Abstract
To The Editor:
K
Case Report
The patient was a 15-year-old girl who had experienced four recurrent episodes –lasting for ∼ 10 days – of severe sleepiness within a 4 month span. During these episodes, she was sleeping most of the day. She could be awakened, but was confused and was unable to maintain concentration or recall recent events during the awakened times of the sleep episodes. Her family described her awake times as “like in a dream.” After the sleepy period, she had an overactive, less sleeping, and anxious period in which she showed erotomanic and referential preoccupations, derealization, compulsive behaviors (i.e., frequent hand washing), and hyperphagia. This episode ended after 7 days and was followed by an asymptomatic period lasting 1 week. Thereafter, another sleepy episode began, and episode durations were similar for all four episodes. During the asymptomatic phase, the patient described partial amnesia for the events that had occurred. She denied any hypersexual behavior during or after the episodes. She had been admitted to a child psychiatry clinic with these complaints and was administered sertraline (25 mg), haloperidol (1 mg), and imipramine at different times. However, no improvement was observed with these medications. She was seen by a neurologist who observed no epileptic activity or neurological pathology. She had normal electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) reports. To support the KLS diagnosis, human leukocyte antigen (HLA) analyses (DQB1) were studied in a genetic laboratory, based on the literature indicating that this antigen group may be related to KLS (Huang et al. 2012). The DQB1*06 and DQB1*03 antigens were found to be positive.
We had diagnosed this patient as having KLS based on the clinical findings and HLA analyses results, according to the International Classification of Sleep Disorders-II (American Academy of Sleep Medicine 2005). The patient's medications were terminated upon admission, and aripiprazole (5 mg/day) was started to target the erotomanic and referential preoccupations during the overactive period. After admission, the overactive period ended after 1 week, and a sleepy episode did not recur. During the patient's follow-up examination after 2 years of aripiprazole treatment, the sleepy and overactive periods had not recurred, and all symptoms had disappeared except for minimal referential thoughts, which were not affecting her functionality.
Discussion
We report a case of KLS with an initial clinical response to aripiprazole, an antipsychotic drug that acts as a partial dopamine (D2, D3) and serotonin (5-HT1A receptor) agonist, in addition to its 5-HT7 antagonistic and 5-HT2B inverse agonistic activity (Fleischhacker 2005; Stahl 2013). No data in the literature were available regarding the effectiveness of aripiprazole on KLS. Information on the effectiveness of aripiprazole on sleep disorders was also limited. To our knowledge, there are no reports on this subject except for reports of its effectiveness in delayed sleep phase syndrome ongoing with excessive daytime sleepiness and restless leg syndrome (two separate reports) (McLean 2004; Takaki and Ujike 2014). We believe that in our case, a complete resolution of KLS symptoms was related to the direct effects of aripiprazole. This is supported by the fact that no clinical symptoms occurred during the 2 year period following aripiprazole treatment.
In past reports, amphetamine, methylphenidate, and modafinil were mostly reported to be effective drugs for KLS symptoms (Arnulf et al. 2005). It has been proposed that these agents may cause wakefulness through their effects on dopaminergic and norepinephrinergic activities in the central nervous system (Wisor and Eriksson 2005). However, an animal study identified the importance of the dopaminergic system for wakefulness by reporting that the efficacy of modafinil on excessive sleepiness was maintained after the blockage of noradrenergic tracts in the brain (Wisor and Eriksson 2005). Dopaminergic activity provides wakefulness by suppressing slow wave and rapid eye movement (REM) phases of sleep. and D1, D2, and D3 receptor activities are responsible for this effect (Monti and Jantos 2008). Therefore, we suggest that the improvement of KLS symptoms with aripiprazole may have been related to its partial agonistic effect on D2 and D3 receptors, which provides a balanced dopaminergic activity.
Previous studies have shown that amphetamines – which have serotonergic, dopaminergic, and noradrenergic properties – provide greater improvement of KLS symptoms than do modafinil and methylphenidate (Arnulf et al. 2005). The superior effect of amphetamines on KLS may be related to their impact on serotonergic mechanisms. Although the data were not consistent in support of this hypothesis, Koerber et al. (1984) reported that serotonin and serotonin metabolite levels in the cerebrospinal fluid of a KLS patient were higher than expected. Studies on the relationship between sleep and serotonergic activity indicate that agonistic activity on 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT3 receptors provides wakefulness (Monti and Jantos 2008; Monti 2011). In contrast, antagonistic activity on 5-HT2B, 5-HT6, and 5-HT7 receptors results in wakefulness (Monti 2011). REM sleep duration was diminished under the antagonistic activity of 5-HT7, and 5-HT2B antagonism provided a shortening in both REM and slow wave sleep (Monti 2011). Aripiprazole has a partial agonistic activity on 5-HT1A receptors, an antagonistic activity on 5-HT7 receptors, and an inverse agonistic activity on 5-HT2B receptors (Fleischhacker 2005). We suggest that this receptor profile of aripiprazole might be responsible for obtaining wakefulness in our case.
Conclusions
In closing, we acknowledge that aripiprazole provided a marked benefit in an adolescent with KLS, and that this efficacy may be related to its effects on dopamine and serotonin receptors. The effect of the aripiprazole for KLS patients definitely needs to be validated with prospective studies.