Critical review of evidence
2. Narcolepsy with and without cataplexy
1 In a subject suspect of narcolepsy with cataplexy, which tests should be performed prior to treatment?
2 Which treatment should be implemented? Among patients with narcolepsy with or without cataplexy, how does pharmacological
treatments affect the probability for reducing daytime sleepiness and/or cataplexy?
3 Which main difficulties can occur with time in relation with the treatment?
Narcolepsy with cataplexy is primarily characterized by exces-sive daytime sleepiness and cataplexy. Excesexces-sive daytime sleepiness is usually the most disabling symptom and the first one to occur. It is characterized by episodes of naps or lapses into sleep across the daytime. Cataplexy, a unique feature of the condition, is characterized by sudden loss of bilateral mus-cle tone provoked by strong emotions that are usually posi-tive, such as a fit of laughter, receiving a compliment, humour expressed by the subject, the sight of prey for the hunter, a well-caught ball, and less often negative, that is anger or stress. Sleep paralysis, hypnagogic hallucinations and noctur-nal sleep disruption commonly occur in patients with nar-colepsy with cataplexy. These three symptoms, however, can occasionally, occur in normal people.
Narcolepsy without cataplexy is a minor phenotype of the same condition. Narcolepsy with cataplexy affects 20–40/
100,000 of the European and North-American population, depending on the methodology of the surveys. Studies using both questionnaires and polysomnography find lower preva-lence of the condition than those relying on questionnaire only. Both sexes are affected with some preponderance of males. Narcolepsy without cataplexy is less frequent, but no prevalence study is available. The natural history of nar-colepsy varies considerably with subjects. In most cases exces-sive daytime sleepiness and irresistible sleep episodes persist throughout the lifetime, although they tend to improve with advancing age. Cataplexy may vanish with age and even spontaneously disappear in some patients. Nocturnal sleep does not improve with age.
Clinical scenario
A 32-year-old secretary complained of excessive daytime sleepiness and irresistible episodes of sleep occurring daily or almost daily for the last year. The interview quickly showed that she had cataplexy at a rate of approximately one attack per week and hypnagogic hallucinations. The diagnosis of narcolepsy with cataplexy was confirmed by an all-night polysomnography followed by a multiple sleep latency test (MSLT) showing three sleep onset REM periods (SOREMPs).
This woman is on the verge of being fired due to falling asleep at work.
Evidence
1 Narcolepsy can be diagnosed on purely clinical grounds.
However additional tests are useful to confirm the diagnosis.
Most commonly, nocturnal polysomnography followed by a MSLT is recommended, and, in a few selected cases, measure-ment of cerebrospinal fluid (CSF) levels of hypocretin-1. In all-night polysomnography, a SOREMP is observed in 25–50%
Chapter 9: Sleep disorders 71
Part 2: Neurological symptoms/problems Table 9.1 Treatment of excessive daytime sleepiness.
