The levels of evidence (Class I-IV) supporting the recommendations and ratings of recommendations (A-C, Good Practice Points [GPP]) are defined at the end of the "Major Recommendations" field.
Excessive Daytime Sleepiness and Irresistible Episodes of Sleep
The first-line pharmacological treatment of excessive daytime sleepiness and irresistible episodes of sleep is not unequivocal. In cases when the most disturbing symptom is excessive daytime sleepiness, modafinil should be prescribed based on its efficacy, limited adverse effects, and easiness of manipulation. Modafinil can be taken in variable doses from 100 to 400 mg/day, given in in one dose in the morning or two doses, one in the morning and one early in the afternoon. However, it is possible to tailor the schedule and dose of administration according to the individual needs of the patient. On the other hand, when excessive daytime somnolence coexists with cataplexy and poor sleep, sodium oxybate may be prescribed, based on its well-evidenced efficacy on the three symptoms. However, this benefit should be balanced with its more delicate manipulation: the dose should be carefully titrated up to an adequate level over several weeks; the drug should not be used in association with other sedatives, respiratory depressants and muscle relaxants; vigilance should be held for the possible development of sleep-disordered breathing; and depressed patients should not be treated with this drug. Sodium oxybate should be given at a starting dose of 4.5 g/night, increasing by increments of 1.5 g at 4-week intervals. Adverse effects may require to reduce the dose and titrate more slowly. The optimal response on excessive daytime sleepiness may take as long as 8 to 12 weeks. Supplementation with modafinil is generally more successful than sodium oxybate alone. Methylphenidate may be an option in case modafinil is insufficiently active and sodium oxybate is not recommended. Moreover, the short-acting effect of methylphenidate is of interest when modafinil needs to be supplemented at a specific time of the day, or in situations where maximum alertness is required. Methylphenidate LP and mazindol may be of interest in a limited number of cases.
Behavioral treatment measures are always advisable. Essentially the studies available support on a B Level the recommendation to have regular nocturnal sleep times and to take planned naps during the day, as naps temporarily 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.
Based on several 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 of 9 g/night, divided into two equal doses of 4.5 g/night, by increments of 1.5 g at 2-week intervals. Adverse effects may need the dose to be reduced and titrated more slowly. Most patients will start to feel better within the first few days, but the optimal response at any given dose may take as long as 8 to 12 weeks. The drug should not be used in association with other sedatives, respiratory depressants, and muscle relaxants; vigilance should be held for the possible development of sleep-disordered breathing; and depressed patients should not be treated with the drug. 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. The starting dosage should always be as low as possible. Selective serotonin re-uptake inhibitors (SSRIs) are slightly less active but have fewer adverse effects. The norepinephrine/serotonin reuptake inhibitor venlafaxine is widely used today but lacks any published clinical evidence of efficacy. The norepinephrine reuptake inhibitors, such as reboxetine and atomoxetine, also lack published clinical evidence. Given the well-evidenced efficacy of sodium oxybate and antidepressants, the place for other compounds is fairly limited. There is no accepted behavioral treatment of cataplexy.
Hallucinations and Sleep Paralysis
Recommendations are as for cataplexy.
According to recent studies with sodium oxybate, this agent appears as the most appropriate to treat poor sleep (Level A). Benzodiazepines or non-benzodiazepine hypnotics may be effective in consolidating nocturnal sleep (Level C). Unfortunately, objective evidence is lacking over intermediate or long-term follow-up. The improvement in poor sleep reported by some patients once established on modafinil is noteworthy.
Based on the available information it is difficult to provide guidance for prescribing in parasomnias associated with narcolepsy other than to recommend conventional medications.
Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) should be treated no differently in narcoleptic patients than the general population, although it has been shown that continuous positive airway pressure (CPAP) does not improve excessive daytime sleepiness in most narcolepsy subjects. There is usually no need to treat periodic limb movements in sleep (PLMS) in narcoleptic patients. Antidepressants and psychotherapy should be used in depressed narcoleptic patients (Level C) as in non-narcoleptic depressed patients.
Psychosocial Support and Counselling
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 (the nature of the disorder, genetic implications, 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 persist with a management plan. 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.
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.