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Grand mal seizures temporally related to cocaine use: clinical and diagnostic features
ORIGINAL CONTRIBUTION cocaine; seizure, grand mal
G r a n d Mal Seizures Temporally Related to Cocaine Use: Clinical and Diagnostic Features From the Departments of Emergency Medicine* and Neurology,t Denver General Hospital, University of Colorado
Reuben W Holland III, MD* John A Marx, MD, FACEP* Michael P Earnest, MD t Stacie Ranniger, MD*
Health Sciences Center, Denver. Receivedfor publication June 28, 1991. Revision received November 2, 1"991.Accepted for publication December 10, 1991. Presented at the American College of Emergency Physicians Scientific Assembly in Washington, DC, September 1989.
Study objectives: Todetermine the appropriate diagnostic workup of the emergency department patient with an uncomplicated cocainerelated grand mal seizure. Design setting: Retrospective analysis. A city and county ED with 45,000 selected visits per year. Type of participants: Thirty-seven patients with acute grand real seizure after cocaine exposure were studied. All had historical or laboratory evidence of cocaine use and no history of prior seizure disorder. Interventions: The diagnostic workup varied among patients. Most received computed head tomography (35), whereas fewer received ECG (18), EEG (16), and lumbar puncture (six). a n d m a i n r e s u l t s : Thirty-three patients with an uncomplicated cocaine-related seizure had an unremarkable series of diagnostic tests. The four patients with remarkable neurologic manifestations were compared with the remainder of patients who were without neurologic abnormalities. Comparison of groups by route of cocaine intake revealed no significant difference in the time interval to seizure (P= .761). Measurements
Conclusion: Diagnostic workup probably is not indicated for the patient experiencing a cocaine-related generalized seizure who will recover promptly and have a normal postictal examination, [Holland RW III, Marx JA, Earnest MP, Ranniger S: Grand mal seizures temporally related to cocaine use: Clinical and diagnostic features. Ann EmergMedJuly 1992;21:772-776.]
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INTRODUCTION During the past decade, cocaine has become an increasingly abused drug in the United States. More than 30 million persons are estimated to have used cocaine, and approximately 5 million persons do so on a regular basis. 1 Numerous medical sequelae of cocaine use have been described, p r i m a r i l y affecting the cardiovascular and central nervous systems and manifesting as myocardial infarction, cardiac dysrhythmias, and stroke. 2-4 To date, little information has been presented in the literature regarding seizures associated with cocaine use. We describe the clinical features and results of diagnostic workup of cocaine-related grand mal seizure in 37 patients who presented to our emergency department.
MATERIALS AND METHODS Patients with suspected cocaine-related grand real seizure were identified by reviewing Denver General Hospital ED records from the period between June 1980 and J a n u a r y 1989. The Denver General Hospital ED is the city and county facility for Denver, Colorado, with 45,000 selected patient visits p e r year. Inclusion criteria for cocaine-related grand mal seizure were history of seizure based on witnessed tonicelonic activity or physical signs of seizure (eg, tongue-biting or u r i n a r y incontinence) or loss of consciousness with postictal state (ie, resolving period of confusion without other explanation); cocaine use confirmed by history or a positive toxicologic screen for either cocaine or its metabolites within eight hours of seizure activity (elapsed time to onset of seizure activity was estimated by either the patient or witnesses to the event); no evidence of other seizure precipitants (eg, trauma, infection, metabolic disturbance, or other toxic exposure); and no history of seizure d i s o r d e r or treatment with anticonvulsant medications. The route of administration was determined by history and divided into IV, intranasal, freebase, and oral groups. Diagnostic workup varied, but most patients received computed tomography (CT) scan of the head, whereas fewer received EEG, l u m b a r puncture, and/or ECG (Table 1). All tests except the E E G were performed while the patient was in the ED. The Mann-Whitney-Wilcoxon test was used for comparison of data.
Table 1. Diagnostic studies in 37 patients with cocaine-related grand mal seizures Study
No. of Patients Tested
Abnormal Results
CT scan of head 35 2* ECG 18 8t EEG 16 1 Lumbar puncture 6 1' * Onerevealedcerebraledema,and one revealedcerebraleneurysmwith subarachnoid hemorrhage. t All had sinustachycardia.Two patientswith chest pain had ST-Twave abnormalities. * Cerebralspinalfluid had 22,000RBCs/mm3 end xanthochromiain the casewith subarachnoid hemorrhage.
