SAN DIEGO—Research in recent years has provided greater insights and better tools for understanding and diagnosing narcolepsy and has led to significant treatment advances that can reduce the condition’s negative impact on quality of life, said Lois E. Krahn, MD. According to one study she cited, the consequences of narcolepsy are comparable to those of Parkinson’s disease and worse than those of epilepsy. Detection is essential, said Dr. Krahn, in order to consider the multiple treatment options.

PREVALENCE AND SYMPTOMS

With a prevalence of one to two out of 100,000, narcolepsy is neither common nor extremely rare. Dr. Krahn, Department Chair of Psychiatry at the Mayo Clinic, Rochester, Minnesota, expects that most physicians have had at least one encounter with a narcolepsy patient.

The disorder most often manifests during the teenage years. Dr. Krahn referenced a Japanese study of 40 patients that showed occurrence peaking around age 14, with a secondary peak around age 20. Other studies corroborate the early onset. Narcolepsy very rarely occurs past the mid-50s. Once manifest, narcolepsy is a chronic disorder.

According to Dr. Krahn, excessive daytime sleepiness is present in all patients with narcolepsy. Excessive daytime sleepiness is characterized as "inappropriate and severe" sleep attacks that can occur at any time. Inappropriate sleep is not limited to passive activities; it can occur in any situation: during arguments, appointments, or even work on an assembly line.

People with narcolepsy have a higher risk for motor vehicle accidents, she noted. In a 1999 study published in Sleep, patients with narcolepsy scored twice the number of errors made by controls in a driving simulation test.

A majority of narcolepsy patients (64% to 80%) also experience cataplexy, said Dr. Krahn. Typically lasting less than 30 seconds, cataplexy is easily observable. Complete attacks may involve the total body except for ocular and respiratory muscle movement. Partial attacks are more subtle, involving a buckling of the knees, sagging facial muscles, and weakness in the jaws and neck. Dr. Krahn said the patient may be "entirely alert during an episode, but cannot move or speak." Speaking at the 17th Annual Meeting of the American Neuropsychiatric Association, she described having a cataplexy attack as being "in limbo" between wakefulness and unconciousness.

Cataplexy is most often brought on by emotional triggers, with laughter being the leading cause, Dr. Krahn continued. A funny story, a surprise, excitement, and happy memories are other triggers. In rare instances, anger, fear, or an unhappy memory can trigger cataplexy.

Many patients report that cataplexy episodes become less frequent as they age. Some patients with cataplexy also experience sleep paralysis, Dr. Krahn noted. Sleep paralysis is associated with the inability to move during transitions from sleep to awakening. A sleep paralysis episode lasts longer than a cataplexy episode and may coexist with hypnagogic hallucinations—highly vivid experiences that may take place when people with narcolepsy fall rapidly into REM sleep. Hypnagogic hallucinations occur most often among adolescents with narcolepsy who present with cataplexy, she said. A study published in Sleep in 2003 found that 59% of patients with cataplexy had also experienced hypnagogic hallucinations.

In addition to the aforementioned major symptoms of the disorder, narcolepsy patients have a higher rate of other sleep disorders, including obstructive sleep apnea, REM behavior disorder, non-REM parasomnias, and periodic limb movements, she noted.

DIAGNOSIS

Most patients with narcolepsy are not diagnosed until 10 or more years after the first symptoms appear, said Dr. Krahn. Excessive daytime sleepiness is the symptom for which patients most often seek treatment. If sleep disorders in addition to suspected narcolepsy are present, they should be treated before testing for narcolepsy, she noted.

Evidence of excessive daytime sleepiness and cataplexy in the patient’s medical history are the minimum diagnostic tools for narcolepsy. Cataplexy is difficult to confirm with certainty. Most clinicians require laboratory confirmation before starting treatment, said Dr. Krahn.

The Multiple Sleep Latency Test (MSLT) is the pivotal test for confirming excessive daytime sleepiness and sleep-onset REM episodes. However, Dr. Krahn cautioned that false-negatives are possible with the MSLT. Sleep laboratory testing with polysomnography and wrist actigraphy, which can identify other causes of excessive daytime sleepiness, should precede the MSLT. Measuring hypocretin levels is a reliable test for patients with cataplexy.

GENETIC LINK?

