Central Disorders of Hypersomnolence

Rui M. De Sousa

Tamara Kaye Sellman

LEARNING OBJECTIVES

On completion of this chapter, the reader should be able to:

1. Describe the two different types of narcolepsy.
2. Name and describe the narcoleptic tetrad.
3. Explain the role of hypocretin in sleep.
4. Define hypersomnia.
5. Describe sleep drunkenness.
6. Name the three salient features of Kleine-Levin syndrome.
7. Name medical disorders that may cause hypersomnia.
8. Name drugs or substances that may cause hypersomnia.
9. Name psychiatric disorders that may cause hypersomnia.

KEY TERMS

Actigraphy

Advanced sleep phase syndrome (ASPS)

Areflexia

Atonia

Cataplexy

Conversion disorder

CSF hypocretin-1

Differential diagnosis

Delayed sleep phase syndrome (DSPS)

Excessive daytime sleepiness (EDS)

Epworth Sleepiness Scale (ESS)

γ-aminobutyric acid (GABA)

Human leukocyte antigen (HLA)

Hyperphagia

Hypersexuality

Hypnagogic and hypnopompic hallucinations

Hypocretin/orexin

Idiopathic

Insufficient sleep syndrome

Kleine-Levin syndrome (KLS)

Long sleep

Mazindol

Menstrual-related hypersomnia

Modafinil

Multiple sleep latency test (MSLT)

Maintenance of wakefulness test (MWT)

Narcolepsy tetrad

Narcolepsy types 1 and 2

Objective versus subjective tests

Oxford Sleep Resistance Test (OSLER)

Pitolisant

Periodic limb movement disorder (PLMD)

Posttraumatic hypersomnia

Rapid eye movement (REM) related

Seasonal affective disorder (SAD)

Sedating substances

Short sleep

Sleep debt

Sleep diary

Sleep drunkenness

Sleep hygiene

Sleep inertia

Sleeping Beauty syndrome

Sodium oxybate

Sleep-onset REM period (SOREMP)

Stanford Sleepiness Scale (SSS)

CENTRAL DISORDERS OF HYPERSOMNOLENCE—INTRODUCTION

Introduction

Hypersomnia, derived from the Greek hyper (over, above, too much) and the Latin somnus (sleep), literally refers to the condition of sleeping too much. However, in current medical terminology, both hypersomnia and the related word hypersomnolence are used more broadly and interchangeably to indicate long sleep duration, excessive daytime sleepiness (EDS), or both.

Hypersomnolence, the state of being excessively sleepy when a person should be alert, is one of the most common sleep-related complaints that patients mention to their doctors. The International Classification of Sleep Disorders (ICSD-3) describes eight central disorders of hypersomnolence. Although the ICSD-3 does not explicitly divide these eight sleep disorders into two categories, we can discern two basic groups of hypersomnias: the primary hypersomnias (not caused by another condition) and secondary hypersomnias (caused by or related to a different condition).

The four primary hypersomnias are those occurring independently of any other condition or effect. They include the two types of narcolepsy, IH, and recurrent hypersomnia.

The most salient feature of primary hypersomnia is an extreme, overwhelming sleepiness during periods when the patient should be alert and awake (usually the daytime hours). Even though the patient’s nighttime sleep may seem to be of normal quality and timing, patients still feel sleepy and lethargic during the day.

A vast array of conditions can cause secondary hypersomnias. They aren’t limited to just other sleep disorders like obstructive sleep apnea (OSA) or periodic limb movement disorder (PLMD), but extend to other medical conditions, disorders, and diseases. For example, drugs (prescribed or not) and other substances will often have side effects that cause extreme sleepiness in those who take them. Hypersomnia is also often noted in psychiatric disorders.

In addition, people sometimes curtail their normal nocturnal sleep on a regular basis, resulting in inappropriate daytime sleepiness.

EDS is the primary concern for many patients presenting with sleep complaints. EDS is a significant public health problem, with prevalence in the community estimated to be anywhere from 4% (2), 18% (3), or almost 28% (4). Yet, because it is an invisible condition, hypersomnolence is linked to social stigmas which often prevent patients from seeking help. Patients who are excessively sleepy are also at greater risk for psychosocial problems, behavioral disorders, motor vehicle and workplace accidents, and obesity (5).

There are several tools, both objective and subjective, that can be used to assess and diagnose sleepiness and disorders of hypersomnolence:

Polysomnography (PSG), the multiple sleep latency test (MSLT), and the maintenance of wakefulness test (MWT) are used to objectively measure sleep and propensity to sleep.
In some cases, actigraphy is an adequate proxy in the absence of PSG.
Scaled questionnaires such as the Epworth Sleepiness Scale and the Stanford Sleepiness Scale that provide subjective information to measure sleepiness.
Self-reported sleep diaries and detailed medical histories are also crucial tools when diagnosing or treating hypersomnia.