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RESULTS Of the 37 patients with cocaine-related grand mal seizure, 24 were men and 13 were women. Mean age was 26 years (range, 17 to 49 years). Route of exposure was IV (18), intranasal (11), freebase (four), or oral (four) (Table 2). The cocaine-related grand mal seizure was subsequent to a single- (30) or multiple- (seven) dose exposure. The elapsed time from cocaine use to seizure was estimated by available history and categorized into time intervals of less than 15 (14), 15 to 120 (12), and more than 120 minutes (seven) (Table 2). Thirty-one patients had no neurologic abnormalities and two had preceding neurologic disease without acute findings. F o u r patients had new Findings on neurologie examination. Of these four patients (I1%), two had acute neurologic abnormalities during evaluation. No patient had Table 2. Characteristics of cocaine exposure
Patient 1 2 3* 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20t 21 22t 23 24 25 26 27
Estimated Amount of Cocaine(g)
Exposure Route
No. of Exposures
? 4 ? 0.25 ? ? ? ? ? ? ? 0.5 ? 0.125 6 0.125 2 0.33 0.25 ? 0.5 ? 3 0.25 2 ? 0.5
IV IV Intranasal Intranasal IV Intranasal IV Oral IV IV Oral IV IV IV IV IV Intranasal Intranasal Intranasal IV iV Oral Freebase Intranasal Intranasal Freebase IV
Single Multiple Single Single Single Single Multiple Multiple Single Single Single Single Single Single Single Single Single Single Single Single Single Single Multiple Single Single Multiple Single
Elapsed Time to Seizure (rain)
< 15 < 15 ? 15-120 < 15 15-120 15-120 ? > 120 < 15 15-120 ? > 120 < 15 < 15 > 120 < 15 < 15 > 120 15-120 < 15 ? < 15 15-120 15-120 15-120 > 120 28* ? IV Single 15 - 120 29* 0.25 Intranasal Single 15 - 120 30 0.5 IV Single > 120 31 ? Oral Single > 120 32 ? Intranasal Single < 15 33 0.5 Freebase Single 15-120 34 ? Freebase Multiple < 15 35 ? Intranasal " Single < 15 36 ? IV Single 15-120 37 ? IV Multiple < 15 * Presentedwith subarachnoidhemorrhage.CTscan and angiographydemonstratedanterior communicating arteryaneurysm. t Presentedin cardiacarrest. Presentedwith chestpain and nonspecificST-Twave abnormalitieson ECG.
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multiple seizures, focal seizures, or status epilepticus after cocaine exposure 4n either the single- or multiple-dose group. No significant difference was found between the route of cocaine exposure and the time to onset of seizure (P = .761). Acute neurologic signs at presentation to the ED were seen in four patients. Two patients were comatose on presentation to the ED, both after a seizure and a cardiac arrest. Whether the seizure was a p r i m a r y event or secondary to cerebral hypoperfusion was unknown. One patient h a d an initial rhythm of ventrieular fibrillation, and the other had asystole. In each case, the postresuscitation ECG revealed only sinus tachyeardia. CT scan demonstrated diffuse cerebral edema in one and was u n r e m a r k a b l e in the other. Both patients presumably sustained diffuse anoxic encephalopathy and died without regaining consciousness within 48 hours of cardiac arrest. The third patient presented with confusion and drowsiness consistent with a postietal state. The mental status abnormalities resolved within four hours of the seizure. CT scan and EEG were normal. The fourth patient presented 14 hours after a grand mal seizure with severe headache, meningismus, photophobia, and right hemiparesis. Her symptoms h a d been present since the seizure. Contrast-enhanced CT scan demonstrated an aneurysm of the anterior communicating artery with possible subaraehnoid hemorrhage. Cerebrospinal fluid analysis showed 22,000 RBCs/mm 3 and xanthochromia in each of four tubes. Angiography demonstrated an aneurysm of the anterior communicating artery. The aneurysm was clipped, and the patient h a d full neurologie recovery. Two other patients h a d pre-existing neurologic disease. One h a d cerebral palsy, and the other had sustained a left cerebrovaseular accident seven years before presentation. The neurologie status of each was at baseline in the ED according to friends or relatives. CT scan in the former patient revealed large ventricles and a mildly abnormal E E G consistent with cerebral palsy. In the latter patient, the CT scan abnormalities were unchanged compared with h e r previous scan. An EEG was normal. Both patients were admitted to the neurology service and discharged without institution of additional diagnostic tests or therapy. The remaining 31 patients had a normal neurologic examination, and their diagnostic evaluations were unrevealing (Table 1). None of these patients was prescribed chronic anticonvulsant therapy. Additional complications of cocaine exposure in our patients were rhabdomyolysis and chest pain. Rhabdomyolysis was diagnosed in one patient (patient 10) who h a d a p e a k creatinine phosphokinase of 4,280 IU/L. Duration of the seizure event was estimated by witnesses to he less than five minutes. This patient was treated with alkaline diuresis and had an u n r e m a r k a b l e course. He h a d no preeipitants for rhabdomyolysis other than cocaine and a seizure (ie, not multiple seizures). Chest pain suggestive of myocardial ischemia occurred in two patients (patients 28 and 29). Both had nonspecific ST-T wave abnormalities on their initial
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ECG and were admitted. F u r t h e r evaluation with serial enzymes and ECGs was u n r e m a r k a b l e . Echocardiography did not reveal wall motion abnormalities. Cardiac catheterization was not performed in either case. Both patients were discharged after an uneventful hospital course.
