Jump to comment:

• Authors' reply to Hirata et al.
  Roderick A Mackenzie
  Published on: 1 July 2004
• Endozepine stupor or recurrent stupor due to covert administration of brotizolam?
  Akira Hirata
  Published on: 17 June 2004

• Published on: 1 July 2004

  Authors' reply to Hirata et al.

  • Roderick A Mackenzie, Neurologist
  • Other Contributors:
    • Samuel F Berkovic, Ron Granot, Malcolm Hopwood, Olaf Drummer, Scott Patterson.

  Dear Editor

  We thank Hirata et al. for their thoughtful letter in response to our recent Case of the Month.[1] Their case is another example of covert benzodiazepine administration , perhaps even Munchausen syndrome by proxy, a condition that we suspect is much under-recognised in an adult setting.

  Elsewhere, we have reviewed the concept of endozepine stupor [2] and agreed with the Bologna group's vi...

  Show More

  Dear Editor

  We thank Hirata et al. for their thoughtful letter in response to our recent Case of the Month.[1] Their case is another example of covert benzodiazepine administration , perhaps even Munchausen syndrome by proxy, a condition that we suspect is much under-recognised in an adult setting.

  Elsewhere, we have reviewed the concept of endozepine stupor [2] and agreed with the Bologna group's view [3] that the existence of this entity is unproven. Indeed, we suspect that previous cases were all probably due to covert benzodiazepine administration. Further putative examples of endozepine stupor will require exhaustive and sophisticated toxicological analysis for benzodiazepines before they can be accepted as evidence for the existence of this syndrome.

  References

  (1)Granot R, Berkovic SF, Patterson S, Hopwood M, Mackenzie R. Idiopathic recurrent stupor: a warning. J Neurosurg Psychiatry 2004;75:368 -9.

  (2) Granot R, Berkovic SF, Patterson S, Hopwood M, Drummer O, Mackenzie R. Endozepine stupor: disease or deception? Sleep 2004; in press.

  (3) Lugaresi E, Montagna P, Tinuper P, Plazzi G, Gallassi R. Suspected covert lorazepam administration misdiagnosed as recurrent endozepine stupor. Brain 1998; 121: 2201.

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top
• Published on: 17 June 2004

  Endozepine stupor or recurrent stupor due to covert administration of brotizolam?

  • Akira Hirata
  • Other Contributors:
    • Goh Ogawa, Hitoshi mochizuki, Kazuo Motoyoshi, Keiko Kamakura (Associate Professor and Corresponding Author)

  Dear Editor

  Benzodiazepines are now the most prescribed group of psychoactive drugs, and their safety for therapeutic use has been established, but there also is the potential for abuse and addiction.[1]

  Endozepine stupor (ES) is characterized by repeated, spontaneous stuporous attacks lasting several hours or days, and responsiveness to flumazenil without administration of benzodiazepine. ES is caused by...

  Show More

  Dear Editor

  Benzodiazepines are now the most prescribed group of psychoactive drugs, and their safety for therapeutic use has been established, but there also is the potential for abuse and addiction.[1]

  Endozepine stupor (ES) is characterized by repeated, spontaneous stuporous attacks lasting several hours or days, and responsiveness to flumazenil without administration of benzodiazepine. ES is caused by "Endozepine-4", an endogenous benzodiazepine receptor ligand, but not by benzodiazepines.[2] ES is difficult to distinguish benzodiazepine intoxication based on the clinical symptoms alone. We read with great interest the paper by Granot et al,[3] because we experienced a similar patient of recurrent stuporous episodes which were similar to ES, but caused by suspected covert administration of benzodiazepines.

  Case report
  A 45 year-old man suddenly experienced spontaneous comatose episodes once or twice a week. These episodes started with the sudden complaint of dizziness. He talked and walked like a drunk, then became disoriented. Drowsiness finally progressed to a stuporous state and deep sleep. That state lasted 8 to 12 hours, after which he woke spontaneously and recovered. The episodes occurred at various times during the day. He was taken to a hospital near his home several times. Each time, he recovered without specific treatment. The factors and cause that triggered the episodes were not evident. He desired a detailed examination and presented at our hospitals. He had been divorced and remarried and had a daughter who was hospitalized due to pulmonary hypertension. In the interictal phase, the physical and neurological examinations were normal. Blood and urinary tests; glucose, electrolytes, hormones, anmonia, pyruvate, lactate, amino acid analysis, and arterial blood gas, were all normal. Cerebrospinal fluid also was normal. No specific abnormalities were detected by brain magnetic resonance imaging. Electroencephalography (EEG) showed rhythmic 9-10 Hz background activity with no abnormalities. In the ictal phase, his blood pressure was stable and there was no arrhythmia. Blood examinations were all normal. A high performance liquid chromatography assay detected no clonazepam, diazepam, and nitrazepam in his blood. EEG showed diffuse, generalized 14 Hz fast waves and occasional 6 Hz slow wave. Intravenous administration of flumazenil (0.5mg) woke him rapidly, and EEG rapidly became normalized. Based on our observations and findings, we tentatively considered him as having ES. However, after he again was divorced, he told us that he no longer suffered these episodes.

