Neurologic and electroencephalographic correlates in glutethimide intoxication Neurologic and electroencephalographic (EEG) examinations were performed every two hours during a case of severe glutethimide intoxication resulting from the acute ingestion of at least 15 grams of glutethimide. Neurologic data were reduced to 10 measurements of brainstem function and plotted as an index that varied cyclically in amplitude during the clinical course. Electroencephalographic data were computer-processed by power spectral methods and related to the brainstem function index. Good positive correlation existed between the frequency and reactivity of EEG activity and the level of brainstem function as reflected in the index. The cyclic and. sometimes. unilateral nature of the clinical findings previously reported in glutethimide coma was confirmed and seen to be reflected in the EEG. The present case also indicates that. in the absence of cerebral ischemia or hypoxemia secondary to cardiopulmonary depression. complete clinical recovery from glutethimide-induced coma is possible no matter how severe the presenting neurologic and EEG signs.
Robert R. Myers and James J. Stockard La Jolla. Calif. University of California. San Diego. School of Medicine. Departments of Bioengineering and Neurosciences
Glutethimide (Doriden) was rapidly accepted in the late 1950' s as an alternative to the barbiturate hypnotics and sedatives as it was claimed to be free of some of the disadvantages of the barbiturates such as drug dependence and withdrawal symptoms. McBay and Katsas 27 reported that two years after the introduction of glutethimide, it had become the sixth most commonly prescribed sedative. The optimism that led to such widespread prescription began Supported by National Institutes of Health grants U.S.P.H.S. NS-08962 and HL-05946. Received for publication Dec. 7, 1973. Accepted for publication Sept. 12, 1974. Reprint requests to: Robert R. Myers, University of California, San Diego, Department of AMES-Bioengineering M-005, La Jolla, Calif. 92037.
212
to wane as the first reports of acute glutethimide intoxication became known.ll Maher, Schreiner, and Westerve1t24 had listed 46 cases of glutethimide poisoning by 1962 and reviewed the clinical aspects of glutethimide intoxication seen in an additional 22 patients of their own. By 1962, 20 cases of glutethimide dependence had been reported. 3t Haas and Marasigan t2 further reported marked cerebellar dysfunction in 3 glutethimide abusers; 2 of these patients were still ataxic I to 2 years after glutethimide use was halted_ Their work, and the work of Bartholonew ,2 Lingl,23 and Nover 28 would indicate that glutethimide is potentially neurotoxic. By mid-1960 it was realized that glutethimide would not replace the barbiturates as an all-purpose sedative and hypnotic since it
Volume 17 Number 2
EEG and neurologic function in glutethimide intoxication
could lead to dependence, was frequently abused,16 and was potentially toxic if used chronically. Although there are several reports of EEG changes in acute glutethimide intoxication in the German literature ,15, 18, 21 we have been unable to find any such reports in English and only 3 reports of glutethimide-induced EEG changes. 1, 19, 22 Acute glutethimide intoxication often results in a unique coma course distinguished from other drug-induced comas by the occasional appearance of lateralized or focal neurologic deficits accompanied by cyclic variations in coma depth. It was felt that frequent EEG and neurologic examinatioms during the course of acute glutethimide poisoning might allow better characterization of these cyclic variations as well as establish the prognostic significance of the associated EEG findings. We present here a case report in which we have carefully documented cyclic variations in neurologic status during recovery from severe glutethimide intoxication. The standard neurologic examination has been weighted to produce an index that can be correlated to serial tracings of the EEG. EEG data are compared in the conventional form and in a computer-derived spectral form that emphasizes frequency and power trends. Methods
Complete neurologic examinations were performed every other hour and followed by a lO-minute EEG. A total of 23 examinations were performed over a period of 45 hours from the time the patient was admitted in Grade IV coma30 (areflexic and without spontaneous respirations) until the time when the patient was conscious and free of residual neurologic or EEG deficit. The neurologic examination included the assessment of: (1) size, position, and reactivity of the pupils, (2) other cephalic reflexes, (3) spinal reflexes, (4) superficial reflexes, (5) pathologic reflexes, (6) muscle tone, (7) spontaneous or involuntary motor activity, and (8) response to nociceptive stimuli. At each examination, vigorous and repeated attempts were made to elicit responses or reflexes that were initially found to be absent
213
(with the exception of caloric tests) because of the unusual condition frequently produced by this drug in which reflexes initially not manifest may subsequently be obtained by persistent strong afferent stimulation. 29 To reduce examiner bias, neurologic data were recorded independently by two examiners at each 2-hour interval. EEG data were recorded with an 8-channel Beckman Accutrace electroencephalograph from 9 scalp electrodes positioned according to the International 10-20 system of electrode placement. 17 A combination of parasagittal and temporal montages was used to obtain bipolar recordings and to produce an 8-channel graphic record representative of activity from the entire cortical surface. Seven of these data channels were magnetically recorded on an instrumentation tape recorder for subsequent spectral analysis on a Digital Equipment Corporation PDP-12 computer. Power spectral calculations were performed on 4- or 8-second epochs of data using a fast Fourier transform algorithm with spectral output plotted by a specialized technique. This technique computes a power spectrum for each epoch of data over a frequency band of 0 to 16 Hertz in 64 discrete frequency components of 0.25 Hertz resolution. Each spectrum is graphed by a digital plotter using the conventional spectral axes of frequency and power with successive spectra plotted directly above the preceding spectra. A number of spectra plotted in this manner assume a 3-dimensional appearance in which the abscissa is the axis of frequency, the ordinate becomes time, and the imaginary third-dimensional axis becomes power expressed as spectral "peak" heights. We have found this method especially useful in observing slowly developing EEG trends since it emphasizes slight shifts in frequency and power while effectively compressing time and thus accentuating trends in EEG activity that are not easily interpreted in the conventional record.13, 26 Correlation of the conventional EEG data with clinical observations posed a difficult problem without additional data reduction. We therefore elected to computer process all EEG data while reviewing the neurologic summaries
214
Myers and Stockard
Clinical Pharmacology and Therapeutics
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Robert R. Myers and James J. Stockard La Jolla. Calif. University of California. San Diego. School of Medicine. Departments of Bioengineering and Neurosciences
Glutethimide (Doriden) was rapidly accepted in the late 1950' s as an alternative to the barbiturate hypnotics and sedatives as it was claimed to be free of some of the disadvantages of the barbiturates such as drug dependence and withdrawal symptoms. McBay and Katsas 27 reported that two years after the introduction of glutethimide, it had become the sixth most commonly prescribed sedative. The optimism that led to such widespread prescription began Supported by National Institutes of Health grants U.S.P.H.S. NS-08962 and HL-05946. Received for publication Dec. 7, 1973. Accepted for publication Sept. 12, 1974. Reprint requests to: Robert R. Myers, University of California, San Diego, Department of AMES-Bioengineering M-005, La Jolla, Calif. 92037.
