Dear Sirs,

Recently, an autosomal-dominant mutation of the gene coding for histidine decarboxylase, the rate-limiting enzyme in histamine synthesis, was demonstrated in a family with eight members suffering from Gilles de la Tourette syndrome (GTS) [1]. Functional analysis suggested that this mutation acts in a dominant-negative manner, thereby diminishing histaminergic neurotransmission. Accordingly, the authors suggested that raising brain histamine levels may decrease tics.

We report on a male patient born in 1988 who developed several motor and vocal tics from age 6 years on but was only diagnosed as GTS at the age of 17 years. In rapid succession, several antipsychotics were tried, e.g., pimozide, risperidone and tetrabenazine, which slightly decreased tics but induced fatigue and sedation. More recently (April 2008), aripiprazole (5, then 10 mg/day) was introduced with moderate effect on tics but less sedation and weight gain. Interestingly, this patient also experienced narcolepsy without cataplexy, characterized by excessive daytime sleepiness and dyssomnia. His total sleep time was 363 min with a sleep efficiency of 72%, and no apnea/hypopnea or leg movements. During daytime multiple sleep latency tests, he fell asleep within a mean of 5.8 min (abnormal is lower than 8 min) sleep onset latency with three sleep onset in REM sleep periods (abnormal is more than 1) [2]. He carried the HLA DBQ1*0602 genotype. The attempts to reduce daytime sleepiness, first with methylphenidate 10 mg/day, then with modafinil 100 mg/day both resulted in a immediate massive increase in tics as well as behavioral problems (irritability and aggressivity) at the lowest dosage and led to rapid discontinuation of these treatments.

Thus, based on the above-mentioned study, we wondered whether treatment by an inverse agonist of the H3 receptor which raises histaminergic neurotransmission might allow to treat his narcolepsy without increasing or even decreasing his tics. This molecule (BF2.649 or tiprolisant or pitolisant, Bioprojet Ltd, France) [3], promotes wakefulness in a recent proof-of-concept trial in narcolepsy [4]. After having obtained the patient’s consent, as well as an individual temporary use authorization from the French drug agency, a baseline evaluation was conducted in May 2010 with two subsequent visits in August and October after slowly increasing the pitolisant doses from 5 to 40 mg/day, as a single morning intake (Table 1).

Table 1 Tic and sleepiness scores following increasing dosages of pitolisant
Full size table

As can be seen, daytime sleepiness decreased dramatically, whereas tic scores remained constant. The benefit was maintained after 9 months of treatment. We conclude that pitolisant (unlike classic psychostimulants such as methylphenidate and modafinil) is able to decrease daytime sleepiness without worsening tics. Conversely, however, in this single patient, we did not witness a clear decrease in tics as might be inferred from the histamine hypothesis of tics. Yet, we feel that these results are encouraging because a non-increase of tics in a sensitive patient may mean a decrease in tics in a ‘non-sensitive’ GTS patient. The association of narcolepsy and GTS is here fortuitous, but methylphenidate and related molecules are used in GTS patients with attention-deficit/hyperactivity disorder, a frequent co-morbidity. Although methylphenidate does not exacerbate tics on average) [5], some patients, such as ours, may respond rather violently and will require a different treatment approach. Therefore, apart from tics, pitolisant may be helpful in treating attention deficit in children suffering from GTS and in reversing neuroleptic-induced daytime sleepiness based on its mechanism of action. Thus, controlled clinical trials of H3 receptor reverse agonists in GTS patients with or without co-morbid attention-deficit/hyperactivity disorder are warranted.