Narcolepsy: The Differential Diagnosis
of Sleepiness and Fatigue

Neil T. Feldman, M.D., Sleep Disorders Center at Palms
of Pasadena Hospital, St. Petersburg, Florida
 

Narcolepsy is a chronic central nervous system (CNS) disorder of unknown etiology that is characterized by excessive daytime sleepiness (EDS), hypnogogic hallucinations, cataplexy, sleep paralysis, and disrupted nocturnal sleep. Mistakenly considered a rare disorder, it is now estimated that one in every one to two thousand Americans may be afflicted with this disease, a prevalence approximating that of multiple sclerosis. ¹ The symptoms of this disorder adversely impact the psychological and social functioning of those afflicted, and is especially debilitating because the disease onset occurs most often in the second and third decade of life, a time of increasing responsibility at school and work. The diagnosis and treatment are often delayed because the complaint of fatigue and sleepiness is often not taken seriously. It is often attributed to events surrounding the psychosocial milieu of the individual, even though the complaint of excessive daytime sleepiness always has an organic, nonfunctional explanation when an organized clinical evaluation is attempted. Both the primary care physician and the specialist play a pivotal role in screening and making appropriate referrals for narcolepsy and other disorders of excessive sleepiness. A high index of suspicion will lead to earlier diagnosis and treatment of this disabling disorder.

Disease Description

Narcolepsy results from a dysregulation of sleep and wakefulness. In narcolepsy control of the onset and offset of both rapid eye movement (REM) and non-REM sleep is impaired. REM sleep occurs at sleep onset and intrudes into wakefulness producing the auxiliary symptoms of the narcoleptic tetrad, which include excessive daytime sleepiness, hypnogogic hallucinations, sleep paralysis, and cataplexy. EDS is generally the most disabling symptom of narcolepsy. ² This symptom, however, does not differentiate patients with narcolepsy from those with other disorders associated with EDS. Hypnogogic hallucinations, sleep paralysis, and disrupted nocturnal sleep are seen in other sleep disorders and occasionally in normals, but cataplexy is highly specific for narcolepsy, and, if present, establishes the diagnosis. ³ These symptoms of narcolepsy severely compromise normal activities and quality of life. Excessive daytime sleepiness increases the risk of serious automobile or machine accidents. Embarrassment and falls may result from cataplectic attacks and the symptoms of narcolepsy often result in individuals being viewed as poorly motivated or depressed making school challenging or the work place a difficult and uncomfortable environment. Such adversity may lead to psychological symptoms such as low self-esteem, social isolation and shame. The diagnosis is not generally made until adulthood but symptoms often appear in adolescence and have been noted in persons as young as three years. Onset appears to peak about age 15 with a second peak about age 36. Initially the disease progresses in severity but then stabilizes and is a chronic life long illness without remission.

In normal individuals sleep unfolds in a non-REM/REM cycle of approximately ninety minutes duration, with REM sleep periods of increasing length. In the narcoleptic, however, the abnormal REM sleep pattern is marked by sleep onset REM periods (SOREMPs). The observation of SOREMPs in the sleep laboratory distinguishes narcolepsy from other disorders of excessive sleepiness.

Human narcolepsy may not be a single disease. Experiments in canine models of narcolepsy suggest an autosomal recessive pattern of inheritance. Studies indicate that narcolepsy in humans is not strongly genetic. ⁴ A lack of concordance in monozygotic twin pairs with narcolepsy indicates that environmental factors play an important role. Data in humans shows that first-degree relatives of narcoleptic patients have a higher incidence of narcolepsy than the general population (1-2% versus .01%). More recent studies indicate that narcolepsy may be due to a deficiency of the neurotransmitter hypocretin. In canine models of narcolepsy Mignot and colleagues have established that the dog lacks the receptor protein for hypocretin, which is located on a limited number of neurons in the hypothalamus. ⁵ In genetically engineered mice with narcolepsy there appears to be an absence of the hypocretin neurotransmitter. In humans, evaluation of the cerebrospinal fluid reveals an absence of hypocretin in ninety percent of narcoleptics. In addition, a study of human brain from autopsy specimens indicates that hypocretin producing neurons from the hypothalamus are absent. In light of the fact that narcolepsy is associated with subtypes of human leukocyte antigen markers, it has been suggested that environmental factors induce an autoimmune response to hypocretin containing neurons leading to a hypocretin deficiency that results in the characteristic symptoms of the disease.