DISCUSSION The mechanism by which cocaine precipitates seizure p r o b a bly is multifactorial. A direct reduction of the seizure threshold has been suggested and is supported by animal studies. The drug's pathophysiology includes central nervous system effects as well as systemic disturbances, which can alter the seizure threshold. Putative central nervous system effects include adrenergic "surge," acute hypertensive episode, cerebral vasospasm, and hyperthermia. 5,6 I n t r a c r a n i a l hemorrhage also has been discovered in patients with cocaine-related grand m a l seizure. In these patients, aneurysms and arteriovenous malformations most often are responsible, and the subaraehnoid space appears to be the most frequent location of bleeding. 7 Vasculitis has been demonstrated after chronic cocaine use, but its role in the genesis of seizures is not yet defined. 8,9 In addition, the role of "cutting agents" cannot he ignored because epileptogenie drugs such as lidoeaine, procaine, pheneyelidine, amphetamines, and quinidine may be a d u l t e r a n t s J ° Finally, a direct reduction of the seizure threshold by cocaine has been suggested and is supported by results of animal studies. 5,6 Metabolic consequences of cocaine use include acid-base disturbances and hyperthermia. Metabolic acidosis, resulting from intense muscular activity, hypoxemia, rhabdomyolysis, or a direct toxin-induced lactic acidosis, can sensitize and potentiate the effect of catecholamines, n,12 This may cause central nervous system depression and adversely affect myocardial performance and increase the potential for dysrhythmias. 5,6,11 Dysrhythmias, with resultant hypotension, may lead to cerebral hypoperfusion and anoxia, increasing the susceptibility to seizure. H y p e r t h e r m i a may play a role in the genesis of cocainerelated grand mal seizure. H y p e r t h e r m i a in cocaine use results from p e r i p h e r a l vasoconstriction, increased skeletal muscle activity, increased cardiac output, and central thermoregulatory dysfunction. 5 Attenuation of this h y p e r t h e r mic response in animal studies was associated with a lower incidence of seizures and decreased mortahty. The influence of patient t e m p e r a t u r e could not be measured in this study due to delay from cocaine-related grand mal seizure to presentation. H y p e r t h e r m i a was not a p r i m a r y concern of any patient in this review. 5,13 The pharmacologic kindling effect may be operative in the production of cocaine-related grand real seizure when repeated doses of cocaine are administeredA 4 This effect accounts for a greater susceptibility to seizure despite the development of tolerance. 13 The high hpid solubility of
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cocaine causes avid uptake in the b r a i n and may contribute to the kindling effect. Large initial plasma cocaine levels may lead to much higher central nervous system levels and, ultimately, seizure. 15 In addition, the psychologic effects of cocaine appear to be related to the rate of change rather than the absolute serum cocaine level. 13 Seizure may be prompted in a similar fashion. Subsequent equilibration keeps plasma levels high despite a decreasing euphoric effect. Seizures have been reported after IV, intranasal, freebase, oral, topical, rectal, and intravaginal cocaine use. lO.16-18 In this study, IV, intranasal, freebase, and oral routes of administration are reported, and the IV route is responsible for nearly half of those with cocaine-related grand mal seizure. The prevailing patterns of cocaine use in Denver during the study period are not known. Therefore, the relative risk of cocaine-related grand mal seizure according to route cannot be determined from our data. The effects of cocaine are numerous and depend on dosage (purity), route of administration, and form in which it is taken. It has a relatively rapid onset and a short duration of action. Peak" euphoria occurs 15 to 30 minutes after administration, with a serum half-life of 50 to 80 minutes. Although the elimination half-life remains constant, variability in absorption affects the clinical response. IV administration of cocaine provides a rapid rise in serum levels with significant physiologic effects. "Crack" cocaine, the alkaloid derivative of the hydrochloride salt, volatilizes when heated and t.hus is able to be inhaled. Rapid and efficient absorption occurs across the pulmonary capillary vasculature with an onset and intensity of effects approximating those of the IV route.15 I n t r a n a s a l cocaine use also may produce toxicity, but this route may create an absorptive b a r r i e r by mucosal vasoconstriction. 