Some significant changes were made to the ICSD between the second and third edition that deserve mention here:

The narcolepsies are no longer divided by the presence or absence of a symptom (narcolepsy with cataplexy vs. narcolepsy without cataplexy [6]); they are now divided by their inferred pathogenesis:
- narcolepsy type 1 (absent or low hypocretin levels)
- narcolepsy type 2 (normal hypocretin levels [7])
IH was also streamlined, from IH (with and without long sleep time) to a more simplified diagnosis of IH.
The recurrent hypersomnias were also combined into just one major concern: KLS and a subtype related to menstruation.

The rest of this chapter will mirror the general blueprint of the hypersomnia disorders as outlined in the ICSD-3.

CENTRAL DISORDERS OF HYPERSOMNOLENCE—NARCOLEPSY

Introduction

Narcolepsy is a rare, chronic, neurologic sleep disorder with no known cure. This lifelong condition is characterized by EDS and deterioration in the brain’s ability to control sleep-wake cycles.

There are two subtypes, narcolepsy type 1, with extremely low concentration of hypocretin, and narcolepsy type 2, with near-normal hypocretin levels.

The Narcolepsy Tetrad

Although the severity and range of symptoms may vary, narcolepsy is generally characterized by a tetrad of symptoms:

Excessive daytime sleepiness: EDS is the most common feature of narcolepsy. It can manifest as difficulty staying awake, irresistible microsleeps, increased napping, memory loss, cognitive problems, and struggles in work, school, or personal life. This sleepiness usually persists throughout the day, irrespective of the quality or quantity of sleep during the night. Naps are characteristically short but refreshing, although the normal wakefulness state between naps will not typically last. The narcoleptic will soon return to a sleepy state after a nap.
Cataplexy: This is a symptom in which strong emotion or laughter causes a person to suffer sudden physical collapse caused by an abrupt loss of voluntary muscle tone (atonia). It is characterized by the preservation of consciousness and memory and occurs for a short duration (less than a few minutes). It is believed that in cataplexy, the processes that produce paralysis during rapid eye movement (REM) sleep become inappropriately active during times of wakefulness.

Typical examples of cataplexy include simple buckling of the knees, head dropping, facial muscle drooping, sagging of the jaw, or weakness in the arms. Slurred speech or a complete inability to speak may also be observed. At times, these “drop attacks” or “sleep attacks” can escalate into episodes of complete muscle paralysis lasting up to several minutes. However, the patient often has sufficient warning of cataplexy and can sit or lay down in time to prevent falls or injury. Episodes may occur several times per day or a few times per year. Longer episodes can sometimes evolve into sleep, often with hypnagogic hallucinations.

Cataplexy usually develops within a few months of EDS symptoms, but may develop 10 to 30 years later. Cataplexy has been reported to improve with age, likely after the patient has learned to better control his or her emotions (7). In rare cases, withdrawal from certain antidepressant or anticataplectic drugs can result in status cataplecticus, a state in which the patient is cataplectic for a prolonged time, often hours (7, 8).

The importance of cataplexy for the diagnosis of narcolepsy has been recognized since its first connection with narcolepsy. Historically, narcolepsy was divided into the presence or absence of cataplexy. More recently, however, this approach has been abandoned for a different model focusing on underlying disease processes rather than witnessed symptoms. The ICSD-3 now divides narcolepsy into two distinct subgroups:
- Those having narcolepsy with very low levels of hypocretin in the cerebrospinal fluid (CSF), often manifesting as cataplexy
- Those having narcolepsy with near-normal con-centrations of hypocretin, which does not result in cataplexy (1)
Hypnagogic and hypnopompic hallucinations: Hallucinations are a common characteristic of narcolepsy. They occur either as the patient is falling asleep (hypnagogic) or right as he or she is waking up (hypnopompic). Although the majority of hallucinations are visual, they can also be auditory or tactile (8).

The hallucinations are often unpleasant, tinged with an underlying current of fear or threat (7). Common themes are hallucinations of an intruder in the room or a sensation of floating. Hypnagogic hallucinations are often associated with sleep attacks (cataplexy). Like cataplexy, these hallucinations are believed to be REM-related phenomena (dreams) intruding into the wake state.
Sleep paralysis: Sleep paralysis is a state in which a person is physically immobile, but fully conscious before or following a period of sleep. This symptom has been reported in 20% to 50% of narcoleptics. Patients with cataplexy experience an inability to move their limbs or lift their head, or describe difficulty breathing. Sleep paralysis is often distressing because it may last up to a few minutes. It is usually interrupted by noise or other stimuli (7). Just like cataplexy and hallucinations, sleep paralysis is likewise believed to be a particular feature of REM-related atonia manifesting into wakefulness. It is also more commonly noted with hypnagogic hallucinations.

