Abstract

Vegetative state (VS) and the minimally conscious state are chronic disorders of consciousness (DOC), following severe brain injury. Zolpidem (Zp) is a non-benzodiazepine sedative/hypnotic drug, acting as a full agonist at the α1-containing gamma-aminobutyric acid (GABAA) receptors. Previously reported data have shown few cases of transient arousal from DOC after Zp administration at the maximum dosage of 20 mg/day,1 although the Zp ‘awakening mechanism’ is still not well known. A 52-year-old woman was in a persistent VS for 3 years following cardiac arrest, with a Coma Recovery Scale-Revised (CRS-R) score of 7. Brain magnetic resonance imaging showed widespread T2 signal abnormalities, mainly involving the basal ganglia, thalamus and frontal cortices, whereas a diffuse low amplitude theta delta-like rhythm was recorded during electroencephalography (EEG). As neither drugs nor behavioral rehabilitation were successful in improving the patient's condition, Zp was introduced and the dose was increased by 5 mg/week. The patient was evaluated through CRS-R and prolonged EEG, before and after the different dosage administrations. An evident improvement in awareness and wakefulness after Zp was detected by the rehabilitation team and her relatives only when a dose of 20 mg was reached. Indeed, EEG showed an increase in amplitude and voltage, with a clear theta rhythm over the right temporo-occipital region, either in resting-state or after acoustic and visual stimulation, and a CRS-Score of 11. Thus, we decided to increase Zp dosage up to 30 mg (administered for around 3 weeks), with a further improvement of CRS-R score (i.e. 13) and EEG (presence of theta-beta rhythm over both the temporal areas), and without relevant side-effects. Our case further supports the hypothesis of a positive effect of Zp, although at higher dosage, in improving consciousness in VS. After brain injury or cerebral anoxic damage there is a change either in the levels of glutamate (resulting in neurotoxicity) or GABA neurotransmission, with reduced cell metabolism and blood flow in brain areas adjacent to the damaged area. By binding to modified GABAA receptors of the ‘neurodormant cells’, Zp may cause reversal of the abnormal state and associated metabolic inhibition, with a consequent arousal.2 For the first time, we used a higher dose of Zp (30 mg) to evaluate whether the drug's response could be dose-dependent. Indeed, our patient's improvement was strictly related to the increase in Zp dosage, with a relatively good response at 30 mg. We are not able to explain this interesting finding, although a more effective action of high-dose Zp on the centrothalamic activity (by potentiating the ‘mesocircuit’),3 could be taken into account. Zp may be a valuable treatment in improving consciousness, although further studies should be fostered to confirm its efficacy, the proper dosage, and long-term safety.

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