15 Furthermore, this n a t u r a l b a r r i e r may prolong the effects of cocaine due to continued absorption across the mucosa. Despite current misconceptions, cocaine taken by the oral route is readily absorbed across the gastric mucosa with adverse affects including intestinal ischemia and systemic toxicity. 19-2~ Classically, these cases involve "body packers" or "mules" attempting to smuggle cocaine. We did not find a statistically significant difference between patients who seized early (less than 15 minutes) and patients who seized late (two to eight hours) with regard to route of administration. This finding was unexpected and may be attributable to differences in exposure pattern, purity, or historical inaccuracies. The patients were categorized into three groups according to the elapsed time to seizure. These time intervals were constructed to differentiate acute seizures corresponding to the time to peak euphoria, a subacute interval approximating one serum half-life, and a more extended period to encompass any delay in effects. Generalized and focal seizures may result from a wide variety of toxic and metabolic disorders. Exposure to numerous medications and drugs, especially cyclic antide-
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pressants and theophylline, can lead to seizure. Withdrawal after chronic substance abuse, particularly ethanol and sedative hypnotics, also can produce seizure. Hypoglycemia is the most common cause of a metabolic-induced generalized seizure. Focal seizure most often is due to nonketotic hyperglycemia. Other less common causes of metabolic seizure include hypoxemia, hepatic encephalopathy, uremia, and various electrolyte disturbances. 22 When a toxic or metabolic etiology is solely responsible for the induction of a seizure, results of neurologic tests usually are unremarkable. Turnbull et al prospectively studied 136 patients to determine the usefulness of laboratory testing in the ED patient with new-onset seizure. 23 When a metabolic etiology of seizure was discovered, computed tomography was u n r e m a r k a b l e in all cases. In all except two cases, both hypoglycemia, there were clues from the history and physical examination that would have raised suspicion of the laboratory abnormalities that were discovered subsequently.23 Ramirez-Lassepas et al retrospectively studied the value of CT after first seizure in 148 adults. 24 Sixteen patients (11%) were thought to have a metabolic etiology responsible for their seizures. Nine of these patients (56%) exhibited focal or partial complex symptomatology, but CT scan evaluation revealed no abnormalities in any of these patients. Longterm anticonvulsant therapy was not instituted unless a primary central nervous system lesion was demonstrated or epileptiform changes were seen on EEG. 2a Occult vascular or structural central nervous system pathology may exist and contribute to the precipitation of toxic-metabolic-related seizures in a subset of patients. 15,25 Earnest et al studied 259 patients with suspected first alcohol withdrawal seizure. 26 Sixteen of his patients (6.2%) had intracranial pathology, and further intervention was required in eight (3.2%). Significantly, the presence or absence of intracranial pathology could not be predicted from the patient's presenting neurologic examination. The presence of an u n r e m a r k a b l e neurologic workup in patients with cocaine-related grand real seizure has been noted by other investigators. Bettinger described one patient with status epileticus after massive oral cocaine ingestion. 2° After resolution of his seizures, the patient's examination normalized. Subsequent diagnostic evaluation, including CT scan and cerebral angiography, was negative, and the patient was discharged from the hospital without neurologic impairment. Seaman and Gushee report two cases of cocaine-related grand real seziure in which investigation revealed unsuspected b r a i n tumors. 25 Both of these patients, however, had persistent focal neurologic deficits at presentation. Ernst and Sanders described four cases of cocaine-related grand real seizure in children. 27 Despite recurrent seizures and focal features in one child, all had an u n r e m a r k a b l e diagnostic workup, including CT scan and blood chemistries. Pascal-Leone et al studied the risk factors a n d confounding variables associated with cocaine-related grand mal seizure. 2a