Recognizing Symptoms of Narcolepsy

Excessive Daytime Sleepiness (EDS): EDS is common with estimates in the general population ranging from one to five percent. ⁶ Sleepiness has a circadian tendency with peaks of sleepiness in midafternoon and early morning. In normals, if the sleep need is satisfied, the tendency to doze during periods of idleness or boring situations is greatly reduced. Sleepiness indicates a sleep disorder when it persists and cannot be resolved by increasing amounts of sleep. Patients with the complaint of fatigue and sleepiness should be asked about their bedtime, wake up time, and napping behavior to determine if sleep deprivation is the cause. Patients will often explain their sleepiness using social or occupational demands to explain or justify this symptom. The astute clinician will ignore these trivial explanations and come to his own conclusion regarding the patient's sleep wake behavior.

Cataplexy: Cataplexy results when the atonia of REM sleep intrudes into wakefulness. It occurs in about two thirds of patients with narcolepsy and the severity of the symptom is quite variable. The symptom is very important because it is pathognomic for narcolepsy. Cataplectic attacks are triggered by emotion such as laughter, excitement, and anger. Attacks of cataplexy may be partial or complete. Limited attacks affect the face or neck muscles and are characterized by drooping eyelids, sagging jaw, or an inclined head. Speech may be slurred or stuttering. More complete episodes may result in a buckling of the knees and a fall. During a cataplectic episode the narcoleptic is fully aware of their surroundings but cannot move. The duration of the episode, whether partial or complete, may vary from a few seconds to thirty minutes. Cataplexy may occur only a few times in a lifetime with very strong emotion or may be totally disabling with multiple attacks in a given day. Cataplexy may not occur for the first time until months to years after the onset of EDS. ⁷

Sleep Paralysis: Approximately sixty percent of individuals with narcolepsy report the experience of sleep paralysis. The frequency of episodes varies from a few lifetime events to daily episodes. The episodes are frequently accompanied by vivid dreams. Sleep paralysis may be hypnopompic or hypnogogic. During an episode the patients find themselves unable to move their extremities or to speak, respiratory distress is rare as phrenic nerve function is preserved.

Hypnogogic Hallucinations: Vivid dreams described as hallucinations occur at the onset of nocturnal sleep, but may also occur during daytime naps or inadvertent sleep episodes. Approximately seventy percent of narcoleptics experience these hallucinations, which occasionally occur in association with sleep paralysis.

Fragmented Night Sleep: Although patients with narcolepsy fall asleep quite easily, they paradoxically often experience insomnia. At least sixty percent of patients with narcolepsy report severe disruption of nocturnal sleep. Many of the patients will present with an insomnia complaint and delay the diagnosis of narcolepsy if it is not considered in the differential diagnosis.

Other Manifestations: Approximately fifty percent of narcoleptic patients experience automatic behavior with retrograde amnesia. ⁸ Automatic behavior occurs when sleep has partially overtaken the brain, but the body continues to perform familiar tasks without conscious awareness of doing them. These episodes are sometimes confused with partial complex seizures. Periodic leg movements during nocturnal sleep occur with a higher incidence in narcoleptics than in the general population.

Office Evaluation

A good starting point for evaluating the complaint of fatigue and excessive daytime sleepiness is the Epworth Sleepiness Scale. (ESS) ⁹ This scale consists of eight questions that subjectively assess the severity of daytime sleepiness. It is a brief self-administered questionnaire that indicates the sleep tendency in eight every day situations. The tendency to doze is indicated by a response from zero to twenty-four. Normal individuals score in the six to eight range. A score above ten warrants further investigation for a sleep disorder. ¹⁰ Figure 1.