It is also important to note that sleep paralysis and hypnagogic hallucinations are not specific for narcolepsy. These symptoms can occur in 15% of otherwise normal persons and can often be precipitated by sleep loss, schedule change, or alcohol consumption. These symptoms can also occur in IH. Narcoleptic hallucinations are sometimes misdiagnosed as schizophrenic ones (7, 8). However, most of the narcolepsy-related hallucinations tend to be visual, whereas the schizophrenic ones are more likely to be auditory.

The presentation of this tetrad is variable in symptoms and intensity across patients and over time. Only about 10% of patients concurrently exhibit all components (9). Other characteristic features outside the narcolepsy tetrad include objective differences in REM sleep (namely, a short latency to REM sleep and REM episodes during short naps), fragmented nocturnal sleep, automatic behavior, loss of concentration and memory, and blurred vision (1, 10).

Presently, treatment for both forms of narcolepsy is tailored to the individual and focused on managing symptoms with various medications and lifestyle changes.

Literature Review and a History of Narcolepsy

A case study by Gélineau (1880) is recognized for giving narcolepsy its name and for recognizing the disorder as a specific clinical entity.

However, Gélineau did not differentiate episodes of muscle weakness and “sleep attacks” triggered by emotions. The first descriptions of narcolepsy-cataplexy were reported in Germany by Westphal (1877) and Fisher (1878). They both reported irresistible sleepiness and episodes of muscle weakness triggered by excitement (11).

Following WWII, as a result of the prevailing psychoanalytic influence, sleep researchers were pressured to describe and treat narcolepsy as a psychosomatic disorder. However, work by Kleitman and Daniels refocused research to investigate an organic cause to narcolepsy (11).

In 1960, Vogel was the first to report REM sleep at sleep onset in a narcoleptic patient, which was confirmed and then extended and expanded by Rechtschaffen and Dement a few years later. These observations were the basis that led to the hypothesis that narcolepsy and REM were associated. This also led to the development of the MSLT test, discussed in further detail later. The first narcolepsy clinic was opened in Stanford University in 1964 by Dement.

The first epidemiologic studies by Solomon (1945) concluded a prevalence rate of 20 per 100,000 (12). Subsequent studies by Roth (13), Dement (14, 15), and Honda (16) estimate the prevalence from 40 to 160 per 100,000. These numbers are the most commonly quoted even today.

In the early 1900s, ephedrine was used as a treatment for EDS in narcolepsy until Prinzmetal and Bloomberg introduced amphetamines in 1935. In 1959, Yoss and Daly used methylphenidate to treat narcolepsy, and in 1960, Akimoto, Honda, and Takahashi used imipramine (a tricyclic antidepressant) in the treatment of human cataplexy, establishing the stimulant/antide-pressant model used to treat narcolepsy to this date (11).

In the mid-1990s, research into the neurogenesis of narcolepsy by two separate and independent teams of researchers revealed the role of a new neuropeptide simultaneously named both hypocretin and orexin. Today, both terms are used interchangeably to reference the same neuropeptide (17, 18).

Prevalence of Narcolepsy

Prevalence of narcolepsy is estimated to be between 0.02% and 0.16% of the general population, with possible ethnic or genetic factors influencing the observed variance in rates (19).

Symptoms usually appear in the middle of adolescence, but diagnosis is typically made later in life. A second, although smaller, peak is observed in the mid-30s. Although the prevalence of narcolepsy type 2 in first-degree relatives of patients with narcolepsy is only 1% to 2%, this still represents a 10 to 40 times higher relative risk of getting narcolepsy compared with the general population (19, 20).

Genetic Determinants of Narcolepsy

Genetic predisposition is suspected because of narcolepsy’s strong association with the human leukocyte antigen (HLA), leading the first investigators to believe that narcolepsy was an autoimmune disorder. Early genetic research into narcolepsy showed a relation with the HLA genes, more specifically, the subtypes DR2/DRB1*1501 and DQB1*0602. Other HLA subtypes have shown a weaker association with narcolepsy.

Current research focuses on the HLA DQB1*0602 allele, present in over 90% of narcoleptic patients. However, because about 20% of the population carries this allele and only 0.05% of the population develops narcolepsy, this association is not specific (21).

