From American Academy of Sleep Medicine: International Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL: American Academy of Sleep Medicine, 2005.

Narcolepsy Syndromes

Narcolepsy is a chronic disorder characterized by excessive daytime sleepiness (EDS) and symptoms related to the abnormal regulation of wakefulness and sleep. It is characterized by a short rapid eye movement (REM) latency and intrusion of REM sleep features into the waking state. Approximately 60% to 70% of all patients with narcolepsy have cataplexy.1–⁴ Cataplexy consists of temporary muscle weakness following emotional stimuli. Narcolepsy with cataplexy (N+C) and narcolepsy without cataplexy (N–C) are now classified as two distinct disorders but share many of the same features¹–⁴ (Table 24–1).

TABLE 24–1

Features of Narcolepsy

FEATURES OF NARCOLEPSY	COMMENTS	SPECIFIC FOR NARCOLEPSY?
CLASSIC TETRAD SYMPTOMS
EDS	• Continuous daytime sleepiness, with exacerbations (sleep attacks). • Usually first symptom. • Present in virtually 100% of narcolepsy patients.	No
Cataplexy	• Muscle weakness triggered by emotion. • Most common triggers: hearing or telling a joke. • Onset usually occurs within a few years of the onset of sleepiness. • Duration: Seconds to minutes. • Consciousness preserved at least at beginning of episodes. • Present in 60–70% of patients with narcolepsy.	Yes
Hypnagogic (at sleep onset) or hypnapompic (on awakening) hallucinations	• Vivid dreamlike images that occur at sleep-wake transitions. • Duration: Several minutes. • Can be associated with SP.	No
Sleep paralysis	• A partial or complete paralysis of the skeletal muscles that occurs at sleep onset or sleep offset. • Can be associated with HPH > HH. The patient is awake but can’t move. • Can be associated with dyspnea, although the diaphragm is not affected. • Duration: A few seconds to several minutes.	No
OTHER MANIFESTATIONS OF NARCOLEPSY
Disturbed nocturnal sleep	• Increased stage N1. • Frequent awakenings. • 20–30% have short nocturnal REM latency (<15 min). • PLMS is common.	No
Automatic behavior	• Semipurposeful activity with amnesia.	No
REM sleep behavior disorder	• Dream enactment—often violent, REM without atonia.	No

EDS = excessive daytime sleepiness; HH = hypnagogic hallucinations; HPH = hypnopompic hallucinations; PLMS = periodic limb movements during sleep; REM = rapid eye movement; SP = sleep paralysis.

As the name implies, definitive cataplexy is present in patients with N+C. Following the discovery of hypocretin (Orexin) peptides in 1998,5,6 it was learned that the majority of patients with N+C have low or undetectable levels of hypocretin-1 (Hcrt1) in the cerebrospinal fluid (CSF).⁷ However, much more much remains to be determined about the pathophysiology of narcolepsy. In the absence of cataplexy, a diagnosis of N–C depends on demonstration of sleep-onset REM (very short REM latency) and an absence of other disorders to explain this finding.¹–⁴

History

The key symptoms of narcolepsy were described by Westphal in 1877.⁸ The term narcolepsy, meaning “to seize with drowsiness,” was coined by Gelinau.⁸ Aidie termed the loss of muscle tone as “cataplexy” in the early 20th century.⁹ Yoss and Daly¹⁰ described the classic tetrad of daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis (SP). In 1960, Vogel¹¹ reported that sleep-onset REM periods were associated with narcolepsy. Initially, the association of narcolepsy with the human leukocyte antigen (HLA) DR2 antigen was described in Japanese patients.¹² Later, the HLA DQB1*0602 was found to be strongly associated with narcolepsy in white and African American populations.¹³ In 1998, two groups simultaneously reported the existence of hypocretin (Orexin) peptides present in the lateral and posterior hypothalamus.^5,6 Cleavage of a single precursor protein produces the peptides hypocretin-1 (Orexin A) and hypocretin-2 (Orexin B). In 2000, the association of narcolepsy with cataplexy and low or undetectable levels of CSF Hcrt1 was described.⁷

Epidemiology

Narcolepsy is present in about 1/2000 persons. Approximately 60% to 70% of patients with narcolepsy have cataplexy.¹⁴ Men and women are affected equally. The average age of onset in most studies is between 20 and 30 years. However, narcolepsy can begin at any age. Dauvilliers and coworkers¹⁵ found two peaks in the age of onset with one around age 15 and the other around 35 years of age.

Genetics

Familial canine narcolepsy is transmitted as a single autosomal recessive gene (canarc-1) with complete penetrance.¹⁶ This form of narcolepsy is due to an abnormal Hcrt2 receptor. However, the human form of the narcolepsy is not a simple genetic disease. Although the majority of cases of human narcolepsy are sporadic, there have been numerous reports of familial narcolepsy in the literature.^16,17 Studies of families of patients with narcolepsy revealed that the risk of a first-degree relative of a narcoleptic developing N+C is 1% to 2%, a 10 to 40 times higher risk than in the general population.¹⁶ However, studies of identical twins show a high degree of discordance for N+C. That is, if one twin has narcolepsy, the other twin will have or develop narcolepsy only about 25% to 31% of the time¹⁶ (Table 24–2). Thus, factors other than genetics are important for the development of human narcolepsy.

