Narcolepsy and Idiopathic Hypersomnia
Narcolepsy and Idiopathic Hypersomnia
After reading the Chapter, test your knowledge with questions from ACCP-SEEK Sleep Medicine, First Edition:
1) Which one of the following statements is true regarding narcolepsy due to medical conditions?
A. The diagnosis requires the presence of reduced or absent CSF hypocretin-1 levels.B. It has been described in association with suprasellar tumors.C. Symptoms are typically refractory to stimulant therapy.D. The presence of cataplexy is an almost universal finding.
See the Answer.
1) Which one of the following statements is true regarding narcolepsy due to medical conditions?
B is CORRECT. It has been described in association with suprasellar tumors.
Narcolepsy due to medical conditions is a rare complication of various neurologic disorders. Several case reports have described narcolepsy in association with neurosarcoidosis, head trauma, diencephalic stroke, suprasellar tumors, CNS infections, paraneoplastic syndromes associated with anti-Ma-2 antibodies, Neiman-Pick type C disease, and as a complication of suprasellar surgery (choice B is correct). It has also been described in association with diffuse neurodegenerative disorders, including multiple sclerosis, Parkinson disease, and multiple system atrophy. In general, the majority of these cases have been associated with lesions affecting the diencephalon and/or brain stem. Hypothalamic involvement in the diencephalon is important, in that the posterior and lateral hypothalamus are the sites of hypocretin-producing neurons that are thought to play a major role in the majority of patients with idiopathic narcolepsy. While associated cataplexy has been described with this syndrome, it is by no means a universal finding (choice D is incorrect).
As is the case for primary narcolepsy, the diagnosis of secondary narcolepsy requires at least one of the following: (1) a definite history of cataplexy; (2) in the absence of definite cataplexy, a mean sleep latency on the multiple sleep latency test (MSLT) < 8 min and two or more sleep onset REM periods; or (3) hypocretin-1 levels of <110 pg/mL (or < 30% of normal control values). As per the diagnostic criteria, reduced CSF hypocretin-1 levels have been demonstrated in some cases of narcolepsy due to medical conditions, but this is not a universal finding, even in patients with significant destruction of their hypothalamus. In addition, measurement of CSF hypocretin-1 is not readily available. Therefore, reduced or absent hypocretin-1 levels are not necessary to make a diagnosis (choice A is incorrect). Patients with neurodegenerative diseases associated with sleep-disordered breathing should have their sleep-disordered breathing adequately treated prior to making this diagnosis.
The diagnosis of narcolepsy due to medical conditions should be considered in patients who present with typical symptoms of narcolepsy with known precipitating diseases, as noted above, or in those patients who present in an atypical fashion. Specifically, patients who present with characteristic symptoms at older or very young ages should be considered for evaluation of abnormalities of the diencephalon. The median age of symptom onset in typical narcolepsy is 16 years, with 90% of patients presenting with symptoms by 33 years of age. Our patient presented with narcolepsy symptoms at the uncharacteristic age of 65 years old. Many patients who present with this form of narcolepsy will also present with other neurologic complaints and/or endocrine abnormalities resulting from hypothalamic dysfunction.
The treatment of narcolepsy due to other medical conditions has been focused on interventions that may resolve the underlying medical disorder, as well as the use of stimulants and anticataplectic agents. While not a universal finding, most case reports demonstrate significant improvements in symptoms of daytime sleepiness and cataplexy with the use of stimulants and various antidepressants (choice C is incorrect). One case report of neurosarcoidosis demonstrated complete resolution of narcoleptic symptoms with low-dose whole-brain irradiation, after high-dose steroids were ineffective at improving the patient’s symptoms.
2) A 24-year-old woman presents with several years of excessive daytime sleepiness associated with bilateral lower extremity weakness precipitated by laughter. Her typical bedtime is 10:30 pm, with a subjective total sleep time of 8 h on most nights. She has no medical problems and takes no medications. Following an overnight polysomnogram with relatively normal results, an MSLT demonstrates a mean sleep latency of 3 min, with three sleep onset rapid eye movement (REM) periods out of four nap trials, supporting a diagnosis of narcolepsy. Therapy with modafinil, 200 mg taken each morning, is initiated and later increased to 400 mg taken each morning. After 4 weeks of therapy, she continues to have significant residual daytime sleepiness, as well as cataplexy.