Although the HLA research is most well known, there are many studies that point to other genetic links with narcolepsy, including polymorphisms in the T-cell receptor-α (TCRA) locus on chromosome 14, TNFSF4 (also called OX40L), Cathepsin H (CTSH), the purinergic receptor P2RY11, the DNA (cytosine-5)-methyltransferase 1, and carnitine palmitoyltransferase (CPT1B) (20).

Despite the genetic evidence in narcolepsy, the picture is complex and incomplete. In fact, even with monozygotic (identical) twins, chances are that narcolepsy is not shared between the two, with reported concordance rates of between 25% and 31% (22). Genetic expression is also likely influenced by environmental factors.

Environmental Factors in Narcolepsy

The nature of possible environmental triggers is unknown; nevertheless, onset of narcolepsy is frequently associated with environmental factors. These include head trauma, stroke, and change in the sleep-wake cycle (22). Recent studies have also shown an association with streptococcal infection (23, 24), influenza A virus subtype H₁N₁ (swine flu) infection (as well as vaccination in European countries) (25), and exposure to heavy metals, insecticides, and weed killers (26). Table 16-1 lists the etiologic factors associated with narcolepsy.

Narcolepsy: A Tale of Two Types

Narcolepsy Type 1

Diagnostic criteria for narcolepsy type 1 (1). Criteria A and B must be met:

The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring over a period greater than or equal to 3 months.
The presence of one or both of the following:
- Cataplexy and a mean sleep latency of less than or equal to 8 minutes and greater than or equal to two sleep-onset REM periods (SOREMPs) on an MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may replace one of the SOREMPs on the MSLT.
- CSF hypocretin-1 concentration, measured by immunoreactivity, is either less than or equal to 110 pg per mL or less than one-third of mean values obtained in normal subjects with the same standardized assay.

To diagnose narcolepsy type 1, the patient must present with irresistible sleep attacks and either cataplexy or decreased hypocretin levels.

Narcolepsy type 1 was previously known as narcolepsy with cataplexy. Narcolepsy type 2 was previously known as narcolepsy without cataplexy. This underlies the role that cataplexy has had in the history of narcolepsy and its diagnosis. However, with the discovery of the neuropeptide hypocretin (also known as orexin), which plays an important role in diagnosing narcolepsy, the ICSD-3 elected to categorize narcolepsy by the absence (type 1) or presence (type 2) of hypocretin, rather than using cataplexy in the diagnostic criteria.

Narcolepsy Type 1: The Role of Hypocretin

Hypocretin is a hypothalamic neuropeptide that is involved in the regulation of arousal, wakefulness, and appetite. Using immunoassay techniques, hypocretins were first discovered in 1998 (17), when their roles in sleep regulation became immediately evident. Narcolepsy type 1 is caused by a lack (or significant reduction) of this neuropeptide in the brain due to destruction of the cells that produce it.

Hypocretins are measured in the CSF, collected via a lumbar puncture (spinal tap). When testing for narcolepsy type 1, CSF concentration of hypocretin is either less than 110 pg per mL or less than one-third of mean values of normal subjects (1).

In the healthy population (those with well-regulated sleep), hypocretins are released when awake to target neurons that promote wakefulness and suppress REM sleep. In people who have narcolepsy type 1, up to 95% of these neurons die off (20, 27). Other neurologic insults may also reduce hypocretin concentrations, such as hypothalamic lesions or injuries to the brain characterized as vascular, inflammatory, or traumatic in nature (see Table 16-1). These insults can affect hypocretin levels either permanently or temporarily (28). The consequent lack of hypocretins results in prolonged sleepiness and poor control of REM sleep. REM sleep can become so poorly regulated that the paralysis or dreaming that normally occurs only in REM sleep can intrude upon wakefulness, causing cataplexy and dreamlike hallucinations.

Table 16-1 Known Primary and Secondary Etiologies of Narcolepsy

Hypocretin deficiency

Hypothalamic lesions

Inherited disorders (e.g., Niemann-Pick disease type C)

Brain tumors

Craniocerebral trauma

Cerebrovascular disorders

Encephalomyelitis

Neurodegenerative diseases

Demyelinating disorders

Data from American Academy of Sleep Medicine. (2014). International classification of sleep disorders (3rd ed.). Darien, IL: Author.

Although low levels of hypocretin can assist in diagnosing narcolepsy, one must be aware that low levels can also be observed in other neurologic disorders, such as Guillain-Barré syndrome, Miller Fisher syndrome, advanced forms of Parkinson disease (PD), and other neurologic conditions associated with lesion or dysfunction of the lateral hypothalamus (29).