TABLE 24–2

Narcolepsy Facts

INCIDENCE OF NARCOLEPSY	1/2000
FAMILIAL RELATIONSHIP	RISK FOR DEVELOPING NARCOLEPSY
Identical twin has narcolepsy with cataplexy.	25–31% of other twin has narcolepsy.
First-degree relative has narcolepsy.	1–2% (10–40 × higher risk).
HLA ANTIGEN PREVALENCE	HLA DQB1*0602 POSITIVE
General population.	12–38%.
N+C.	90% (≤10% negative).
N–C.	40–60%.
HYPOCRETIN	CSF HYPOCRETIN-1
N+C	Absent or low 90–100%. Normal in up to 10%.
N–C	90% normal levels. 5–10% reduced levels (most + for DQB1*0602).

CSF = cerebrospinal fluid; HLA = human leukocyte antigen; N+C = narcolepsy with cataplexy; N–C = narcolepsy without cataplexy.

HLA Typing

N+C is strongly linked to specific HLAs. Approximately 90% to 95% of patients with N+C have the DQB1*0602 allele regardless of race ¹⁶ (see Table 24–2). However, this allele is present in about 12% of Japanese, 25% of whites, and 38% of African Americans without the syndrome. The percentage of patients with N–C that are DQB1*0602 positive is lower (40–60%). In general, patients with narcolepsy who are DQB1*602-positive have more severe symptoms.²

Importance of Hcrt Neurons

Hcrt neurons located in the lateral or posterior hypothalamus project widely in the CNS (Fig. 24–1A). They augment the activity of brain areas active during wakefulness (tuberomammillary nucleus [TMN]—histamine, locus coeruleus—norepinephrine [NE], and dorsal raphe—serotonin).¹⁸–²³ Their activity is believed to stabilize the sleep-wake system to prevent abrupt transitions between sleep and wakefulness. Histaminergic neurons are located exclusively in the TMN of the posterior hypothalamus and project to various brain regions associated with regulation of sleep-wake cycles. Activity of these histaminergic neurons is believed to help promote wakefulness. Hcrt neurons project to the TMN and stimulate the TMN neurons via Hcrt2 receptors.

FIGURE 24–1 A, Orexin (Hypocretin) neurons in the hypothalamus project widely to many brain areas responsible for maintenance of wakefulness including the tuberomammillary nucleus (TMN), dorsal raphe, and locus coeruleus (LC). B, Possible pathways mediating atonia of REM sleep. Neurons in the atonia areas of the pons, the sublateral dorsal nucleus (SLD), project directly to interneurons in the spinal cord that inhibit motor neurons. An indirect pathway via the supraolivary medulla (SOM) is also illustrated. Other pathways are also likely important. The atonia neurons are glutaminergic and the inhibitory spinal cord interneurons secrete glycine (Gly) and gamma-aminobutyric acid (GABA). Glu = glucose. A, Adapted from Scammell TE: The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003;53:154–166. B, Vetrivelan R, Fuller PM, Tong Q, Lu J: Medullary circuitry regulating rapid eye movement sleep and motor atonia. J Neurosci 2009;29:9361–9369.

Pathophysiology of Narcolepsy

N+C Group

As noted previously, canine N+C is usually secondary to a defect in the receptor for Hcrt2. Human N+C is associated with absent or very low CSF levels of Hcrt1 (90–100% of patients).15,24–26 Brains of patients with N+C have reduced staining for Hcrt in the hypothalamus.^27,28 N+C is associated with a loss of approximately 90% of Hcrt neurons. Melanin-concentrating hormone neurons, which are intermixed with Hcrt cells in the normal brain, were not reduced in number, indicating that cell loss is relatively specific for Hcrt neurons. It is believed that hypothalamic Hcrt cells are destroyed before disease onset. Mutations in Hcrt genes do not appear to be the cause of most human narcolepsy.²⁹ Of note, up to 10% of patients with N+C have normal CSF Hcrt1 levels.^25,26 Thus, other abnormalities of the Hcrt system or other mechanisms must be the cause of the syndrome in these patients. The cause of the loss of Hcrt cells in patients with N+C is unknown. Because of the association of narcolepsy with HLA antigens, an autoimmune mechanism has been hypothesized but has been difficult to document.³⁰ Elevated antistreptococcal antibodies were found in one study of patients with recent narcolepsy onset.³¹ Another study found that narcolepsy is also associated with a polymorphism in the T-cell receptor alpha gene.³² Recently, several studies have found that some patients with narcolepsy have elevated levels of antibodies against a protein known as Tribbles homolog 2 (TRIB2).³³–³⁵ In one study, antibodies were found in about 25% of patients with N+C but in only 3.5% in patients with N–C or 4.5% in normal controls.³⁵ The presence of TRIB2 antibodies was associated with a short duration since disease onset (recent onset of narcolepsy). TRIB2 is produced in Hcrt neurons, providing some of the firmest evidence yet for an autoimmune cause of narcolepsy. However, whether the Tribbles antibodies cause Hcrt damage, occur secondary to damage of the Hcrt neurons, or are simply an associated phenomenon secondary to another cause of Hcrt neuron injury is unknown.³⁶

