The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C, Good Practice Points) are defined at the end of the "Major Recommendations" field.
Excessive Daytime Sleepiness and Irresistible Episodes of Sleep
First-line pharmacological treatment of excessive daytime sleepiness and irresistible episodes of sleep should rely on modafinil, 100 to 400 mg/day, given in two doses, one in the morning and one early in the afternoon (level A). In a few cases dosage should be increased up to 300 mg twice a day. Increase of the daily dosage above 600 mg is in general not advisable. Second line pharmacological treatment is methylphenidate at a daily dosage of 10–60 mg. Of note a growing practice in the USA, based on level A evidence, of using sodium oxybate as a first line treatment of excessive daytime sleepiness. This could be the case in Europe as well, if sodium oxybate is registered for narcolepsy (including cataplexy, excessive daytime sleepiness and disturbed nocturnal sleep). In severe cases the combination of modafinil and sodium oxybate appears to be beneficial. Given these various possibilities the role of other compounds becomes fairly limited, unless recommended treatments have failed. Behavioral treatment measures are always advisable. Essentially the studies available support on a B level the recommendation to take planned naps during the day, as naps decrease sleep tendency and shorten reaction time. Because of varying performance demands and limitations on work or home times for taking them, naps are best scheduled on a patient-by-patient basis.
Cataplexy
Based on class I evidence (level A rating) studies, first-line pharmacological treatment of cataplexy is sodium oxybate at a starting dose of 4.5 g/night divided into two equal doses of 2.25 g/night. The dose may be increased to a maximum dosage of 9 g/night, divided into two equal doses of 4.5 g/night, by increments of 1.5 g. Most patients will start to feel better within the first few days, but optimal response at any given dose may take as long as 8 to 12 weeks. For this reason adjustment should typically occur at least at 2-week intervals. Second-line pharmacological treatments are antidepressants. Tricyclic antidepressants, particularly clomipramine (10 to 75 mg), are the most potent anticataplectic drugs. However they have the drawback of anticholinergic adverse effects. Starting dosage should be as low as possible. Selective serotonin re-uptake inhibitors (SSRIs) are slightly less active but have less adverse effects. The norepinephrine/serotonin reuptake inhibitor venlafaxine is widely used today but lacks any published clinical evidence of efficacy. Norepinephrine reuptake inhibitors, such as reboxetine and atomoxetine, also lack published clinical evidence. Given the availability of sodium oxybate and the activity of antidepressants, the place for other compounds is fairly limited. There is no accepted behavioral treatment of cataplexy. However, advice to some subjects should include the avoidance of known triggers, whenever possible.
Hallucinations and Sleep Paralysis
As for cataplexy but there is a lack of studies with these outcome parameters.
Poor Sleep
Benzodiazepines or non-benzodiazepine hypnotics may be effective in consolidating nocturnal sleep (level C). Objective evidence is lacking over intermediate or long-term follow-up. The improvement reported by some patients once established on modafinil is noteworthy. According to level A studies with gamma-hydroxybutyrate and sodium oxybate, sodium oxybate might become the most appropriate option.
Parasomnias
Based on available information it is difficult to provide guidance for prescribing in parasomnias associated with narcolepsy other than to recommend conventional medications.
Associated Features
Obstructive sleep apnea (OSA) should be treated no differently to the general population, although some experts have the experience that the majority of patients refuse to continue continuous positive airway pressure (CPAP) therapy because of a lack of clinical improvement. There is usually no need to treat periodic limb movements in sleep (PLMS) in narcoleptic patients. Antidepressants and/or psychotherapy should be used in depressed narcoleptic patients as in non-narcoleptic depressed patients.
Psychosocial Support and Counseling
Interaction with narcoleptic patients and counseling from trained social workers are recommended (level C).
Good Practice Points
A prerequisite before implementing a potentially lifelong treatment is to establish an accurate diagnosis of narcolepsy with or without cataplexy, and to check for possible comorbidity. Following a complete interview the patient should undergo an all-night polysomnography followed immediately by a multiple sleep latency test (MSLT). Human leucocyte antigen (HLA) typing is rarely helpful. Cerebrospinal fluid (CSF) hypocretin-1 measurement may be of help and is added as diagnostic test in the revised International Classification of Sleep Disorders, particularly if the MSLT cannot be used or provides conflicting information. Levels of CSF hypocretin are only significantly reduced or absent in cases of narcolepsy with cataplexy. In the absence of cataplexy, the value of measuring hypocretin is debatable.
Once diagnosed, patients must be given as much information as possible about their condition (nature of the disorder, genetic implication, medications available and their potential adverse effects) to help them cope with a potentially debilitating condition.
Regular follow-up is essential to monitor response to treatment, adapt the treatment in case of insufficient response or adverse effects, and above all encourage the patient to stand on an efficacious therapy. Another polysomnographic evaluation of patients should be considered in case of worsening of symptoms or development of other symptoms, but not for evaluating treatment in general.
Definitions:
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of Recommendations
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.
Good Practice Points Where there was a lack of evidence but consensus was clear, the Task Force has stated their opinion as good practice points.