212
to wane as the first reports of acute glutethimide intoxication became known.ll Maher, Schreiner, and Westerve1t24 had listed 46 cases of glutethimide poisoning by 1962 and reviewed the clinical aspects of glutethimide intoxication seen in an additional 22 patients of their own. By 1962, 20 cases of glutethimide dependence had been reported. 3t Haas and Marasigan t2 further reported marked cerebellar dysfunction in 3 glutethimide abusers; 2 of these patients were still ataxic I to 2 years after glutethimide use was halted_ Their work, and the work of Bartholonew ,2 Lingl,23 and Nover 28 would indicate that glutethimide is potentially neurotoxic. By mid-1960 it was realized that glutethimide would not replace the barbiturates as an all-purpose sedative and hypnotic since it
Volume 17 Number 2
EEG and neurologic function in glutethimide intoxication
could lead to dependence, was frequently abused,16 and was potentially toxic if used chronically. Although there are several reports of EEG changes in acute glutethimide intoxication in the German literature ,15, 18, 21 we have been unable to find any such reports in English and only 3 reports of glutethimide-induced EEG changes. 1, 19, 22 Acute glutethimide intoxication often results in a unique coma course distinguished from other drug-induced comas by the occasional appearance of lateralized or focal neurologic deficits accompanied by cyclic variations in coma depth. It was felt that frequent EEG and neurologic examinatioms during the course of acute glutethimide poisoning might allow better characterization of these cyclic variations as well as establish the prognostic significance of the associated EEG findings. We present here a case report in which we have carefully documented cyclic variations in neurologic status during recovery from severe glutethimide intoxication. The standard neurologic examination has been weighted to produce an index that can be correlated to serial tracings of the EEG. EEG data are compared in the conventional form and in a computer-derived spectral form that emphasizes frequency and power trends. Methods
Complete neurologic examinations were performed every other hour and followed by a lO-minute EEG. A total of 23 examinations were performed over a period of 45 hours from the time the patient was admitted in Grade IV coma30 (areflexic and without spontaneous respirations) until the time when the patient was conscious and free of residual neurologic or EEG deficit. The neurologic examination included the assessment of: (1) size, position, and reactivity of the pupils, (2) other cephalic reflexes, (3) spinal reflexes, (4) superficial reflexes, (5) pathologic reflexes, (6) muscle tone, (7) spontaneous or involuntary motor activity, and (8) response to nociceptive stimuli. At each examination, vigorous and repeated attempts were made to elicit responses or reflexes that were initially found to be absent
213
(with the exception of caloric tests) because of the unusual condition frequently produced by this drug in which reflexes initially not manifest may subsequently be obtained by persistent strong afferent stimulation. 29 To reduce examiner bias, neurologic data were recorded independently by two examiners at each 2-hour interval. EEG data were recorded with an 8-channel Beckman Accutrace electroencephalograph from 9 scalp electrodes positioned according to the International 10-20 system of electrode placement. 17 A combination of parasagittal and temporal montages was used to obtain bipolar recordings and to produce an 8-channel graphic record representative of activity from the entire cortical surface. Seven of these data channels were magnetically recorded on an instrumentation tape recorder for subsequent spectral analysis on a Digital Equipment Corporation PDP-12 computer. Power spectral calculations were performed on 4- or 8-second epochs of data using a fast Fourier transform algorithm with spectral output plotted by a specialized technique. This technique computes a power spectrum for each epoch of data over a frequency band of 0 to 16 Hertz in 64 discrete frequency components of 0.25 Hertz resolution. Each spectrum is graphed by a digital plotter using the conventional spectral axes of frequency and power with successive spectra plotted directly above the preceding spectra. A number of spectra plotted in this manner assume a 3-dimensional appearance in which the abscissa is the axis of frequency, the ordinate becomes time, and the imaginary third-dimensional axis becomes power expressed as spectral "peak" heights. We have found this method especially useful in observing slowly developing EEG trends since it emphasizes slight shifts in frequency and power while effectively compressing time and thus accentuating trends in EEG activity that are not easily interpreted in the conventional record.13, 26 Correlation of the conventional EEG data with clinical observations posed a difficult problem without additional data reduction. We therefore elected to computer process all EEG data while reviewing the neurologic summaries
214
Myers and Stockard
Clinical Pharmacology and Therapeutics
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