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Of the 13 first-time cocaine users with seizure, only a patient with subarachnoid hemorrhage had an a b n o r m a l CT scan. Of the 19 patients with habitual cocaine use, 52.6% were noted to have diffuse cerebral atrophy. Neurologic examination of these patients was not documented. Choy-Kwong and Lipton reported four of 283 patients with a history of cocaine abuse who presented to the ED with cocaine-related grand mal seizure. 29 Focal and generalized seizures were observed in this group. However, neurologic examination and CT scan did not reveal underlying structural b r a i n lesions. These reports and our data suggest that neurologic workup, including CT scan, for the patient with an uncomplicated generalized seizure associated with cocaine intoxication may not be necessary. Patients with an uncomplicated cocaine-related grand real seizure, ie, without focality, a prolonged course, or persistence of neurologic abnormalities are unlikely to have underlying i n t r a c r a n i a l pathology. Management should attend ongoing toxic or metabolic concerns. Acute anticonvulsant t h e r a p y and institution of chronic anticonvulsant medication are not indicated in this setting. Rhabdomyolysis, a recently described complication of cocaine abuse, was seen in one of our patients. Although seizure alone has been implicated in causing rhabdomyolysis, this condition is associated with cocaine use in the absence of tonic-clonic activity. Suggested pathophysiologic mechanisms arc vasoconstriction within the skeletal muscle with subsequent ischemia and loss of cell m e m b r a n e integrity and a direct toxic effect to the muscle cell. Previous studies have documented a 33% incidence of acute renal failure associated with rhabdomyolysis, including cases caused by cocaine exposure. 1,30 This did not occur in the single episode in our series. Limitations of our study included its retrospective n a t u r e , the unknown reliability of historical data, and the small number o f cases. The eight-hour time limit used in this study also may underestimate the incidence of cocaine-related grand mal seizure due to disparate absorption and solubility between plasma and central nervous system tissue. In fact, cocaine-related grand real seizure have been r e p o r t e d as long as 12 hours after cocaine use.14 Finally, the potential exists that undetected adulterants or an idiopathic seizure disorder complicated the cocaine use. CONCLUSION Patients described in this study experienced a single uncomplicated generalized seizure temporally related to cocaine use with either historical or l a b o r a t o r y c o r r o b o r a tion of cocaine exposure. Our limited d a t a suggest that patients with cocalne-related grand real seizure who r e t u r n to their baseline neurologic status do not have their management altered by the performance of any diagnostic study. We emphasize that these observations are not applicable to patients with complicated seizures.
REFERENCES 1. Roth D, Alarcon FJ, FernandezJA, et al: Acute rhabdomyolysis associated with cocaine intoxication. N EnglJ Med 1988;319:673-677. 2. Derlet RW: Emergency department presentation of cocaine intoxication. Ann Emerg Med1989;18:182-186. 3. Buchanan J P: Cocaine intoxication: A review of the presentation and treatment of medical complications. HaspPhys1988;24:24-35. 4. Cregler LL, Mark H: Medical complications of cocaine abuse. NEnglJMed 1986;315:1495-1500. 5. Catravas JD, Waters IW: Acute cocaine intoxication in the conscious dog: Studies on the mechanism of lethality. JPharmaco/Exp Ther1981;217:350-356. 6. Jonosson S, O'Meara M, Young JB: Acute cocaine poisoning, Am J Med 1983;75:1061-1064. 7. Klonoff DC, Andrew BT, Obana WG: Stroke associated witll cocaine use. Arch Neural 1989;46:989-993. 8. Levine SR, Welch KMA, Brust JCM: Cerebral vesculitis associated with cocaine abuse or subarachnoid hemorrhage. JAMA 1988;259:1648. 9. Mody CK, Miller BL, Mclntyre HR, et al: Neurologic complications of cocaine abuse. Neurology1988;38:1189-1193. 10. Wetli CV, Wright RK: Death caused by recreational cocaine use. JAMA 1979;241:2519-2522. 11. Drake TR, Henry T, Marx J, et al: Severe acid-base abnormalities associated with cocaine abuse. J EmergMed 1990;8:331-334. 