Hypocretin, Histamine and the Restless Legs Syndrome

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DESCRIPTION (provided by applicant): Restless Legs Syndrome (RLS) is a common sensory-motor disorders whose symptoms predominant at night and often lead to significant sleep loss and changes in one's quality of life. Rest and transiting between sleep and wake exacerbates RLS symptoms. Accordingly, alerting activities reduce while soporific ones exacerbate the symptoms. Sedating medications such as benzodiazepines, however, do not appear to exacerbate the disorder. RLS when even moderately severe profoundly disturbs sleep, reducing sleep times to 5-6 hours or less. Patients report some daytime problems with alertness and cognitive clarity but despite this reduction in sleep times untreated patients do not describe profound episodes of sleepiness that occur for normal subjects maintained on such restricted sleep schedules. There is apparently some alerting mechanism partially compensating for the sleep loss. Our recent work has found that nocturnal CSF values of hypocretin/orexin (Hcrt) are elevated in RLS patients not currently on treatment. Hcrt is almost absent in narcoleptics and serves to maintain wakefulness operating at least in part through the stimulating aspects of the histamine system. Several RLS patients on treatment with dopamine agents report some problems with sleepiness they had not previously experienced and several also report marked exacerbation of RLS symptoms by sedating anti-histamines. We have proposed that the Hcrt and histamine system activation reduces RLS symptoms for some RLS patients. DA treatment may reduce the activating benefit from this system leaving the patient vulnerable to sleepiness but also to further exacerbation of the symptoms by further reduction in this system by an anti-histamine medication. Thus, in this model, nocturnal Hcrt levels will be less for DA treated patients and anti-histamine challenge provides a test discriminating those patients who have this aspect of RLS, identified in our prior work as those with the familial early-onset form of RLS. The anti-histamine challenge may therefore provide a new technique for discriminating types of RLS, possibly aiding in the diagnosis of RLS and opening up a new area of RLS research. The approach may also be extended to other DA related conditions involving sleepiness with DA treatment. This project seeks to determine if the nocturnal CSF hypocretin of RLS patients is lower when on DA treatment and to explore the development and evaluation of anti-histamine challenge for testing RLS patients.