Brain, Vol 121, Issue 1 127-133, Copyright © 1998 by Oxford University Press
E Lugaresi, P Montagna, P Tinuper, G Plazzi, R Gallassi, TC Wang, SP Markey and JD Rothstein
Recurring stupor can be caused by repeated metabolic, toxic or structural
brain disturbances. Recently, cases of recurring stupor, with fast EEG
activity were shown to display increased endogenous benzodiazepine-like
activity during the episodes of stupor. Patients with recurring stupor
underwent extensive metabolic and toxicologic screening, EEG and brain
imaging. Endozepines and exogenously administered benzodiazepines were
assayed in plasma and CSF by means of mass spectrometry. Flumazenil, a
benzodiazepine antagonist was administered and the behavioural and EEG
responses monitored. Treatment with oral flumazenil was attempted in
selected cases. Twenty patients were found with recurring stupor. Episodes
had begun between ages 18 and 67 years, and in nine patients, had
disappeared spontaneously after 4-6 years with symptoms. Stupor lasted
hours or days. Onset of the episodes and frequency were unpredictable.
Patients were normal between attacks. Stupor was characterized by initial
drowsiness, staggering and behavioural changes, followed by deep sleep and
spontaneous recovery with post-ictal amnesia. Biochemical screening and
brain imaging were always normal. Ictal EEG showed fast background
activity, and flumazenil transiently awoke the patients and normalized the
EEG. In the nine cases examined, endozepine-4 levels were increased during
the stupor. Oral flumazenil reduced the frequency of the attacks in three
of these nine patients. Recurring episodes of stupor may be due to
increased endozepine-4. We propose the term 'endozepine stupor' for such
episodes. Endozepine-4 is an endogenous ligand for the benzodiazepine
recognition site at the GABAA receptor, with unknown molecular structure.
ARTICLES
Endozepine stupor. Recurring stupor linked to endozepine-4 accumulation
Institute of Clinical Neurology, University of Bologna, Italy.
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