Suspected covert lorazepam administration misdiagnosed as recurrent endozepine stupor

Abstract

Istituto di Clinica Neurologica dell’Universita`di Bologna, Bologna, ItalyCorrespondence to: Professor Elio Lugaresi, Clinica Neurologica, Via Ugo Foscolo 7, 40123 Bologna, ItalyWe recently reported in Brain (Lugaresi et al., 1998) 20cases of idiopathic recurrent stupor due to endozepine-4accumulation in the blood. Samples obtained from nine ofthese patients were analysed by gas chromatography–massspectrometry to rule out contaminating synthetic benzo-diazepines (Rothstein et al., 1992). All these samplescontained endozepine-4 concentrations high enough toaccount for the stuporous state of the patients. The other 11cases of idiopathic recurring stupor were diagnosed on thebasis of clinical criteria alone since they were identical tothe patients with documented endozepine-4 accumulation.All presented the same clinical picture and EEG pattern (lowamplitude, unreactive, background activity) during stuporand a reversal of the stuporous state after flumazeniladministration (awakening and EEG normalization). Again,toxicological immunoenzymatic tests failed to detect eventraces of synthetic benzodiazepines.We subsequently investigated a cluster of nine patientspresenting recurrent stuporous attacks with almostsimultaneous onset which had occurred in a restricted ruralarea near Lucca in Tuscany. Except for the extraordinaryclustering in time and space, these patients were in allrespects similar to the sporadic idiopathic recurring stuporpatients previously encountered by us. The stuporous episodesin fact lasted 1–2 days and were followed by confusion andamnesia; ictal EEG was characterized by the typical lowvoltage, 13–14 Hz background activity, and flumazeniladministration led to transient awakening and EEGnormalization. Routine toxicological immunoenzymatic assayhad ruled out the presence of benzodiazepines.However, in the meantime, a newer more specific toxico-logical assay, liquid chromatography–mass spectrometry, hadbecome available to us. Because of the unusual epidemiology,we used this technique to re-analyse blood samples from theTuscan patients. This time we detected in the blood of all ofthese patients the benzodiazepine lorazepam which had not© Oxford University Press 1998been disclosed when we had used gas chromatography–massspectrometry analysis. We could therefore deduce a fraudulentlorazepam intoxication in these patients, and exclude anendogenous benzodiazepine (endozepine) origin of the stupor.Besides highlighting the difficulties inherent to theascertainment of surreptitious benzodiazepine administration,we wish here to offer also the following conclusions:(i) Toxicological immunoenzyme assays for benzo-diazepines currently implemented by the hospital emergencyservices, though they may reveal diazepam and otherbenzodiazepines, may prove negative if the drug present inthe blood is lorazepam.(ii) Biological tests on the chromatographic fractioncontaining endozepine-4 do not rule out that the episodes ofrecurrent stupor are due to lorazepam intoxication sincelorazepam migrates in the same chromatographic fraction asendozepine during high performance liquid chromatography.(iii) The agent responsible for recurrent stuporous attackscan only be identified by means of liquid chromatography–mass spectrometry.Finally, in the light of the above findings, the endozepineorigin of the stuporous episodes in the patients we recentlyreported in Brain (Lugaresi et al., 1998), especially in thosewho did not undergo gas chromatography–mass spectrometry,should be considered as still unproven.