Reference Methods Participants Interventions Outcome measures Outcome
Billiard et al. 12-week, placebo- 50 narcolepsy with Modafinil, 300 mg Maintenance of Wakefulness Modafinil improves daytime sleepiness (1994) controlled trial. cataplexy subjects (2 divided doses) 100 mg Test (MWT)
Crossover design in a.m. and 200 mg at Global Symptoms Index (GSI)
noon or vice versa
Broughton et al. 6-week, randomized 75 narcoleptic subjects Modafinil 200 or 400 mg MWT Modafinil effective in keeping narcolepy
(1997) placebo-controlled in divided doses (morning Epworth Sleepiness Scale patients awake
trial. Crossover and noon), versus placebo (ESS)
design
US Modafinil in 9-week, randomized 283 narcoleptic subjects Modafinil 200 or 400 mg, ESS Modafinil 200 mg and 400 mg
Narcolepsy Study placebo-controlled versus placebo, followed MSLT significantly reduced all measures of
Group (1998) trial by an open-label MWT sleepiness
treatment period GSI
US Modafinil in 9-week, randomized 271 narcoleptic Modafinil 200 or 400 mg MSLT Effective for treatment of daytime
Narcolepsy Study placebo-controlled subjects versus placebo MWT sleepiness in narcolepsy for 9 weeks
Group (2000) trial ESS
US Xyrem 4-week, 136 narcolepsy with Sodium oxybate, 3, 6, Daily diaries (n° of inadvertent Frequency of inadvertent naps/sleep attacks Multicenter Study randomized cataplexy subjects or 9 g, versus placebo naps/sleep attacks) and nightime awakenings, reduced at all doses,
Group (2002) placebo- ESS becoming significant at the 9 g dose
controlled trial Clinical Global Impression of ESS reduced at all doses, becoming significant
Change (CGI-c) at the 9 g dose
CGI-c demonstrated a dose-related improvement, significant at the 9 g dose US Xyrem 12-month, open- 118 narcolepsy with Sodium oxybate 6 g Daily diaries (n° of inadvertent Overall improvement in excessive daytime Multicenter label trial cataplexy subjects nightly, taken in equally naps/sleep attacks) sleepiness, which were significant at 4 weeks
Study previously enrolled in a divided doses at ESS and maximal after 8 weeks
Group (2003) 4-week double-blind bedtime and 2.5–4 h CGI-c
sodium oxybate trial later. The study protocol permitted the dose to be increased or decreased in 1.5 g increments at 2 week intervals, based on efficacy response or adverse experiences, but staying within the range of 3–9 g nightly
_4_009.qxd 2/7/07 2:47PM Page 72
Chapter 9: Sleep disorders73 Table 9.2 Treatment of cataplexy.
Reference Methods Participants Interventions Outcome measures Outcome
The US Xyrem 4-week, randomized 136 narcolepsy Sodium oxybate, 3, 6, or 9 g, versus placebo Daily diaries (n° of cataplectic Weekly cataplectic attacks were
Multicenter Study placebo-controlled with cataplexy attacks) decreased by sodium oxybate at the
Group (2002) trial subjects CGI-c 6 g dose and significantly at the 9 g
dose
CGI-c demonstrated a dose-related improvement, significant at the 9 g dose
US Xyrem Method: 12-month, 118 narcolepsy Sodium oxybate 6 g nightly, taken in equally Daily diaries (n° of cataplexy Significant decrease in frequency of Multicenter Study open-label trial subjects previously divided doses at bedtime and 2.5–4 h later. attacks) cataplexy attacks
Group (2003) enrolled in a The study protocol permitted the dose to be CGI-c
4-week double- increased or decreased in 1.5 g increments at blind sodium 2-week intervals based on efficacy response or oxybate trial adverse experiences, but staying within the
range of 3–9 g nightly
US Xyrem Double-blind 55 narcolepsy Subjects enrolled in a 2-week single-blind Daily diaries (n° of cataplexy The abrupt cessation of sodium Multicenter Study treatment withdrawal with cataplexy sodium oxybate treatment phase to establish attacks) oxybate therapy in the placebo patients
Group (2004) paradigm in subjects a baseline for the weekly occurrence of resulted in a significant increase in the
patients who had cataplexy, followed by a 2-week double-blind number of cataplexy attacks compared
received continuous phase in which patients were randomized to to patients who remained on sodium
treatment with receive unchanged drug therapy versus oxybate
sodium oxybate for placebo
7–44 months (mean 21 months)
Xyrem 8-week, double- 22 narcolepsy Subjects randomized to receive 4.5, 6 or 9 g Daily diaries (n° of cataplexy Compared to placebo, nightly doses of International blind, placebo- with cataplexy sodium oxybate nightly for 8 weeks versus attacks) 4.5, 6 and 9 g sodium oxybate resulted
Study Group controlled subjects placebo in statistically significant median
(2005) decreases in weekly cataplexy attacks of
57.0%, 65.0% and 84.7%, respectively.