12. Ford GD, Clinte WH Jr, Fleming WW: Influence of lactic acidosis on cardiovascular response of sympathomimetic amines. Am JPhysio/1968;215:1123-1129. 13. Zaccara G, Muscas GC, Messori A: Clinical features, pathogenesis and management of drug-induced seizures. DrugSafety1990;5:109-151. 14. Lowenstein DH, Massa SM, Rowbatham MC, et al: Acute neurologic and psychiatric complications associated with cocaine abuse, Am J Med1987;83:841-846. 15. Van Dyke C, Byck R: Cocaine. SciAm 1982;248:128-141. 16. Difazio C: Local anesthetics: Action, metabolism, and toxicity. OtolaryngolC/in NorthAm 1981;14:515-519, 17. Ettinger TB, Stine RJ: Sudden death temporally related to vaginal cocaine abuse. Am J EmergMed 1989;7:129-136. 18. Myers JA, Earnest MP: Generalized seizures and cocaine abuse. Neurology 1984;34:675-676, 19. Gerkin RD Jr: Cocaine, in Tintinalli JE, Krome RL, Ruiz E (eds): EmergencyMedicine: A ComprehensiveStudyGuide,ed 2. New York, McGraw-Hill Book Co, 1988,p 711-712. 20. Bettinger J: Cocaine intoxication: Massive oral overdose. Ann EmergMed 1980;9:429-480. 21. Nalbandian H, Sheth N, Dietrich R, et al: Intestinal ischemia caused by cocaine ingestion: Report of two cases. Surgery1985;97:374-376. 22. Berkovic SF, Johns JA, Bladin PF: Focal seizures and systemic metabolic disorders. Aust N Z J Med 1982;12:620-623. 23. TurnbuffTL, Vanden HookTL, EisnerRF: Utility of laboratory studies in the emergency department patient with a new-onset seizure.Ann EmergMed 1990;19:373-377. 24. Ramirez-LessepasM, Cipolle RJ, Morillo LR, et al: Value of computed tomogrephic scan in the evaluation of adult patients after their first seizure.Ann Neure/1984;15:536-543. 25. Seaman M, Gushee D: Investigation of cocaine-related seizures showing unsuspected brain tumors. Ann EmergMed 1990;19:733-734. 26. Earnest MP, Feldman H, Marx JA, et al: Intracranial lesions shown by CT scans in 259 cases of first alcohol related seizure. Neurology1988",38:1561-1565. 27. Ernst AA, Sanders WM: Unexpected cocaine intoxication presenting as seizures in children. Ann EmergMed1989;18:774-777. 28. Pascal-Leone A, Dhuna A, Altafullah I, et al: Cocaine-induced seizures. Neurology 1990;40:404-487. 29. Choy-Kwong M, Lipton RB: Seizures in hospitalized cocaine users. Neurology 1989;39:425-427. 30. Gabow P, Kaehny WD, Kelleber SP: The spectrum of rhabdomyolysis. Medicine 1982;61:141-152. Address for reprints: John A Marx, MD, FACEP, Carolinas Medical Center, Department of Emergency Medicine, PO Box 32861, Charlotte, North Carolina 28232.
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G r a n d Mal Seizures Temporally Related to Cocaine Use: Clinical and Diagnostic Features From the Departments of Emergency Medicine* and Neurology,t Denver General Hospital, University of Colorado
Reuben W Holland III, MD* John A Marx, MD, FACEP* Michael P Earnest, MD t Stacie Ranniger, MD*
Health Sciences Center, Denver. Receivedfor publication June 28, 1991. Revision received November 2, 1"991.Accepted for publication December 10, 1991. Presented at the American College of Emergency Physicians Scientific Assembly in Washington, DC, September 1989.
Study objectives: Todetermine the appropriate diagnostic workup of the emergency department patient with an uncomplicated cocainerelated grand mal seizure. Design setting: Retrospective analysis. A city and county ED with 45,000 selected visits per year. Type of participants: Thirty-seven patients with acute grand real seizure after cocaine exposure were studied. All had historical or laboratory evidence of cocaine use and no history of prior seizure disorder. Interventions: The diagnostic workup varied among patients. Most received computed head tomography (35), whereas fewer received ECG (18), EEG (16), and lumbar puncture (six). a n d m a i n r e s u l t s : Thirty-three patients with an uncomplicated cocaine-related seizure had an unremarkable series of diagnostic tests. The four patients with remarkable neurologic manifestations were compared with the remainder of patients who were without neurologic abnormalities. Comparison of groups by route of cocaine intake revealed no significant difference in the time interval to seizure (P= .761). Measurements
Conclusion: Diagnostic workup probably is not indicated for the patient experiencing a cocaine-related generalized seizure who will recover promptly and have a normal postictal examination, [Holland RW III, Marx JA, Earnest MP, Ranniger S: Grand mal seizures temporally related to cocaine use: Clinical and diagnostic features. Ann EmergMedJuly 1992;21:772-776.]