Next a detailed sleep history and physical examination should be performed. The duration, severity, and consistency of daytime sleepiness should be assessed. A complete history with regard to bedtime, wake up time, job change, activity schedule, and circadian misalignment should all be investigated. Medical causes of fatigue and sleepiness include hypothyroidism, multiple sclerosis, infectious diseases, cancer and autoimmune processes. They are often associated with fatigue, but in general, they are unlikely to be confused with narcolepsy or a sleep disorder.

Differential Diagnosis

Once the presence of excessive daytime sleepiness is established and the diagnosis of sleep deprivation, drug induced sleepiness, and circadian rhythm disturbances are eliminated the differential diagnosis of excessive daytime sleepiness requires that the patient be referred to a sleep disorders laboratory for evaluation by nocturnal polysomnography and possibly multiple sleep latency testing. The vast majority of patients with a disorder of excessive daytime sleepiness will suffer from obstructive sleep apnea/hypopnea syndrome, upper airways resistance syndrome, narcolepsy, idiopathic CNS hypersomnia or period limb movement disorder.

Obstructive Sleep Apnea (OSA): Obstructive sleep apnea is associated with EDS, which results from fragmentation of nocturnal sleep due to repetitive hypnogenic upper airway obstruction. Loud snoring is a cardinal symptom of obstructive sleep apnea, but may be diminished in patients who have undergone previous surgical procedures. Clinical markers include male gender, obesity, and hypertension, although this disorder clearly extends beyond these few risk factors. Sleep apnea should also be considered in children with tonsillar hypertrophy or craniofacial abnormalities and in thin adults, particularly females, with Type II malocclusion or retrognathic mandibles, large tongues, and an elongated webbed vellum. OSA is the most common diagnosis of patients who seek care at US sleep centers with the complaint of excessive daytime sleepiness. ¹¹ All of these patients will require nocturnal polysomnography to document the presence and severity of the disorder.

Upper Airways Resistance Syndrome: A more subtle form of sleep disordered breathing known as upper airways resistance syndrome (UARS) may be associated with severe EDS. ¹² In this disorder, in contrast to OSA, increased respiratory effort due to increased upper airways resistance causes frequent arousals and sleep fragmentation in the absence of airflow changes recorded by a thermister. Nasal pressure or esophageal pressure recordings may be used to document flow limitation or increased respiratory effort thereby establishing the diagnosis of UARS.

Idiopathic CNS Hypersomnia: Idiopathic CNS hypersomnia is characterized by lifelong EDS, but with no REM sleep abnormality identified with sleep laboratory testing and in the absence of the auxiliary symptoms of the narcoleptic tetrad. The diagnosis does require formal sleep testing with both polysomnography to rule out nocturnal sleep fragmentation and the multiple sleep latency test to document the short sleep latencies. Idiopathic hypersomnia is a diagnosis of exclusion, since the results of the polysomnogram are expected to be unremarkable while the MSLT should reveal sleep latencies of less than five minutes without the occurrence of SOREMPs. As in narcolepsy, neuroimaging studies are not indicated in the absence of clinical findings that suggest a structural CNS abnormality.

Periodic Limb Movement Disorder (PLMD): PLMD may be associated with restless leg syndrome (RLS). Patients with RLS experience a dysesthesia or aching discomfort between the knee and ankle that is brought on by rest, and is associated with an irresistible urge to move the legs that interferes with the onset or return to sleep. While the diagnosis of RLS is easily established on the basis of the history, the documentation or periodic leg or arm movements requires nocturnal polysomnography with the appropriate placement of EMG electrodes to detect the limb movements.

Polysomnography and Multiple Sleep Latency Testing: A typical polysomnographic montage includes electroencephalographic, electro-oculographic and electromyographic measures to stage sleep and, in addition, records air flow, respiratory effort, electrocardiogram, and oximetry and leg movements. It is performed to document the adequacy of sleep and will indicate whether etiologies of EDS such as sleep apnea or periodic leg movements are present. The MSLT is the primary test utilized to diagnose narcolepsy. This test assesses the two major components of narcolepsy: hypersomnolence and the presence of SOREMPs. ¹³ The mean sleep latency (number of minutes required to fall asleep) indicates the tendency to fall asleep during normal waking hours. Four or five twenty-minute nap opportunities are offered at two-hour intervals. During these nap opportunities the stages of sleep are recorded. In normal tests the sleep latency is greater than ten minutes and REM sleep does not occur during these short naps. Patients with narcolepsy, however, typically fall asleep in five minutes or less and usually display SOREMPs on at least two of the five daytime nap periods. The MSLT measures sleepiness irrespective of its cause. SOREMPs periods may be observed in occasional patients with sleep apnea and severe sleep deprivation, but they are uncommon in the non-narcoleptic.