Lower levels of hypocretin aren’t the only concern for those with narcolepsy type 1. Cataplexy and sleep paralysis are states in which the processes that produce paralysis during REM sleep become activated during wakefulness. During REM sleep, most muscles are temporarily paralyzed by processes controlled by the lower brainstem. The release of the neurotransmitters norepinephrine and serotonin is typically blocked by the brainstem during wakefulness in those experiencing cataplexy or sleep paralysis. Along with reduced levels of hypocretins, levels of these other neurotransmitters may also be lower, permitting abnormal periods of paralysis even during wakefulness. This observation provides a basis for treating cataplexy with antidepressants, which serve to increase brain levels of norepinephrine and serotonin.

The role of hypocretins may also explain how cataplexy may be triggered by strong emotions. The amygdala and prefrontal cortex, brain regions that regulate emotional responses, connect with the paralysis pathways in the brainstem. Neurons in the amygdala and prefrontal cortex have been found to be active during cataplexy.

Researchers have also learned that deactivating either of these regions reduces cataplexy in mice with narcolepsy. As these triggering pathways become better understood, it may be possible to target them with new medications (30).

Narcolepsy Type 2

Diagnostic criteria narcolepsy type 2 (1). Criteria A to E must be met:

The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring over a period greater than or equal to 3 months.
A mean sleep latency of less than or equal to 8 minutes and greater than or equal to two sleep-onset REM periods (SOREMPs) is found on an MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal PSG may replace one of the SOREMPs on the MSLT.
Cataplexy is absent.
Either CSF hypocretin-1 concentration has not been measured or CSF hypocretin-1 concentration measured by immunoreactivity is more than 110 pg per mL or greater than one-third of mean values obtained in normal subjects with the same standardized assay.
The hypersomnolence and/or MSLT findings are not better explained by other causes such as insufficient sleep, OSA, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal.

As mentioned previously, the ICSD-3 no longer divides narcolepsy by symptom (i.e., presence or absence of cataplexy), but rather by hypocretin levels.

Between 15% and 25% of all narcolepsy cases present without cataplexy. Of these, about 24% will present with abnormally low CSF hypocretin-1 levels, and almost all of these subjects will test positive for the HLA DQB1*0602 antigen (1). These noncataplectic narcoleptics share more in common with narcolepsy type 1 and should be classified as such.

However, because the lumbar puncture procedure is not common, nor recommended, in diagnosing simple narcolepsy, it is possible that some narcolepsy cases may go misdiagnosed as narcolepsy type 2 (noncataplexy) rather than narcolepsy type 1 (which shows low hypocretin concentrations). If so, an estimated 10% of type 2 narcoleptics may go on to develop cataplexy as their disease progresses, necessitating a revised diagnosis to narcolepsy type 1.

Because of the nonspecific nature of the HLA DQB1*0602 test (25% test HLA positive in the general population), it is not recommended as a diagnostic tool for narcolepsy. However, virtually all narcolepsy type 1 cases test positive for the HLA DQB1*0602 antigen. Consequently, a negative HLA test can be a useful shortcut for eliminating a narcolepsy type 1 diagnosis in a known narcoleptic patient with questionable, borderline, or mild cataplexy before a lumbar puncture is performed (1).

The HLA test is safer and less invasive than lumbar puncture. If the HLA test result is positive, then narcolepsy type 1 cannot be ruled out and the lumbar puncture can be performed to definitively test for CSF hypocretin concentration if the test is deemed of necessary value.

Diagnosis

The first step in the diagnosis of narcolepsy is a complete and thorough sleep history from the patient and, if possible, from partners, relatives, and friends.

The physical examination should be normal unless the patient is having an attack of cataplexy. In this case, muscle atonia and areflexia (the absence of reflexes) would be noted, lasting from a few seconds to a couple of minutes.

The sleep history should reflect all or part of the narcoleptic tetrad, most notably EDS, throughout the day, with possible episodes of sleep attacks, varying severity and frequency of cataplexy, possible hypnagogic or hypnopompic hallucinations, and probable sleep paralysis.

The frequency and number of the narcoleptic tetrad markers vary from patient to patient, although EDS is its most persistent symptom.

Because EDS is the most salient feature of narcolepsy, it is crucial that it be measured as accurately as possible. To this end, there are a number of subjective and objective tests at our disposal.

Subjective Scales of Sleepiness

Two widely used subjective measures are the Epworth Sleepiness Scale (ESS) and the Stanford Sleepiness Scale (SSS). The major advantages of both of these scales are that they are rapidly taken, easily scored, and inexpensive to administer.

The Epworth Sleepiness Scale

The ESS is a self-administered questionnaire in which patients rate their likelihood of falling asleep in eight different life situations. Each situation is scored from 0 to 3 and the total score varies from 0 to 24 (see Fig. 16-1). Deceptively simplistic and rudimentary, it has been validated across different clinical situations and various languages (31). Internal consistency and external validity are well established.