  To obtain further information about his episodes, we performed an immunoenzymatic assay (Triage-8, Biosite, CA, USA) which showed a trace of benzodiazepine in his stored urine samples from the ictal phase. We performed gas chromatography-mass spectroscopy to identify the specific benzodiazepine present in his serum and urine collected during the episode. Brotizolam was detected in his serum (24.8 ng/ml) and urine (650 ng/ml). Its concentration in his serum corresponded to a concentration one to two hours after oral ingestion of more than 1.5-2 mg brotizolam; enough to explain his consciousness disturbance.

  Comment
  Recurrent consciousness disturbance in this patient's case was caused by brotizolam intoxication, and the gas chromatography-mass spectroscopy was required to exclude the possibility of ES. When diagnosing and treating drug intoxication, it is essential to clarify what kind and what quantity of the drugs the patient has taken. It is also essential to ascertain the reasons for taking drugs. When as in our patient's case, the reasons for drug intoxication are not clear, ES was difficult to distinguish benzodiazepine intoxication based on the clinical symptoms alone. The clinical setting of a pleasant gentleman, always accompanied by his worried wife, gave no reason to suspect drug abuse. As Granot et al. have suggested, we should look at "the patient's ever present partner" instead of the literature,[3] and we also agreed with Simini's advice that "the gullibility of the experts might surpass that of the lay".[4]

  Although a remarkable property of the benzodiazepines is their relative safety after an overdose, the outcome of abuse and covert administration of benzodiazepine may be dangerous or fatal when these kinds of drugs are ingested together with ethanol or other sedative agents, especially in the elderly and in patients with lung diseases1. It is therefore important that the possibility of benzodiazepine intoxication be carefully ruled out in the cases of consciousness disturbance. The description of the disease entity of ES reveals a hidden aspect in diagnosis of these conditions. Although differential diagnosis of stupor is a common problem in emergency or neurology department,[3] immunoenzymatic assays to detect benzodiazepines are reported to give false-negatives as well as false- positive1. Furthermore, Lugaresi et al. pointed out that much effort was required to detect some benzodiazepines such as lorazepam.[5] Thus, a proposal of such novel disease entity may highlight the difficulty in diagnosis of benzodiazepine intoxication and detecting blood and urine benzodiazepine. Further studies are still needed, and continued research should clarify once and for all whether all cases of recurrent stupor involve the covert administration of a benzodiazepine, as well as the detailed pathogenesis of ES, as Riva et al. [6] have suggested.

  Acknowledgment

  We are grateful to Professor Elio Lugaresi of University of Bologna, and Professor Jeffery Rothstein of Johns Hopkins Hospital for their suggestions and encouragement of our clinical study of this patient. We also are grateful to the members of Mitsubishi Biochemical Laboratory (MBC) for their collaboration.

  References

  1 Farrell SE, Benzodiazepine, In: Ford MD, Delaney KA, Ling LT, Erickson T eds. Clinical toxicology. Pennsylvania: W.B. Saunders, 2001:575-81.

  2 Lugaresi E, Montagna P, Tinuper P, Plazzi T, Gallassi R, Wang T-CL, Markey SP, Rothstein JD. Endozepine stupor : recurring stupor linked to endozepine-4 accumulation. Brain 1998 ; 121 :127-33.

  3 Granot R, Berkovic SF, Patterson S, Hopwood M, Mackenzie R. Idiopathic recurrent stupor: a warning. J Neurol Neurosurg Psychiatry 2004; 75: 368-9.

  4 Simini B. Endozepine yarn. Lancet 1998 ; 351 : 458.

  5 Lugaresi E, Montagna P, Tinuper P, Plazzi T, Gallassi R. Suspected covert lorazepam administration misdiagnosed as recurrent endozepine stupor. Brain 1998 ; 121 : 2201.

  6 Riva R, Lugwesi E, Fanelliu R, Mennini T, Chiabrando C. Spining more yarn: endozepine. Lancet 1998; 351: 1138.

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top