Two investigations have documented low CSF histamine in patients with narcolepsy (with and without cataplexy) and idiopathic hypersomnia (IH).37,38 As noted previously, histamine secretion is believed important for maintaining wakefulness. It is not clear whether low CSF histamine is a cause or an effect of EDS in these patients. Recall that Hcrt neurons stimulate histaminergic neurons in the TMN. However, CSF histamine was low even in patients without Hcrt ligand deficiency (N–C and IH). Therefore, other defects beside Hcrt deficiency must be involved in producing low CSF histamine levels.

N–C Group

The pathophysiology of N–C is not well understood. A small percentage (5–10%) of N–C patients have a reduced CSF Hcrt (most are positive for HLA DQB1*0602). N–C patients negative for the HLA DQB1*0602 almost always have normal CSF Hcrt1 levels.7,25,26 The etiology of N–C is currently unknown but may represent a dysfunction of the Hcrt system without total loss of Hcrt-producing cells. Thannickal and coworkers³⁹ examined the brain of one patient with N–C and found a 33% reduction in hypocretin cells (compared to normals) with maximal loss in the posterior hypothalamus. Thus, partial loss of Hcrt neurons and other alterations in the Hcrt system without a reduction in CSF Hcrt could be the etiology of N–C. As noted previously, CSF histamine is low in N–C patients.^37,38 This may be a marker of hypersomnia, or reduced histamine secretion could be part of the pathogenesis of the disorder.

Mechanisms of Cataplexy

The mechanisms inducing cataplexy are still under investigation.40–⁴² The atonia of REM sleep is thought to be due to inhibition of the spinal alpha motor neurons of the anterior horn cells by glycine and gamma-aminobutyric acid (GABA) secreted by spinal interneurons (see Fig. 24–1B). The interneurons are activated directly by projections from areas in the pons responsible for atonia or via an intermediate relay area in the ventral medulla. Glutamate is believed to activate the spinal interneurons. The atonia neurons of the pontine reticular formation are located ventral to the locus coeruleus and are often called the subcoeruleus (SubC) or sublaterodorsal nucleus (SLD). The neurons are believed to be glutaminergic. During REM sleep, there also appears to be inhibition of pathways normally promoting alpha motor neuron activity.

Cataplexy and the atonia of REM sleep may share some common pathways, but there are important differences. John and colleagues ⁴¹ reported that histaminergic neurons in the ventral posterior lateral hypothalamus remain active during cataplexy as opposed to REM sleep (Fig. 24–2). Because histamine is associated with wakefulness, this may at least partially explain why patients remain conscious during cataplexy but not REM sleep. The other important difference between REM-associated atonia and cataplexy is the triggering emotional stimulus for cataplexy. Neural pathways involving the amygdala are thought to be important for the emotional induction of cataplexy.

FIGURE 24–2 Posterior hypothalamic (histaminergic) neurons remained active during cataplexy (CAT) whereas dorsal raphe (serotonergic) reduced discharge and locus coeruleus neurons (noradrenergic) nearly ceased discharge. Note the difference between rapid eye movement (REM) and cataplexy for posterior hypothalamic neurons and dorsal raphe neurons. AW = active wake; NREM = non–rapid eye movement; QW = quiet wake. From John J, Wu MF, Boehmer LN, Siegel JM: Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 2004;42:619–634.

Manifestations of Narcolepsy

Similarities and differences between N+C, N–C, and IH are outlined in Table 24-3. IH is discussed in detail in a later section.

TABLE 24–3

Features of Narcolepsy Syndromes versus Idiopathic Hypersomnia

	N+C	N–C	IH
SYMPTOMS
Daytime sleepiness	Yes	Yes	Yes
Hypnagogic hallucinations (%)	70–86	15–60	40
Sleep paralysis (%)	50–70	25–60	40–50
POLYSOMNOGRAPHY
Sleep latency	Short	Short	Variable
Nocturnal REM latency < 15 min	33%^†	24%^†	Normal REM latency
Disturbed nighttime sleep	Yes	Yes	No
Sleep efficiency (%)*	81	91	93
Stage N1 sleep	Increased	Mildly increased	Normal
24-hr total sleep time	Normal to slight increase	Normal to slight increase	Very increased in patients with IH with long sleep time
MSLT
Mean sleep latency (min)	2.7^§	3.5^§	6.2 ± 3.0^‡
Sleep-onset REM periods (N)	≥2	≥2	0–1
Sleep-onset REM periods (N)	(3–3.7 SOREMPs)^§	(2–3.3 SOREMPs)^§	0–1
DQB1*0602 (% positive)	90–100	40–60	52
CSF hypocretin-1	Undetectable in 90–95% ≤10% normal	Normal in 90% Reduced in 5–10%	Normal
Neuropathology	Marked reduction in hypocretin neurons	Unknown	Unknown
Body mass index	Increased in 5–15%	Normal	Normal