Epworth scores can be interpreted as follows:

0 to 5 lower normal daytime sleepiness
6 to 10 higher normal daytime sleepiness
11 to 12 mild EDS
13 to 15 moderate EDS
16 to 24 severe EDS

The Stanford Sleepiness Scale

The SSS is a subjective instrument (see Fig. 16-2) that rates EDS according to subjects’ perceptions of sleepiness/alertness at a particular time. When averaged throughout the day, scores are found to correlate highly with performance tasks known to be sensitive to moderate amounts of sleep (32). The SSS may provide useful information on sleep loss, drug effects, and clinical states in sleep disorders.

Objective Tools for Assessing Sleepiness

Other kinds of tests can be used to collect scientific data that more objectively measure sleepiness as an aid in diagnosing narcolepsy. These include the PSG, the MSLT, genetic testing (HLA), and immunoassay testing (CSF hypocretin-1 levels).

Note that these subjective scales and the objective tests do not always correlate highly with each other, and appropriate clinical judgment and a detailed medical history must be considered as well.

Polysomnogram

PSG is used to reveal other possible causes of EDS, thus possibly ruling out narcolepsy as a cause of daytime sleepiness. It is also used to investigate other features of narcolepsy, such as sleep-onset REM and fragmented sleep. The PSG is most often performed the night before the MSLT.

The Multiple Sleep Latency Test

The MSLT is the standard diagnostic test for narcolepsy (33). It is a diurnal sleep test, with designated nap times every 2 hours.

Figure 16-1 The Epworth Sleepiness Scale. (From Johns, M. W. (1991). A new method for measuring daytime sleepiness: The Epworth sleepiness scale. Sleep, 14(6), 540-545.)

Each nap can last from 20 to 35 minutes, and 4 or 5 scheduled naps, 2 hours apart, are run during the day. Patients are required to stay awake between each nap opportunity and asked to try and sleep during the 20-minute nap window.

Various measures are recorded; of particular interest are sleep latency (the length of time it takes one to fall asleep) and the presence of SOREMPs in each nap window. SOREMPs are more common in narcolepsy than in the general population.

In the MSLT, a SOREMP is defined as a REM period during the first 15 minutes following sleep onset. A mean sleep latency of less than or equal to 8 minutes and greater than or equal to two SOREMPs should be found on an MSLT in order to confirm a narcolepsy diagnosis. A SOREMP found on the preceding nocturnal PSG may replace one of the SOREMPs on the MSLT (1).

A mean sleep latency of less than 5 minutes is indicative of significant EDS; when longer than 10 minutes, it is considered within normal levels of alertness. Approximately 90% of narcoleptics have a mean sleep latency of 8 minutes or less; however, SOREMPs remain a more specific predictor of narcolepsy (1).

Genetic Testing (HLA)

Although narcolepsy (HLA DQB1*0602) genotyping may help rule out narcolepsy when clinical history and sleep studies are inconclusive, it is not diagnostic by itself and should be used only to help when clinical tests
and past medical history are inconclusive. Although this allele is present in a very high percentage of narcoleptic patients, its low specificity limits the diagnostic strength of this test.

Figure 16-2 Stanford Sleepiness Scale. (From Hoddes, E., Zarcone, V., Smythe, H., et al. (1973). Quantification of sleepiness: A new approach. Psychophysiology, 10(4), 431-436.)

Immunoassay Testing (CSF Hypocretin-1 Levels)

Immunoassay testing of hypocretin-1 concentration in the CSF is a valid and reliable way to test for narcolepsy type 1. In short, a low concentration of hypocretin in the CSF meets diagnostic criteria for narcolepsy type 1, even in the absence of cataplexy. Low concentration is defined as less than or equal to 110 pg per mL or less than one-third of mean values obtained in normal subjects.

Differential Diagnosis

One of the biggest challenges in diagnosing hypersomnias relates to arriving at a differential diagnosis, because so many symptoms are shared between this family of sleep disorders. By definition, daytime sleepiness is the most common symptom underlying all hypersomnias. Although IH may present with the extreme EDS that afflicts narcoleptics, people with IH do not have cataplexy (separating them from narcolepsy type 1). Mean sleep latency may be similar in the MSLT; however, IH patients have fewer than two SOREMPs. Meanwhile, sleep efficiency tends to be higher in IH patients, and overall sleep for them is better consolidated. Daytime naps also tend to be longer and less refreshing than naps of narcoleptic patients.

