminergic (mainly by blocking the norepinephrine (NE) transporter) activity [94].
Tricyclic antidepressants (TCAs), serotonin reuptake inhibitors, and NE reuptake
inhibitors have demonstrated benet in animal studies (which is believed to be a
function of the NE reuptake inhibition). Sodium oxybate is highly efcacious for
the treatment of cataplexy in narcolepsy and, as of the writing of this chapter,
remains the only FDA-approved medication for its management.
Several small open-label studies and several decades of use have demonstrated
that the TCAs desmethylimipramine, protriptyline, imipramine, and desipramine
have benecial anticataplectic effects [95]; however, clomipramine remains the
most widely used. Adverse events commonly associated with TCA therapy include
nausea, anorexia, dry mouth, urinary retention, and tachycardia. Men may encounter decreased libido, impotency, or delayed ejaculation. An unusual property of
TCAs is the rebound cataplexy phenomenon that occurs upon abrupt discontinuation of TCA therapy. When severe, this is known as status cataplecticus and can be
disabling for several days [96].
Similar to TCAs, the SSRIs including uvoxamine, zimeldine, femoxetine, paroxetine, and uoxetine have all demonstrated anticataplectic activity; however,
uoxetine appears to be the most commonly used of the SSRIs for the treatment of
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cataplexy [97]. As a class, the SSRIs are generally less efcacious than TCAs; however, they have a better safety prole and are better tolerated than the older antidepressants. Reported adverse events include headache, nausea, weight gain, dry
mouth, and delayed ejaculation [97]. Other antidepressant medications have also
been found to have some anticataplectic activity; these include monoamine oxidase
inhibitors such as phenelzine and selegiline as well as other atypical antidepressants
with pronounced NE reuptake inhibition, such as venlafaxine and atomoxetine.
Given the evidence supporting an autoimmune etiology of narcolepsy, intravenous immunoglobulin therapy (IVIG) has been used for the treatment of narcolepsy.
Unfortunately, the studies evaluating its use are limited, and the few case reports
have yielded conicting results. Currently, it is not considered a valid treatment
option [98].
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Fragmented Nocturnal Sleep
As mentioned earlier, sodium oxybate taken at bedtime and again during the night
increases slow wave sleep, decreases light sleep (stage N1 sleep), and decreases the
number of arousals. REM sleep is initially increased, but then decreases after
increasing dose and duration of therapy [87].
Other medications have also been tried in the management of the fragmented
sleep of narcoleptics. A study evaluating 0.25mg of triazolam taken at bedtime
showed improved sleep efciency and overall sleep quality, but had no benecial
effect on daytime sleepiness [99]. Unlike the GABA-A receptor agonists mentioned
earlier, baclofen is actually a GABA B receptor agonist that has shown some efcacy in the treatment of EDS as well as sleep fragmentation in adolescent narcolepsy. Morse et al. described ve patients that failed treatment with traditional
narcolepsy medications, but reported subjective improvement in sleep maintenance
and daytime sleepiness. Accordingly, baclofen may be an effective treatment option
in narcolepsy that warrants further study [100]. Other medications such as zolpidem, eszopiclone, or clonazepam have been used with varying success in some
patients (personal experience and conversations with other sleep medicine physicians). For symptoms of sleep paralysis and hypnagogic hallucinations, TCAs,
other REM suppressant medications, and sodium oxybate have been successful.
Conclusion
Narcolepsy and idiopathic hypersomnia are primary central hypersomnias characterized by either EDS or prolonged nocturnal sleep. Whereas cataplexy is pathognomonic for narcolepsy, there is no pathognomonic symptom for idiopathic hypersomnia.
Narcolepsy is believed to be due to a deciency in hypocretin- producing neurons in
the lateral hypothalamus, possibly as a result of an autoimmune disorder. The
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I. Ahmed and M. Thorpy
pathophysiology of idiopathic hypersomnia is currently unknown. The diagnosis is
currently made by a combination of appropriate clinical symptoms, polysomnography followed by an MSLT and/or CSF hypocretin-1 testing. There are both nonpharmacologic and symptom directed pharmacologic treatments using medications
targeting monoaminergic or GABA receptors. New formulations of oxybate and
orexin receptor agonists are under investigation, as well as alternative NERIs and
histaminergic medications. The effective pharmacologic management of narcolepsy
is becoming a reality, although the treatment options are many and medication combinations are usually required for optimal management of cataplexy and excessive
sleepiness.
Summary of Keypoints
• Narcolepsy is a syndrome consisting of EDS, cataplexy, sleep paralysis,
and hypnagogic hallucinations. Additional features include automatic
behaviors and fragmented or disrupted nighttime sleep.
• Classic narcolepsy symptoms are difcult to identify in children as sleepiness may manifest as inattentiveness, lack of energy, behavioral problems,
or decreased performance.
• Cataplexy is the most specic symptom of narcolepsy consisting of an
abrupt, bilateral loss of skeletal muscle tone, triggered by sudden emotion
such as laughter. Cataplexy is seen in 60–90% of patients with narcolepsy.
• Poor nighttime sleep is also common in narcolepsy, due to a dysfunction of
central sleep regulation which causes frequent transitions between sleep
and wakefulness throughout the entire 24-hcycle.
• Most cases of NT1 are associated with reduced or absent csf hypocretin;
cases of NT2 may be caused by a partial loss of hypocretin-containing
hypothalamic neurons.
• Sleep disturbances, including excessive sleepiness, may occur following
TBI.It is important to consider TBI among the causes of EDS.
• Appropriate sleep hygiene is critically important in patients with narcolepsy or idiopathic hypersomnia. Short naps (15–20min) 2–3 times/day
can help control sleepiness in narcolepsy and improve alertness. However,
scheduled naps are not recommended in idiopathic hypersomnia.
• Alerting medications are the mainstay of management of daytime sleepiness in patients with narcolepsy or idiopathic hypersomnia, with most
clinical studies reporting objective improvements in sleepiness in 65–85%
of subjects. Cataplexy can be effectively treated with oxybate, H3 receptor
inverse agonists, or NERIs.
• New formulations of current medications and orexin receptor agonists are
currently under investigation and hold promise of greatly improving patient
management.
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