Treatment

In narcolepsy the goal of treatment is to provide symptom control and specifically to relieve the most troubling symptoms, EDS and cataplexy. EDS is primarily treated with stimulants or wake promoting agents. The commonly prescribed stimulant agents include amphetamine, methylphenidate, and pemoline. ¹⁴ These are CNS stimulants that increase alertness and assist the patient to remain awake. These agents are associated with some undesirable side effects, which include insomnia, hypertension, palpitations and irritability. Tolerance to long-term stimulant therapy may occur necessitating an increase in dosage to achieve the same control. Methylphenidate is the most widely used stimulant. The dose required for effective treatment varies widely from patient to patient. The usual range of methylphenidate dosage is 30-60 mg per day in the adult. Reports of severe liver toxicity due to pemoline have limited its usefulness. Modafinil is a novel wake promoting agent recently approved by the Food and Drug Administration (FDA) for the treatment of narcolepsy. ¹⁵ It has been shown to reduce daytime sleepiness with few side effects. Because of its improved safety profile and Schedule IV labeling, many experienced clinicians utilize the drug modafinil as the drug of first choice in the treatment of EDS of narcolepsy.

Stimulants and modafinil are not effective in the treatment of symptoms associated with abnormal REM sleep, hypnogogic hallucinations, sleep paralysis and cataplexy. These symptoms respond to tricyclic antidepressants that include imipramine, protriptyline, clomipramine and selective seratonin re-uptake inhibitors (fluoxetine, sertraline and fluvoxamine). These agents appear to act by suppressing REM sleep. Although the doses generally used to treat cataplexy are lower than those required to treat depression, side effects, particularly with the tricyclic group, are common. These include dry mouth, constipation, tachycardia, urinary retention and impotence.

Sodium oxybate or gammahydroxybutyrate (GHB) is an endogenous compound found in many tissues of the body that appears to be very effective for the treatment of cataplexy. ¹⁶ This compound is currently being considered for approval by the FDA. Data from clinical trials suggests that this drug consolidates sleep and increases slow wave sleep time, resulting in suppression of the auxiliary symptoms of narcolepsy and improving daytime sleepiness. Sodium oxybate is given at bedtime and repeated four hours later. It has been shown to be well tolerated and it is believed by this clinician to be the most effective agent for the treatment of cataplexy.

Abuse Potential of Treatment Agents

Methylphenidate and amphetamine are Schedule II drugs. Schedule II drugs carry the risk of substance abuse or illicit use. The abuse potential of these agents in the treatment of narcolepsy, however, is greatly overrated. In some states, but not in Florida, Schedule II prescription drugs require triplicate prescriptions. Sodium oxybate has been implicated in cases of "date rape". Formulations used in these anecdotal cases have been developed in home laboratories or have been purchased in health food stores and are not pharmaceutical grade products. Recently, legislation has been enacted by Congress to classify illicit GHB as a Schedule I agent, but when used in FDA approved clinical trials, it has been designated as a Schedule III. This legislation allows research with this agent to continue, but gives law enforcement the tools it needs to prosecute illicit activity.

Conclusion

Diagnostic criteria and sleep laboratory examination allow the accurate identification of patients with narcolepsy. Progress continues in developing new and more effective therapy. The discovery of the hypocretin mechanism represents a major advance in our knowledge and raises the hope that in the future this disease can be effectively treated and even prevented. Progress for the individual patient, however, starts with careful consideration of narcolepsy as a diagnostic possibility when patients complain of fatigue and sleepiness.

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Jacksonville Medicine / March, 2001

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