Sleepiness may also be secondary to other sleep disorders, such as OSA, delayed sleep phase syndrome (DSPS), ISS, or PLMD. Sleepiness may also be a direct result of shift work, or the use or abuse of prescribed medications, illicit drugs, environmental toxins, or other substances. Other medical conditions, such as chronic fatigue syndrome, multiple sclerosis, congestive heart failure, depression, and malingering, should also be ruled out.

In short, all of these variables need to be addressed and other disorders or influences ruled out before a diagnosis of narcolepsy can be declared.

Treatment

There is presently no cure for narcolepsy. Treatment involves controlling and improving symptoms, especially daytime sleepiness and cataplexy.

Scheduling several short naps throughout the day (under 20 minutes) has been shown to reduce EDS, both subjectively and objectively, but it is not recommended as the only course of treatment. Other lifestyle strategies include keeping a consistent sleep schedule by going to sleep and waking up at the same
time every day, including weekends. Getting regular exercise and avoiding the use of tobacco, alcohol, or drugs may also help increase energy during the day. These strategies should improve sleep consolidation during the night and could lead to more daytime alertness. However, pharmacologic interventions are currently the most effective way to manage narcolepsy (see Table 16-2).

First-line drug therapy for the management of EDS is currently modafinil (Provigil) and armodafinil (Nuvigil) (20). Although not as widely used anymore, occasional use of dextroamphetamine (Dexedrine), amphetamine/dextroamphetamine (Adderall), and methylphenidate (Ritalin, Concerta) is still warranted in patients who do not respond adequately to first-choice options.

The current first-line therapy for the treatment of cataplexy and EDS is γ-hydroxybutyrate (GHB), also known as sodium oxybate (Xyrem). There is some evidence that sodium oxybate may also improve hypnagogic hallucinations and sleep paralysis (20).

Various antidepressants are still prescribed as alternatives to, or in conjunction with, the above-mentioned medications, albeit less commonly than in the past:

Venlafaxine (Effexor), a serotonin-norepinephrine reuptake inhibitor
Fluoxetine (Prozac) and sertraline (Zoloft), selective serotonin reuptake inhibitors
Imipramine (Tofranil) and clomipramine (Anafranil), tricyclic antidepressants (20)

Table 16-2 Current Medication for Narcolepsy

For Cataplexy, Hypnogogic Hallucinations, and Sleep Paralysis	For Excessive Daytime Sleepiness
First-Line Therapy
Sodium oxybate (Xyrem)	Modafinil (Provigil) Armodafinil (Nuvigil)
Second-Line Therapy
Venlafaxine (Effexor) Atomoxetine (Strattera) Fluoxetine (Prozac) Sertraline (Zoloft) Protriptyline (Vivactil) Clomipramine (Anafranil)	Methylphenidate three forms: Immediate release (Methylin, Ritalin) Extended release (Metadate CD, Ritalin LA, Concerta) Sustained release (Ritalin LA) Dextroamphetamine (Dexedrine, Dextrostat) Amphetamine/dextroamphetamine (Adderall) Pitolisant (Wakix) Mazindol (Sanorex, Mazanor)

Future Directions

With our deeper understanding of narcolepsy comes a renewed and exciting search for novel medications. The discovery of the role of hypocretin/orexin focuses new research on hypocretin-based therapies, and new immunotherapies aim to prevent hypocretin loss. Various hypocretin replacement therapies have been pursued, including cell transplantation (from one area of the brain to another), peptide replacement (doses of hypocretin-1), and gene replacement therapy. So far, only gene replacement therapy has shown promise, although it’s still a long way from coming to market (20).

Pitolisant (Wakix), a histamine inverse-agonist, is currently approved to treat EDS in narcolepsy and is now in phase III clinical trials for treating cataplexy symptoms (34).

Mazindol (Sanorex) is a tricyclic nonamphetamine stimulant. Although used as an appetite suppressant, recent evidence indicates an improvement in EDS and cataplexy in patients taking mazindol (35, 36).

CENTRAL DISORDERS OF HYPERSOMNOLENCE—IDIOPATHIC HYPERSOMNIA

Diagnostic criteria (1)

Criteria A to F must be met:

The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring over a period of at least 3 months.
Cataplexy is absent.
An MSLT shows fewer than two sleep-onset REM periods or no sleep-onset REM periods if the REM latency on the preceding PSG was less than or equal to 15 minutes.
At least one of the following is present:
- The MSLT shows a mean sleep latency of less than or equal to 8 minutes.
- Total 24-hour sleep time is more than or equal to 660 minutes (typically 12 to 14 hours) on 24-hour PSG monitoring (after correction of chronic sleep deprivation), or by wrist actigraphy in association with a sleep log (averaged over at least 7 days with unrestricted sleep).
ISS is ruled out.
The hypersomnolence and/or MSLT findings are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of drugs or medications.