CSF = cerebrospinal fluid; IH = idiopathic hypersomnia; MSLT = multiple sleep latency test; N+C = narcolepsy with cataplexy; N–C = narcolepsy without cataplexy; REM = rapid eye movement; SOREMPs = sleep-onset rapid eye movement periods.

^*Sleep efficiency = total sleep time/total recording time.

^†From Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620–629.

^‡From Arand D, Bonnet M, Hurwitz T, et al: A review by the MSLT and MWT Task Force of the Standards of Practice Committee of the AASM. The clinical use of the MSLT and MWT. Sleep 2005;28:123–147.

^§From Scammel TE: The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003;53:154–166.

Adapted from Scammel TE: The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003;53:154–166, with permission.

Excessive Daytime Sleepiness (N+C and N–C)

The EDS of narcolepsy can occur as discrete “sleep attacks” or as constant sleepiness with intermittent worsening. Unrelenting EDS is usually the first and most prominent symptom of narcolepsy.1–4,43 Sleepiness may occur throughout the day, regardless of the amount or quality of prior nighttime sleep. Sleep episodes may occur at work and social events, while eating, talking, and driving, and in other similarly inappropriate situations. Napping is usually restorative but provides only temporary relief. It has been said that falling asleep while standing or eating is especially suggestive of narcolepsy. Even though patients may sleep at every hour of the day, the total sleep time over a 24-hour period is normal or only slightly increased.^44,45 Rogers and associates⁴⁴ performed 24-hour polysomnography (PSG) in a group of narcolepsy patients who were “well controlled.” Of 25 subjects with narcolepsy, 10 had no daytime sleep but the other 14 averaged 2.7 naps and 76.2 minutes of sleep during the day (compared with 4.8 min for controls).⁴⁴ The two groups did not differ in the total amount of sleep or the total amount of REM sleep in 24 hours. Figure 24–3 compares the 24-hour hypnograms of a patient with narcolepsy and a normal subject. The hypnogram shows sleep episodes scattered throughout the day, and some of the daytime sleep episodes contain REM sleep.

FIGURE 24–3 Hypnogram of a normal individual and a patient with narcolepsy. Sleep and rapid eye movement (REM) periods were noted throughout the day in the patient with narcolepsy. PSG = polysomnography. From Rogers AE, Aldrich MS, Caruso CC: Patterns of sleep and wakefulness in treated narcolepsy subjects. Sleep 1994;17:590–597.

In a study comparing narcoleptics and normal subjects using 24-hour ambulatory monitoring, Broughton and coworkers ⁴⁵ found no increase in the total amount of sleep in 24 hours. However, narcoleptics had more daytime and less nighttime sleep than normal persons.

Sleep-Related Hallucinations (N+C and N–C)

Sleep Paralysis (N+C and N–C)

SP is partial or complete paralysis during the onset of sleep or upon awakening. Patients are awake and conscious during the attack. There is no emotional precipitant. The episodes may last longer than a typical cataplectic attack. People who experience SP sometimes experience hallucinations simultaneously. Studies have found that up to 50% to 80% of patients with N+C report SP, with a lower percentage in the N–C group.4,43

Adequate ventilation is maintained during SP because diaphragmatic function is spared. However, some patients have a sensation of dyspnea. SP is often very frightening owing to the inability to move, speak, or communicate during the episode. SP is also reported in patients with sleep apnea and occasionally in normal subjects especially after periods of sleep deprivation. A syndrome of isolated recurrent SP (narcolepsy not present) exists and can be very problematic for affected individuals.