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INTRODUCTION During the past decade, cocaine has become an increasingly abused drug in the United States. More than 30 million persons are estimated to have used cocaine, and approximately 5 million persons do so on a regular basis. 1 Numerous medical sequelae of cocaine use have been described, p r i m a r i l y affecting the cardiovascular and central nervous systems and manifesting as myocardial infarction, cardiac dysrhythmias, and stroke. 2-4 To date, little information has been presented in the literature regarding seizures associated with cocaine use. We describe the clinical features and results of diagnostic workup of cocaine-related grand mal seizure in 37 patients who presented to our emergency department.
MATERIALS AND METHODS Patients with suspected cocaine-related grand real seizure were identified by reviewing Denver General Hospital ED records from the period between June 1980 and J a n u a r y 1989. The Denver General Hospital ED is the city and county facility for Denver, Colorado, with 45,000 selected patient visits p e r year. Inclusion criteria for cocaine-related grand mal seizure were history of seizure based on witnessed tonicelonic activity or physical signs of seizure (eg, tongue-biting or u r i n a r y incontinence) or loss of consciousness with postictal state (ie, resolving period of confusion without other explanation); cocaine use confirmed by history or a positive toxicologic screen for either cocaine or its metabolites within eight hours of seizure activity (elapsed time to onset of seizure activity was estimated by either the patient or witnesses to the event); no evidence of other seizure precipitants (eg, trauma, infection, metabolic disturbance, or other toxic exposure); and no history of seizure d i s o r d e r or treatment with anticonvulsant medications. The route of administration was determined by history and divided into IV, intranasal, freebase, and oral groups. Diagnostic workup varied, but most patients received computed tomography (CT) scan of the head, whereas fewer received EEG, l u m b a r puncture, and/or ECG (Table 1). All tests except the E E G were performed while the patient was in the ED. The Mann-Whitney-Wilcoxon test was used for comparison of data.
Table 1. Diagnostic studies in 37 patients with cocaine-related grand mal seizures Study
No. of Patients Tested
Abnormal Results
CT scan of head 35 2* ECG 18 8t EEG 16 1 Lumbar puncture 6 1' * Onerevealedcerebraledema,and one revealedcerebraleneurysmwith subarachnoid hemorrhage. t All had sinustachycardia.Two patientswith chest pain had ST-Twave abnormalities. * Cerebralspinalfluid had 22,000RBCs/mm3 end xanthochromiain the casewith subarachnoid hemorrhage.
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RESULTS Of the 37 patients with cocaine-related grand mal seizure, 24 were men and 13 were women. Mean age was 26 years (range, 17 to 49 years). Route of exposure was IV (18), intranasal (11), freebase (four), or oral (four) (Table 2). The cocaine-related grand mal seizure was subsequent to a single- (30) or multiple- (seven) dose exposure. The elapsed time from cocaine use to seizure was estimated by available history and categorized into time intervals of less than 15 (14), 15 to 120 (12), and more than 120 minutes (seven) (Table 2). Thirty-one patients had no neurologic abnormalities and two had preceding neurologic disease without acute findings. F o u r patients had new Findings on neurologie examination. Of these four patients (I1%), two had acute neurologic abnormalities during evaluation. No patient had Table 2. Characteristics of cocaine exposure
Patient 1 2 3* 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20t 21 22t 23 24 25 26 27
Estimated Amount of Cocaine(g)
Exposure Route
No. of Exposures
? 4 ? 0.25 ? ? ? ? ? ? ? 0.5 ? 0.125 6 0.125 2 0.33 0.25 ? 0.5 ? 3 0.25 2 ? 0.5
IV IV Intranasal Intranasal IV Intranasal IV Oral IV IV Oral IV IV IV IV IV Intranasal Intranasal Intranasal IV iV Oral Freebase Intranasal Intranasal Freebase IV
Single Multiple Single Single Single Single Multiple Multiple Single Single Single Single Single Single Single Single Single Single Single Single Single Single Multiple Single Single Multiple Single
Elapsed Time to Seizure (rain)
< 15 < 15 ? 15-120 < 15 15-120 15-120 ? > 120 < 15 15-120 ? > 120 < 15 < 15 > 120 < 15 < 15 > 120 15-120 < 15 ? < 15 15-120 15-120 15-120 > 120 28* ? IV Single 15 - 120 29* 0.25 Intranasal Single 15 - 120 30 0.5 IV Single > 120 31 ? Oral Single > 120 32 ? Intranasal Single < 15 33 0.5 Freebase Single 15-120 34 ? Freebase Multiple < 15 35 ? Intranasal " Single < 15 36 ? IV Single 15-120 37 ? IV Multiple < 15 * Presentedwith subarachnoidhemorrhage.CTscan and angiographydemonstratedanterior communicating arteryaneurysm. t Presentedin cardiacarrest. Presentedwith chestpain and nonspecificST-Twave abnormalitieson ECG.