Which of the following could you recommend to better treat the patient’s symptoms?
A. Increase modafinil from once-a-day to twice-a-day dosing.B. Add methamphetamine.C. Add sodium oxybate.D. Add methylphenidate SR.
See the Answer.
2) A 24-year-old woman presents with several years of excessive daytime sleepiness associated with bilateral lower extremity weakness precipitated by laughter. Her typical bedtime is 10:30 pm, with a subjective total sleep time of 8 h on most nights. She has no medical problems and takes no medications. Following an overnight polysomnogram with relatively normal results, an MSLT demonstrates a mean sleep latency of 3 min, with three sleep onset rapid eye movement (REM) periods out of four nap trials, supporting a diagnosis of narcolepsy. Therapy with modafinil, 200 mg taken each morning, is initiated and later increased to 400 mg taken each morning. After 4 weeks of therapy, she continues to have significant residual daytime sleepiness, as well as cataplexy.
Which of the following could you recommend to better treat the patient’s symptoms?
C is CORRECT. Add sodium oxybate.
Because narcolepsy is a chronic disease, without known cures, treatment is focused on therapies that improve or relieve symptoms. Sodium oxybate is the only treatment that has been demonstrated in several randomized clinical trials to significantly improve all of the core symptoms of narcolepsy, including daytime sleepiness, objective alertness, cataplexy, insomnia, disrupted sleep, and quality of life (choice C is correct). Sodium oxybate is derived from γ-hydroxybutyrate. The precise mechanisms of action responsible for its clinical outcomes in narcolepsy are unknown. Sodium oxybate is supplied as a liquid and is prescribed in doses between 3 and 9 g per night. It is prescribed in equally divided doses due to a short half-life of 2 to 3 h, with an initial dose taken at bedtime and a second dose taken 2.5 to 4 h later. Doses may be titrated up 1.5 g per night every 2 to 4 weeks, depending on the symptomatic response. Side effects may include dizziness, vomiting, sleep walking, confusion, and enuresis. At higher doses, it can also act as a respiratory suppressant and should not be used with other sedatives, including alcohol. Initial studies with sodium oxybate focused on the treatment of cataplexy. Sodium oxybate has been demonstrated in several randomized controlled trials to reduce episodes of cataplexy in a dose-dependent fashion over periods of 4 to 8 weeks. These improvements in cataplexy symptoms have been observed to persist for up to 12 months in observational studies, without the development of tolerance to any specific dose. Importantly, there are no significant withdrawal symptoms upon discontinuing the drug. Status catiplecticus, commonly observed upon discontinuing other REM suppressant medications used for cataplexy, typically does not occur upon stopping sodium oxybate. Early trials evaluating sodium oxybate for cataplexy also demonstrate significant reductions in subjective daytime sleepiness compared with placebo. Two randomized placebo-controlled trials have specifically evaluated the use of sodium oxybate for symptomatic improvement in daytime sleepiness in patients with narcolepsy. Sodium oxybate at doses of 6 and 9 g per night results in significant improvements in daytime sleepiness, as defined by the Epworth Sleepiness Scale, when added to concomitant baseline stimulant use. Significant improvements in objective alertness, as defined by the Maintenance of Wakefulness Test, are also seen with sodium oxybate in the 9-g dose range when used in combination with other stimulants. When used as the sole agent, sodium oxybate at doses of 6 and 9 g per night results in improvements in subjective sleepiness and daytime alertness similar to those with 200 to 400 mg per day of modafinil. Finally, the combination of sodium oxybate and modafinil appears to result in an additive effect on these sleepiness parameters when compared with placebo, though statistically the combination of these two drugs was no better than either one used alone. Based on these data, sodium oxybate is currently the only drug FDA approved for the treatments of both cataplexy and daytime sleepiness in patients with narcolepsy. Modafinil has been demonstrated in randomized trials to significantly improve symptoms of daytime sleepiness but has not been demonstrated to have any significant effects on cataplexy (choice A is incorrect). Amphetamines and methylphenidate, while used for the treatment of daytime sleepiness, have not been evaluated in randomized trials and have not demonstrated any efficacy in the treatment of cataplexy (choices B and D are incorrect). These agents are considered second-line therapies to both modafinil and sodium oxybate due to their potential significant sympathomimetic side effect profiles.