Disturbed Nocturnal Sleep and Other Symptoms: N+C, N–C

Although HH/HPH, SP, and daytime sleepiness are the classic narcolepsy symptoms, patients often report other associated symptoms that can be significant (see Table 24–1). Narcolepsy patients often experience disturbed nighttime sleep with tossing and turning in bed, leg jerks, nightmares, and frequent awakenings. The amount of stage N1 sleep is increased. In general, N+C patients have more disturbed sleep than N–C patients.¹–⁴ Automatic behavior is present in up to 50% of patients. Automatic behavior is defined as performing a seemingly purposeful task with no clear memory of having performed the activity. For example, patients report driving a car and not remembering the trip. They may find themselves doing activities that make no sense like putting salt in iced tea. These episodes typically involve activities that are habitual or not demanding of skill. Inattentiveness related to drowsiness may occur. Aldrich⁴ reported that the proportions of patients reporting automatic behavior were similar in groups of N+C and N–C patients. Patients with narcolepsy may also have the rapid eye movement sleep behavior disorder (RBD).⁴⁶ In this disorder, skeletal muscle atonia is absent during REM sleep and dreams may be acted out. Because the Hcrt system has affects on appetite, it is not surprising that some patients with N+C have an increased body-mass index.^4,47 Obstructive sleep apnea (OSA) is also not uncommon.⁴⁸ If cataplexy is not present in a patient with OSA, narcolepsy may be suspected only if daytime sleepiness persists after adequate treatment of the sleep apnea. Periodic leg movements in sleep (PLMS) are also common in narcolepsy.⁴⁹ PLMS may be present during REM sleep, a feature uncommon in most patients with PLMS.

Cataplexy: N+C

As the name implies, cataplexy is an essential criterion for the diagnosis of N+C. Cataplexy is the only symptom relatively “specific” to narcolepsy.1–4,50 Isolated cataplexy or cataplexy with sleepiness (secondary narcolepsy) can occur in a few rare neurologic disorders associated with mental retardation and obvious neurologic deficits. These are discussed in a later section. In a patient with daytime sleepiness and a normal neurologic examination, cataplexy is virtually diagnostic of narcolepsy.

Cataplexy is characterized by the sudden, temporary loss of bilateral muscle tone with preserved consciousness triggered by strong emotions such as laughter, anger, or surprise.43,50 After cataplexy episodes, patients have total recall of the entire event. If the episodes last longer than a few minutes, the patient may transition into REM sleep and experience HHs. A systematic survey of symptoms of muscle weakness associated with emotion in a large group of patients with daytime sleepiness found that weakness during joking (telling or hearing a joke), laughter, and anger were the most specific for cataplexy associated with narcolepsy.^43,50 Involvement of the legs also seemed to be more specific for narcolepsy.

When loss of muscle strength during cataplexy is severe, almost all of the voluntary muscles in the body are affected, leading to complete collapse. The muscles of the eyes are not affected during cataplexy; individuals can move their eyes during a cataplectic episode. Diaphragmatic activity is also not impaired. In one study, the legs and knees were most frequently affected during cataplexy.⁵⁰ In milder cases of cataplexy, the loss in muscle strength can be quite subtle, involving only a few muscle groups or occurring unilaterally. For example, ptosis, difficulty speaking, or partial neck muscle weakness may occur (head nodding). In some patients, partial attacks are more frequent than complete attacks. Loss of muscle function may not be evident, and the patient may experience only a vague feeling of weakness. Patients may fall to the ground, and injuries do occur. However, most people are able to find support at the onset of an attack. The attacks do start abruptly but usually take several seconds to reach their maximum intensity. Episodes of cataplexy usually last from seconds to minutes; rarely does an attack last longer than 2 minutes. Clinical signs during an attack are the loss of muscle tone and loss of deep tendon reflexes including a loss or decrease in the H reflex. During an attack of cataplexy, there are cardiovascular changes consisting of increased blood pressure and decreased heart rate. The phenomenon of virtually continuous attacks of cataplexy (status catapleticus) can occur after sudden withdrawal of medications that suppress cataplexy.

Diagnostic Testing for Narcolepsy

History

Patients with daytime sleepiness are invariably questioned about SP, HH/HPHs, and the severity and nature of the daytime sleepiness. However, none of these historical elements is specific for narcolepsy and they can occur in sleep apnea and other causes of daytime sleepiness including IH ⁴ (Table 24–4). A history of cataplexy is the most important symptom to elicit. In patients with EDS, unequivocal cataplexy, and a normal neurologic examination, a clinical diagnosis of narcolepsy can be made with some certainty. Even if cataplexy is present, most physicians would still seek objective confirmation with PSG followed by a multiple sleep latency test (MSLT).¹ Daytime naps are often refreshing in patients with narcolepsy. In contrast, naps are not commonly refreshing in patients with IH.

Polysomnography

The nocturnal sleep study is used to rule out other significant sleep disorders (sleep apnea) that might explain daytime sleepiness. Nocturnal PSG often reveals a short sleep latency and impaired sleep quality with increased stage N1 sleep and decreased stage N3 sleep. The total sleep time may be reduced but the amount of REM sleep is usually normal.51,52 Patients with N+C on average have lower sleep efficiency, lower amounts of stage N3 sleep, more stage N1 sleep, and more awakenings than those with N–C.^2,4 PLMS are common in patients with narcolepsy.^49,52 Sleep-onset rapid eye movement sleep (SOREM) is defined as a REM latency less than 15 minutes. Aldrich and colleagues⁵³ found that 33% of N+C, 24% of N–C, and 1% of SRBD patients had a SOREM on nocturnal PSG. Of interest, the finding of a SOREM period on the nocturnal PSG had a 98.5% specificity and 68% positive predictive value (true positives/total number of positives) for the diagnosis of narcolepsy. Therefore, although a minority of patients with narcolepsy have a nocturnal SOREMP (sleep-onset rapid eye movement period) on a given PSG, the finding is highly suggestive of narcolepsy. This is especially true if no other factor is present to explain the short REM latency such as depression, OSA, recent withdrawal of REM-suppressing medication, or sleep deprivation.

