Modafinil for excessive daytime sleepiness in myotonic dystrophy

Patients and methods.

Eleven ambulatory patients, 10 with genetically proven classic DM with an expanded CTG repeat on chromosome 19q13.3 (DM1) and one with maternally inherited proximal myotonic myopathy and no CTG repeat in the myotonic protein kinase gene (PROMM syndrome), were referred because of EDS. The length of CTG trinucleotide repeats in the DM1 group ranged from 100 to 450 (mean: 280 triplet repeats). The tableshows general clinical data. All patients underwent clinical examination including routine blood tests, full cardiologic examination, pulmonary function testing, and screening for sleep apnea syndrome (by recording continuous nocturnal blood gas, ECG monitoring, and observation of sleep in an intermediate care unit). Formal polysomnography was performed in patients 2, 4, 5, 9, and 11. Multiple Sleep Latency Test (MSLT) was performed under standard conditions, and subjective daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS).7,8⇓ Other exclusion criteria besides obstructive sleep apnea were hypertension and severe cardiac arrhythmia. In accordance with the Helsinki Declaration of 1975, informed consent was obtained from eligible patients if EDS was found, and they were offered treatment with modafinil 200 mg per day, which could be increased to a maximum of 400 mg per day. Follow-up examination included blood tests, EKG, blood pressure monitoring, MSLT, and ESS. Paired Student’s t-tests were used for comparison of MSLT and ESS results before and during treatment.

Results.

All patients were fully ambulatory and able to perform activities of daily living without assistance; weakness was generally mild to moderate and confined to distal muscles in patients with DM1 (table). Six patients were employed, one was unemployed, two were employed at home, and two were retired because of DM. All considered their excessive daytime sleepiness a major disability. Patient 5 had lost his job and driver’s license because of falling asleep, and two of the patients considered their employment threatened because of sleepiness. All patients had reduced sleep latency as measured by the MSLT ( figure 1) and an elevated ESS score ( figure 2), confirming EDS. None had thyroid dysfunction, relevant cardiac arrhythmia, cardiomyopathy, or hypertension, although a tendency toward systemic hypotension was common. Mild restrictive pulmonary dysfunction was found in three cases (Patients 4, 7, and 10). Nine of the 11 patients were considered eligible for treatment with modafinil. Two were excluded because of obstructive sleep apnea diagnosed by polysomnography (Patient 9) and blood gas and sleep monitoring in the intermediate care unit (Patient 10); they were referred elsewhere for conventional treatment. Patient 10 subsequently died of what was reported as a “sudden cardiac death” at home. The Mini-Mental State Examination scores obtained from patients who were eligible for treatment with modafinil were 29 (n = 6) and 30 (n = 2), and there was no cognitive dysfunction in any case. The patient with PROMM underwent full Wechsler intelligence testing and had an IQ score of 122.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1. Multiple sleep latency test results showing average sleep latency of Patients 1 through 8 before (light) and during (dark) treatment with modafinil. Hypersomnolence is considered severe with <5 minutes sleep latency and moderate with 5 to 10 minutes sleep latency.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2. Epworth Sleepiness Scale (ESS) self-rated sleepiness scores before (light) and during (dark) treatment with modafinil (normal range: 5.9 ± 2.2).

Modafinil was well tolerated in the nine patients treated; there were no dropouts, and no significant side effects were observed. The patient with PROMM, whose first MSLT result indicated a mean sleep latency of 5 minutes, refused follow-up examination, claiming that he was not sleepy any longer and did not need confirmatory tests. Follow-up examination was completed after a minimum of 16 weeks on a steady dose (average: 16.4 weeks) in all but Patient 4, for whom follow-up was completed after only 3 weeks. Blood pressure remained normal (average pretreatment: 125/75 mmHg; during treatment: 120/80 mmHg) and night sleep was unimpaired; there were no psychiatric side effects. Mean sleep latency as measured by the MSLT increased significantly from 7.3 (range: 4.0 to 17.75) to 22.7 (range: 12.25 to 29.0) minutes (p = 0.00013; figure 1). All patients reported a major improvement in daytime sleepiness. Three patients reported feeling “perfectly normal”; the others reported still being sleepy sometimes but considered wakefulness and quality of life satisfactorily improved. Only one patient considered that she might need more than 400 mg per day. The mean ESS score decreased significantly from 13.25 (range: 8 to 18) to 7.75 (range: 3 to 14) points (p = 0.01028; figure 2). No increase in dosage was needed or loss of efficacy noted during the follow-up period.

Discussion.

Hypersomnolence is a frequent complication of DM.1 Sleepiness can be a major symptom of the disease, especially in individuals who are otherwise only moderately affected, like our patients. The benefit of treatment in this study was promising, especially compared with the results of previous trials. Selegiline and baclofen had no significant wake-promoting effect,3,4⇓ whereas methylphenidate was efficacious in seven of 11 patients but had limiting side effects or early tolerance development in the others.5

Modafinil has become a useful drug for the treatment of narcolepsy. Compared with CNS stimulants the potential for addiction appears to be less, and craving or withdrawal symptoms, tolerance, hangover, paradoxical sleep rebound, or excessive sleepiness upon discontinuation are not expected.6 During treatment, the ability to sleep at night is preserved, and psychiatric side effects have not been reported. An increase in systolic blood pressure is the most common side effect of modafinil, which is reversible on discontinuation of the drug and which limits the normal dose to 600 mg per day. In narcolepsy, 100 to 200 mg per day usually ensures a sufficient therapeutic effect. The wake-promoting effect of modafinil has been attributed to a regulatory effect on the sleep-wake cycle, and it has been shown to activate orexin-containing neurons; more generalized CNS stimulation has not been observed.

Interestingly, noninvasive ventilation has not been helpful for sleepiness in patients with DM and sleep apnea.9 Modafinil, on the other hand, has recently proved effective in the treatment of obstructive sleep apnea,10 which we considered a reason for exclusion from this trial. Such rigorous selection might therefore not be necessary, but close monitoring of cardiac and respiratory function is clearly appropriate. One special aspect of DM is frequent cardiac involvement, and although there was no indication that modafinil influenced cardiac function in our patients, the effect on relevant heart disease has not been studied and long-term prescription warrants particular caution. The cardiac risk in patients with DM is highlighted by the fact that Patient 10, whom we had excluded because of sleep apnea syndrome, died before treatment could be begun at his local sleep laboratory even though Holter monitoring and echocardiography had not indicated threatening arrhythmia or cardiomyopathy. Therefore, even careful evaluation cannot ensure the safety of arrhythmogenic drugs such as antidepressants, so further defining the safety profile of modafinil is most important. Further investigation is also necessary to determine whether modafinil is effective and well-tolerated in patients with more severe muscular disease or with cognitive impairment.