Introduction

IH is a rare sleep disorder of unknown etiology. Evaluation of the prevalence of IH in the general population is difficult because of the limited number of patients with IH and the difficulty of making a definitive diagnosis. It has been reported to occur 6 to 10 times less frequently than narcolepsy (37, 38), suggesting a prevalence in the general population between 1 in 10,000 and 1 in 50,000.

As the name suggests, IH is characterized by EDS, and the patient often wakes up with difficulty, feeling disoriented or confused, seemingly “drunk” with sleep (sleep drunkenness). This sleepiness is pervasive and lasts all day. The severity of sleepiness, though, may fluctuate from person to person and from day to day.

Unlike narcolepsy, however, there is no evidence of cataplexy with IH, and SOREMPs in the PSG and MSLT together are rare (maximum 1 SOREMP combined). Also, unlike narcolepsy, naps in IH tend to last longer, sometimes hours, and are usually unrefreshing (2, 39).

There is some recent research that suggests that IH and narcolepsy type 2 (without cataplexy, HLA negative) may be related pathophysiologically. This is especially evident after criteria for diagnosing narcolepsy were divided into types 1 and 2 in the ICSD-3.

Narcolepsy type 1 can easily be differentiated from both narcolepsy type 2 and IH because narcolepsy type 1 has clear and easily observed symptoms (i.e., cataplexy and/or very low hypocretin concentrations). However, the differences between narcolepsy type 2 and IH are less distinct. Both are genetically similar (HLA negative, with normal or near-normal hypocretin levels) and clinical observations show equivalent severity of hypersomnia (40, 41, 42).

Despite the similarities between narcolepsy type 2 and IH, there are still some significant features that help differentiate them:

an absence of multiple SOREMPs on the MSLT
the presence of long habitual sleep periods, long unrefreshing naps, and sleep inertia; and
a high sleep efficiency on the overnight PSG (2, 43)

Literature Review and a History of Idiopathic Hypersomnia

The term idiopathic hypersomnia was used as early as 1829 by Schindler (“die idiopathische chronische Schlafsucht”) for EDS of undetermined origin. Narcolepsy was then described in the literature by Gélineau in 1880.

By 1928, Wilson had described several “narcolepsies” and often used the term narcolepsy to refer to any condition characterized by irresistible sleepiness (37). The discovery of REM sleep in 1953 by Aserinsky, Kleitman, and Dement helped establish the premise that true narcolepsy could be diagnosed by analyzing the REM sleep of the patient (44).

Subsequent work in the development of the MSLT in the mid-1980s by Carskadon provided objective evidence to separate narcolepsy (which had REM-related features) and hypersomnia (which did not) (33).

It wasn’t until the 1976 paper by Roth that IH was described in its modern definition. Roth reviewed almost 650 personal cases of “narcolepsies” and classified them according to etiology, clinical form, and suspected pathophysiology. At that time, Roth divided hypersomnias into symptomatic and functional groups (45, 46). Subsequently, he described a large cohort of patients distinct from those with narcolepsy with EDS. These patients had significant sleepiness, often with prolonged nocturnal sleep but without clinical or electrophysiologic features of REM sleep disturbance. That is, no cataplexy was noted and the MSLT did not show significant SOREMPs during naps.

Roth further classified these patients as monosymptomatic (having normal nighttime sleep period with EDS) and polysymptomatic (having prolonged sleep time with sleep drunkenness and EDS) (45, 46). These forms
were eventually described as idiopathic hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time, respectively, in the original ICSD (47) in 1979. IH was then defined as a central nervous system disorder associated with a normal or prolonged major sleep episode (nighttime sleep) and excessive sleepiness consisting of prolonged (1- to 2-hour) episodes of NREM sleep during daytime naps.

Today, the ICSD-3 has since eliminated these diagnostic classifications because recent research shows there is no significant pathophysiologic or therapeutic difference between either. A comparison of patients with more than or equal to 10 hours of sleep with those with less than 10 hours shows no differences in ESS scores, MSLT mean sleep latencies, sleep drunkenness, unrefreshing naps, hypnagogic hallucinations, or sleep paralysis.

The only reported differences are that the group with long sleep is somewhat marginally younger and thinner (1). IH patients also tend to overestimate their total sleep time by an average of an hour. For this reason, taking a detailed medical history will be subject to these perceptual inconsistencies, which can make criterion of sleep time (long vs. short) almost meaningless. As research using objective measures like actigraphy becomes more commonplace, these criteria may yet be revisited. For now, however, one may continue to note sleep duration as an important clinical feature, but not consider it diagnostic or defining. Separating IH into distinct conditions must await further research and a better understanding of its underlying pathophysiology (1).

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