Recurring Stupor Linked to Endozepine-4 Accumulation
ABSTRACT & COMMENTARY
Source: Lugaresi E, et al. Endozepine stupor. Recurring stupor linked to endozepine-4 accumulation. Brain 1998;121: 127-133.
The title identifies a novel disorder that randomly produces irresistible episodes of unexpected stupor or near-coma lasting from a minimum of two hours to a maximum of five days. The condition first drew published attention in an abstract by Montague et al (Ann Neurol 1990;28:254). Shortly afterward, Rothstein et al (Olasma, et al. J Neurochem 1990;55:2015-2023; Rothstein, et al. Neurosci Lett 1992a;143:210-214; Rothstein, et al. J Neurochem 1992;58:2102-2115) purified, characterized, and identified an endogenous benzodiazepine ligand that was greatly elevated in either serum or CSF exclusively during the recurrent, otherwise unexplainable stuporous attacks. Close structural analysis and half life of the agent resembled only lorazepam in the benzodiazepine family, but mass spectrometry distinguished the endogenous agent from exogenous ones. Identification of endozepine is chemically difficult since the substance closely resembles exogenous lorazepam. High pressure liquid chromatography (HPLC) identifies endozepine but may also identify lorazepam. Gas chromatography-mass spectometry is required to distinguish the existence of the agent from lorazepam. Labeling the agent "endozepine," Lugaresi et al now describe 20 patients (4 were previously described) with "recurrent endozepine stupor."
All patients in this study were identified clinically in various areas of Italy during the past decade. Two other patients, one in Canada and the other in South Africa, have also been described and biochemically validated as having a similar problem. In this new series, endozepine levels were analyzed in the blood of nine of the 20 patients during stuporous periods; four had concurrent CSF analyses. Serum levels of endozepine ranged between 455 and 20,850 pmol/mL, and concurrent CSF levels of four of these reached between 100 and 4100 pmol/mL. Normal persons show no evidence of endozepine in the blood during sleep or wakefulness. By contrast, the patients described here generated endozepine during stupor but lost all traces of the agent during wakefulness and sleep at all other (healthy) times.
Typical episodes of endozepine stupor were sometimes anticipated by feelings of fatigue and increasing lethargy and drowsiness. Some attacks, however, started abruptly, and a few began with adverse or docile behavior. Most sufferers just fell asleep rapidly. Interruptable stupor occurred in most persons, but near-coma affected a few. EEGs showed low amplitude 13-16 Hz patterns, similar to those found in patients taking benzodiazepines. Otherwise, almost all available standard laboratory tests, plus liver biopsy in three patients and brain imaging in all, showed no abnormality. Attacks lasted between two and 120 hours with post-attack amnesia; slow awakening affected several patients. Males prevailed 16/4; nine patients had other illnesses: obstructive pulmonary disease (3); obstructive sleep apnea (3), restless legs (1), diabetes mellitus (1), and peptic ulcer (1). Although no exogenous benzodiazepines were identified in the serum of any patient, intravenous flumazenil infections induced 10-15 minutes of wakefulness, after which stupor returned. Five patients received a prophylactic trial of oral flumazenil at 20 mg/d. Two withdrew because of side effects. Among the other three who previously had more than six attacks per year, all were reduced to one minor attack during a period of more than a year.
COMMENTARY
Endozepine stupor seems to be a unique, infrequent, and previously unrecognized illness. No epidemiologic evidence exists to suggest inheritance; males dominate in the distribution of cases, and seven of the affected 20 patients suffer a notable comorbidity as indicated above. The single major and important clue as to cause consists of finding a high level of a nonprotein, benzodiazepine ligand antagonist circulating in blood and CSF during the attacks, but not in-between.
The authors, together with Rothstein, have vigorously attempted to prove that stupefying endozepine is not exogenous, but the condition is certainly peculiar. Cases are geographically widely distributed, but all but two validated patients reside in Italy despite the fact that they eat different foods and appear to have no toxic exposure. The condition differs from the rare Kleine-Levin syndrome, which almost exclusively affects obese children with somnolence lasting 1-2 weeks.
Hopefully, any of our Neurology Alert readers who may encounter patients with similarly undiagnosed episodes of recurrent stupor would do well to contact Dr. Lugaresi. Your editor remains puzzled that such an unusual disorder is largely confined to a specific geographic area but shows no hint of regional genetic influences or a common diet. What other environmental mechanism might be related? Presently, a full explanation of this curious condition is far from complete. -fp
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