Multiple Sleep Latency Test

The MSLT is the standard objective test for the assessment of sleepiness and the diagnosis of narcolepsy 53–⁵⁵ (Table 24–5; see also Table 24–4). Overnight PSG during the patient’s habitual sleep period should precede the MSLT. The purpose of the PSG is to exclude other causes of excessive daytime sleepiness such as OSA and periodic limb movement disorder (PLMD). A sleep diary or actigraphy should document a regular and sufficient amount of sleep for at least 7 days before the study. Medications that can alter sleepiness (stimulants) or REM sleep should be withdrawn at least 15 days before testing. REM-suppressing medications can alter the ability to detect REM sleep. However, acute withdrawal of REM-suppressing agents can cause a false-positive test.

TABLE 24–5

Multiple Sleep Latency Test Findings in Patients Evaluated for Daytime Sleepiness

	N+C	N–C*	SRBD
N	106	64	1251
MSL <5 min	87%	81%	39%
MSL <8 min	93%	97%	63%
≥2 SOREMPs	74%	91%	7%
≥2 SOREMPs + MSL <5 min	67%	75%	4%
≥2 SOREMPs + MSL <8 min	71%	91%	6%
SOREMPs on PSG	33%	24%	1%

MSL = mean sleep latency; N+C = narcolepsy with cataplexy; N–C = narcolepsy without cataplexy; PSG = polysomnography; SOREMPs = sleep-onset rapid eye movement periods; SRBD = sleep-related breathing disorder.

^*Diagnosis made in patients with N–C by repeat MSLT if initial test negative.

Adapted from Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620–629.

The ICSD-2 criteria for the diagnosis of narcolepsy include a mean sleep latency of 8 minutes or less and two or more SOREMPs during five naps.¹ Aldrich and colleagues⁵³ found that the MSLT had improved sensitivity when a sleep latency of 8 minutes rather than 5 minutes was used as a criterion for sleep latency in patients with N–C. A meta-analysis found the mean sleep latency for narcolepsy patients to be 3.1 ± 2.9 minutes.^54,55 Up to 30% of the general population have a mean sleep latency less than 8 minutes. However, the finding of two or more SOREMPs is much more specific for narcolepsy. Up to 2% of the normal population will have two SOREMPs, and in other studies, approximately 6% of patients with SRBDs will have a mean sleep latency less than 8 minutes with two SOREMPs on an MSLT.^53,56 A few patients with narcolepsy will occasionally have a mean sleep latency above 10 minutes. However, the mean sleep latency is less than 5 minutes in the vast majority of patients with narcolepsy (Fig. 24–4). The mean sleep latency in patients with SRBDs tends to be higher than in narcolepsy, although overlap does occur.

FIGURE 24–4 Distribution of mean sleep latency (MSL) results for groups of patients with narcolepsy and sleep-related breathing disorders. Although considerable overlap is noted, patients with narcolepsy tend to have much lower MSL. From Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620–629.

Unfortunately, the MSLT is not very sensitive or completely specific for the diagnosis of narcolepsy. Aldrich and colleagues ⁵³ reviewed MSLT findings in patients evaluated for daytime sleepiness (see Table 24–5). A diagnosis of narcolepsy in patients without cataplexy required a repeat MSLT in some cases. In patients with N+C, a single MSLT was positive only about 70% of the time. Hence, a negative MSLT does not rule out the diagnosis of narcolepsy. In patients ultimately believed to have only an SRBD, approximately 6% had a positive MSLT^53,56 (see Table 24–5).

HLA Typing

Although a high percentage of patients with N+C are positive for the HLA DQB1*602 antigen, this test is not very useful for ruling in narcolepsy (for either N+C or N–C). The HLA DQB1*0602 is found in 12% to 38% of the general population. Therefore, a positive result does not rule in N+C. Conversely, a negative test for presence of DQB1*0602 is not useful because up to 10% of N+C patients and 40% to 60% of N–C patients are negative for the antigen.1,2,13,57

CSF Hcrt Levels

Hcrt1 levels of the CSF can be assayed at a few centers. In patients with N+C, over 90% have very low or undetectable Hcrt1 levels. In one study of patients with many neurologic diseases, only patients with N+C and a few patients with Guillain-Barré had undetectable Hcrt levels.58,59 Patients with a number of neurologic diseases had levels that were lower than normal but still detectable. As noted previously, patients with N–C usually have normal levels of CSF Hcrt1. However, about 10% of N–C patients have low CSF Hcrt1. Most of these N–C patients with low CSF Hcrt1 are positive for the HLA DBQ1*602.⁵⁸–⁶⁰

Diagnostic Criteria and Important Findings for N+C and N–C Forms of Narcolepsy

Narcolepsy with Cataplexy (N+C)

The ICSD-2 diagnostic criteria for N+C ¹ are listed in Box 24–2. EDS for at least 3 months is required along with cataplexy. When possible, the diagnosis should be confirmed by an MSLT (sleep latency ≤8 min and two or more SOREMPs). A low CSF Hcrt1 level is considered confirmatory even in the absence of an MSLT meeting diagnostic criteria. Other sleep disorders causing the abnormal MSLT should be excluded.