"Most sleep disorders run in families, and there is mounting evidence of genetic influence in narcolepsy," Dr. Krahn said. In particular, data associating human leukocyte antigen (HLA) DR2/DQ6 with narcolepsy suggest that narcolepsy may have a genetic link. A study of Japanese narcolepsy patients found 100% of the participants had DR2-positivity. The results were later confirmed in American Caucasians, while lower rates of DR2 were found in African-American patients, Dr. Krahn noted. The study also found that a strong majority (85% to 93%) of patients with classic cataplexy carried the DQB1*0602 genotype, compared with 35% to 56% of those without cataplexy and 20% of controls, she added. However, HLA-DQB1*0602 is not considered a reliable diagnostic test for narcolepsy, because 20% of the general population is HLA-positive, Dr. Krahn said.

Any discussion of a genetic influence in narcolepsy must inevitably turn to the hypocretin system, Dr. Krahn observed. "Most patients with narcolepsy have very low levels of hypocretin peptides in their cerebral spinal fluid and no or barely discernible neurons containing hypocretin in their hypothalamus," she said. Autopsy studies of patients with narcolepsy have found a 90% reduction of hypocretin in the hypothalamus. Current research suggests that this deficiency is associated with cataplexy in these patients. The evidence also suggests that defects in the hypocretinergic system are responsible for the unstable functioning of awake/ sleep cycles among narcolepsy patients.

In the course of her research, Dr. Krahn has observed that only 38% of patients with familial narcolepsy have depleted hypocretin levels. The search for hypocretin mutations has yielded few gene or receptor mutations, she noted. There is one reported case of a point mutation, which occurred in an early-onset patient.

TREATMENT

The treatment of narcolepsy patients focuses on reducing excessive daytime sleepiness, preventing cataplexy, reducing disturbing dreams, improving nocturnal sleep, and improving daytime functioning and mood, said Dr. Krahn.

Behavioral treatment goals are to avoid sleep deprivation, follow optimal sleep hygiene, maintain a consistent sleep/wake schedule, avoid shift work, take scheduled naps, and be able to function in a stimulating environment without triggering cataplexy, Dr. Krahn said.

Among pharmacologic treatments, modafinil has emerged as the first-line treatment for narcolepsy. "Modafinil is believed to work through activation of the hypothalamic regions," Dr. Krahn said. Side effects include headache and nausea.

Psychostimulants such as methylphenidate and amphetamines in their original compounds are FDA approved for the treatment of narcolepsy. These sympathomimetic agents release catecholamines including adrenaline, noradrenaline, and dopamine. Several new pyschostimulant formulations with more sustained action have been brought to market but are currently FDA approved only for the treatment of ADHD, she noted.

Antidepressants, particularly the tricyclics, have been found in trials to be effective in suppressing REM sleep and cataplexy. "SSRI antidepressants are less effective but carry less risk of side effects," Dr. Krahn said. No antidepressants are FDA approved for narcolepsy.

Benzodiazepines are hypnotic agents that have been prescribed for several years. Hypnotics improve sleep continuity and reduce dream enactment. Dr. Krahn said they could be useful for narcolepsy patients with REM behavior disorder. "A drawback is that tolerance can develop, and they may offer only a partial response, especially in severe cases."

Sodium oxybate has been used as an effective treatment for narcolepsy since the 1970s, Dr. Krahn said. Sodium oxybate increases slow-wave sleep, prevents awakenings, and decreases the incidence of excessive daytime sleepiness. It also reduces the incidence of cataplexy, sleep paralysis, and hallucinations. Sodium oxybate did not gain FDA approval until 2002 because of concerns about potential drug abuse, she noted. Side effects include headache, dizziness, nausea, sleepwalking, nocturnal confusion, and respiratory complications.

"All current treatments are based on treating symptoms, but research may soon lead to a treatment that directly replaces the hypocretin neurotransmitter," Dr. Krahn concluded.

—Kathy Stone

Suggested Reading
Findley LJ, Suratt PM, Dinges DF. Time-on-task decrements in "steer clear" performance of patients with sleep apnea and narcolepsy. Sleep. 1999;22:804-809.
Fujiki N, Yoshida Y, Ripley B, et al. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep. 2003;26:953-959.
Rogers AE, Meehan I, Guilleminault C, et al. HLA DR15 (DR2) and DQB1*0602 typing studies in 188 narcoleptic patients with cataplexy. Neurology. 1997;48:1550-1556.

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