The decrease in cataplexy at the 4.5 g dose represented a novel finding
74 Part 2: Neurological symptoms/problems
of cases of narcolepsy with cataplexy and is a highly specific finding. In addition a disruption of the normal sleep pattern with repeated awakenings is a frequent feature. The MSLT demonstrates a mean sleep latency of less than 8 min and two or more SOREMPs. However a few typical cases of nar-colepsy may have only one SOREMP or even none, specially in elderly subjects. Measuring CSF levels of hypocretin-1 is highly specific and sensitive for the diagnosis of narcolepsy with cataplexy. Values below 110 pg/mL are found in approxi-mately 90% of cases of narcolepsy with cataplexy. However due to the limited number of laboratories providing this ser-vice, the test should be used in a few selected indications only:
need to objectively document a diagnosis when the MSLT cannot be used; already treated patients if the diagnosis is in doubt; in young children and in cases with associated psy-chiatric or neurological disorders. This test is of much less value in narcolepsy without cataplexy as only 10% of patients show low values [6].
2 The two more recently introduced treatments of excessive daytime sleepiness, modafinil and sodium oxybate, are the most commonly used agents in newly diagnosed narcoleptic patients (Table 9.1, [7–12]). Modafinil is given at a daily dose of 400 mg (range 100–400 mg), with one dose in the morn-ing and one dose early in the afternoon. One of the major advantages of modafinil is its relative lack of adverse effects.
It can be administered concurrently with anticataplectic med-ications without problems. Sodium oxybate (not yet regis-tered for excessive daytime sleepiness in Europe) is taken orally upon getting into bed and again 2.5–4 h later. The cur-rent recommended starting dose is 4.5 g/day divided into two equal dose of 2.25 g. The dose may be increased to a maximum of 9 g/day by increments of 1.5 g. Two weeks are recommended between dosage increments. In addition to either modafinil or sodium oxybate, behavioural measures are always advisable, the main recommandation being to take naps during the day, on a patient-by-patient basis. Previous treatments included methylphenidate, 10–60 mg/day, and in case of non-response, dextroamphetamine or methamphet-amine under close control.
Treatment of cataplexy relies on sodium oxybate with the same mode of administration already recommended for excessive daytime sleepiness (Table 9.2, [11–14]). Second line treatments include tricyclic antidepressants, mainly clomipramine selective serotonine reuptake inhibitors (SSRIs), such as fluoxetine or fluvoxamine, a norepinephrine uptake inhibitor, viloxazine, a norepinephrine and serotonine uptake inhibitor, venlafaxine. However the use of these drugs is based on no or few randomized, placebo-controlled clinical trials, and none of them is registered forcataplexy except clomipramine in few European countries.
Benzodiazepines or non-benzodiazepine hypnotics may be effective in consolidating sleep. Unfortunately objective evi-dence is lacking over intermediate or long-term follow-up.
According to US Xyrem studies [11–12], a significant decrease
of nighttime awakenings is obtained with sodium oxybate 3–9 g, given in two doses, one at bedtime and another one during the night.
3 As already pointed out adverse effects are limited with modafinil. Headache is the most common complaint followed by nausea, rhinitis and nervousness. As for sodium oxybate most commonly reported adverse effects include vomiting, incontinence, sleepwalking and confusion, in a limited num-ber of cases. However some patients do not respond to stimu-lants or to anticataplectic drugs or both; some patients show an insufficient response and in some patients an originally good response progressively fades out with time. This is the reason why novel therapies are in a phase of research, either hypocre-tin-based therapies (peptide agonists, non-peptide agonists and cell transplantation or gene therapy) or immune-based therapies (steroid therapies, intravenous-immunoglobulins or plasmapheresis [15].
3. Idiopathic hypersomnia with and without long