Box 24–2

Narcolepsy with Cataplexy—Diagnostic Criteria

A The patient has a complaint of excessive daytime sleepiness occurring almost daily for at least 3 months.

B A definite history of cataplexy defined as sudden and transient episodes of loss of muscle tone triggered by emotions is present.

Cataplexy = episodes must be triggered by strong emotion—most reliably laughing or joking—and must be bilateral and brief (<2 min). Consciousness must be preserved (at least in the beginning)

Strong evidence = observed cataplexy with loss of DTRs.

C The diagnosis of narcolepsy with cataplexy should, whenever possible, be confirmed by nocturnal PSG followed by an MSLT with a mean sleep latency less than or equal to 8 minutes with two or more SOREMPs observed following sufficient nocturnal sleep (minimum of 6 hr) during the night prior to the test.

Alternatively: CSF hypocretin-1 level <110 pg/mL or less than one third of the mean of normal values.

D Hypersomnia is not better explained by another sleep disorder, medical or neurologic disorder, medication, or substance use disorder.

CSF = cerebrospinal fluid; DTRs = deep tendon reflexes; MSLT = multiple sleep latency test; PSG = polysomnography; SOREMPs = sleep-onset rapid eye movement periods.

From American Academy of Sleep Medicine: International Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL: American Academy of Sleep Medicine, 2005.

N+C Manifestations

Whereas only daytime sleepiness and cataplexy are required to make the diagnosis of N+C, other manifestations such as sleep-related hallucinations, SP, and automatic behavior are often present (see Table 24–1). Only 10% to 15% of patients have the classic symptom tetrad of daytime sleepiness, cataplexy, HGH/HPHs, and SP. Patients with N+C tend to have a higher frequency of SP, HHs, and more severe sleepiness than N–C patients. During PSG, sleep is more disturbed in N+C patients than in N–C patients. On the MSLT, N+C patients tend to have more SOREMPs. Although 90% of N+C patients are positive for DQBQ1*602, this is not useful diagnostically.

Onset of N+C

The manifestations of N+C generally begin between the ages of 15 and 30 years.⁴³ However, this form of narcolepsy can present in the pediatric age group or in patients older than 60 years. EDS alone or in combination with HHs and/or SP is the presenting symptom in approximately 90% of patients.⁴³ Cataplexy may develop several years after symptoms begin. However, most patients with N+C develop cataplexy within 3 to 5 years of the onset of daytime sleepiness.^14,43 Rarely, cataplexy can precede daytime sleepiness.

Polysomnography

Typical findings include a short sleep latency and approximately 20% to 30% have a short nocturnal REM latency.⁵³ Of interest, in one study, the presence of sleep-onset REM during the nocturnal sleep study had a high positive predictive value for the presence of narcolepsy.⁵³ There tends to be an increase in stage N1 sleep.

Multiple Sleep Latency Test

Approximately 70% of patients with N+C will have a MSLT meeting criteria for narcolepsy. The mean sleep latency tends to be slightly less in N+C than in N–C patients and SOREMPs are slightly more frequent than in patients with N–C (see Table 24–3).

Other Studies in N+C

1. Absent to low Hcrt1 in the CSF fluid (90–100%).

2. Absence of Hcrt-staining cells in the hypothalamus.

3. Ninety percent are positive for DQBQ1*602 antigen.

Narcolepsy without Cataplexy (N–C)

The ICSD-2 diagnostic criteria for N–C are listed in Box 24–3. Daytime sleepiness must be present for at least 3 months but typical cataplexy is NOT present. An MSLT shows a mean sleep latency of 8 minutes or less and two or more SOREMPs. The other manifestations of narcolepsy including SP, HHs, and automatic behavior may or may not be present. Compared with patients with N+C, a lower percentage of patients with N–C report SP or HH (see Table 24–3).²

Box 24–3

Narcolepsy without Cataplexy—Diagnostic Criteria

A Complaint of excessive daytime sleepiness almost daily for at least 3 months.

B Typical cataplexy is not present.

C Nocturnal PSG followed by MSLT findings:

• MSL less than or equal to 8 min.

• Two or more SOREMPs (MSLT)

• Sufficient nocturnal sleep (at least 6 hr).

D Hypersomnia is not better explained by another sleep disorder, medical or neurologic disorder, medication, or substance use disorder.

MSLT = multiple sleep latency test; PSG = polysomnography; SOREMPs = sleep-onset rapid eye movement periods.

From American Academy of Sleep Medicine: International Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL: American Academy of Sleep Medicine, 2005.

Polysomnography (N–C)

N–C patients have a short nocturnal sleep latency and 20% to 30% have a short nocturnal REM latency.⁵³ The amount of stage N1 sleep is increased. N–C patients tend to have less disturbed sleep than N+C patients.

MSLT Findings (N–C)

The findings are similar to those of N+C patients. However, there may be a slightly longer mean sleep latency and fewer SOREMPs. Patients with N–C tend to have milder sleepiness and fewer numbers of naps with sleep-onset REM sleep compared with N+C patients. Unfortunately, as discussed previously, an MSLT meeting criteria for the diagnosis of narcolepsy is not completely sensitive or specific. If clinically indicated, repeat testing could be needed. This is in contrast to patients in whom definitive cataplexy is present. A diagnosis of N+C can be made even if the MSLT does not meet criteria if daytime sleepiness and unequivocal cataplexy are present.

Treatment of Narcolepsy

The treatment of narcolepsy is usually broken into two components: (1) treatment of EDS and (2) treatment of cataplexy, SP, and HGH/HPHs.61–⁶⁴

Treatment of EDS

The treatment of daytime sleepiness includes conservative measures (adequate sleep time, good sleep hygiene, scheduled daily naps ⁶⁵), stimulant medications, alerting medications, and sodium oxybate (Table 24–6). Adequate control of daytime sleepiness can be attained in about 60% to 80% of patients. The stimulant medications used to treat the daytime sleepiness of narcolepsy include amphetamine (racemic), dextroamphetamine, methamphetamine, and methylphenidate. Dextroamphetamine and methylphenidate are U.S. Food and Drug Administration (FDA) approved for treatment of narcolepsy. A mixture of amphetamine and dextroamphetamine (~25% l-amphetamine and 75% d-amphetamine) is also available (Adderall). Some patients respond best to a mixture, although d-amphetamine may cause less anxiety. Methamphetamine is effective but has a high abuse potential. The FDA does not list narcolepsy as an indication for methamphetamine. The stimulant medications are indirect sympathomimetic stimulants (increase the synaptic availability of dopamine and norepinepherine).

TABLE 24–6

Medications Used to Treat Excessive Daytime Sleepiness

Medication (FDA PREGNANCY CATEGORY)	BRAND NAME	DOSE	MAXIMUM DOSE (DAILY)	HALF-LIFE (hr)	SELECTED SIDE EFFECTS
Methylphenidate* (C)	Ritalin	10–30 mg bid or 10–20 mg tid (5, 10, 20 mg tabs)	100 mg	2–4	Nervousness, tremulousness, headache
Methylphenidate SR	Metadate and others Concerta	10–20 mg SR qam (10, 20 mg tabs) + 10 to 20 mg short-acting in afternoon
Methylphenidate SR	Metadate and others Concerta	18–36 mg SR qam (18, 27, 36, 54 mg tabs) + 10 to 20 mg short-acting in afternoon
Dextroamphetamine* (C)	Dexedrine Dextrostat and others	5–60 mg qd 5–30 mg bid (5, 10 mg tabs)	60 mg	10–30	Nervousness, tremulousness, headache
Amphetamine/dextroamphetamine	Adderall	(5, 7.5, 12.5, 15 mg tabs)
Dextroamphetamine	SR	10 mg SR qam 5, 10, 15 mg tabs +10 to 20 mg short-acting in afternoon
SR
Amphetamine/dextroamphetamine XR	Adderall XR	5, 10, 15, 20, 25, 30 mg capsules
Methamphetamine* (C)	Desoxyn	5 to 60 mg qd (5, 10 mg tabs)	60 mg	12–34	Nervousness, tremulousness, headache
Lisdexamfetamine dimesylate* (C)	Vyvanse	20, 30, 40, 50, 60 mg	70 mg	12–13 (duration of action)	Nervousness, tremulousness, headache
Modafinil^† (C)	Provigil	200 or 400 mg qd (100, 200 mg tabs)	400 mg	9–14	Headache, drug interactions, nervousness
Armodafinil^† (C)	Nuvigil	150–250 mg daily 150, 250 mg tabs	250 mg	10–14	Headache, drug interactions, nervousness
Sodium oxybate (B)	Xyrem	4.5–9 g/night in 2 divided doses	9 g	1–3	Sedation, enuresis, respiratory suppression
Selegiline (C)	Eldepryl	20–40 mg	40 mg	9–14	Nausea, dizziness, confusion, dry mouth, requires low-tyramine diet, drug interactions
FDA approved for treatment of EDS in narcolepsy: modafinil, armodafinil, dextroamphetamine, methylphenidate, sodium oxybate.