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multiple seizures, focal seizures, or status epilepticus after cocaine exposure 4n either the single- or multiple-dose group. No significant difference was found between the route of cocaine exposure and the time to onset of seizure (P = .761). Acute neurologic signs at presentation to the ED were seen in four patients. Two patients were comatose on presentation to the ED, both after a seizure and a cardiac arrest. Whether the seizure was a p r i m a r y event or secondary to cerebral hypoperfusion was unknown. One patient h a d an initial rhythm of ventrieular fibrillation, and the other had asystole. In each case, the postresuscitation ECG revealed only sinus tachyeardia. CT scan demonstrated diffuse cerebral edema in one and was u n r e m a r k a b l e in the other. Both patients presumably sustained diffuse anoxic encephalopathy and died without regaining consciousness within 48 hours of cardiac arrest. The third patient presented with confusion and drowsiness consistent with a postietal state. The mental status abnormalities resolved within four hours of the seizure. CT scan and EEG were normal. The fourth patient presented 14 hours after a grand mal seizure with severe headache, meningismus, photophobia, and right hemiparesis. Her symptoms h a d been present since the seizure. Contrast-enhanced CT scan demonstrated an aneurysm of the anterior communicating artery with possible subaraehnoid hemorrhage. Cerebrospinal fluid analysis showed 22,000 RBCs/mm 3 and xanthochromia in each of four tubes. Angiography demonstrated an aneurysm of the anterior communicating artery. The aneurysm was clipped, and the patient h a d full neurologie recovery. Two other patients h a d pre-existing neurologic disease. One h a d cerebral palsy, and the other had sustained a left cerebrovaseular accident seven years before presentation. The neurologie status of each was at baseline in the ED according to friends or relatives. CT scan in the former patient revealed large ventricles and a mildly abnormal E E G consistent with cerebral palsy. In the latter patient, the CT scan abnormalities were unchanged compared with h e r previous scan. An EEG was normal. Both patients were admitted to the neurology service and discharged without institution of additional diagnostic tests or therapy. The remaining 31 patients had a normal neurologic examination, and their diagnostic evaluations were unrevealing (Table 1). None of these patients was prescribed chronic anticonvulsant therapy. Additional complications of cocaine exposure in our patients were rhabdomyolysis and chest pain. Rhabdomyolysis was diagnosed in one patient (patient 10) who h a d a p e a k creatinine phosphokinase of 4,280 IU/L. Duration of the seizure event was estimated by witnesses to he less than five minutes. This patient was treated with alkaline diuresis and had an u n r e m a r k a b l e course. He h a d no preeipitants for rhabdomyolysis other than cocaine and a seizure (ie, not multiple seizures). Chest pain suggestive of myocardial ischemia occurred in two patients (patients 28 and 29). Both had nonspecific ST-T wave abnormalities on their initial
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ECG and were admitted. F u r t h e r evaluation with serial enzymes and ECGs was u n r e m a r k a b l e . Echocardiography did not reveal wall motion abnormalities. Cardiac catheterization was not performed in either case. Both patients were discharged after an uneventful hospital course.
DISCUSSION The mechanism by which cocaine precipitates seizure p r o b a bly is multifactorial. A direct reduction of the seizure threshold has been suggested and is supported by animal studies. The drug's pathophysiology includes central nervous system effects as well as systemic disturbances, which can alter the seizure threshold. Putative central nervous system effects include adrenergic "surge," acute hypertensive episode, cerebral vasospasm, and hyperthermia. 5,6 I n t r a c r a n i a l hemorrhage also has been discovered in patients with cocaine-related grand m a l seizure. In these patients, aneurysms and arteriovenous malformations most often are responsible, and the subaraehnoid space appears to be the most frequent location of bleeding. 7 Vasculitis has been demonstrated after chronic cocaine use, but its role in the genesis of seizures is not yet defined. 8,9 In addition, the role of "cutting agents" cannot he ignored because epileptogenie drugs such as lidoeaine, procaine, pheneyelidine, amphetamines, and quinidine may be a d u l t e r a n t s J ° Finally, a direct reduction of the seizure threshold by cocaine has been suggested and is supported by results of animal studies. 5,6 Metabolic consequences of cocaine use include acid-base disturbances and hyperthermia. Metabolic acidosis, resulting from intense muscular activity, hypoxemia, rhabdomyolysis, or a direct toxin-induced lactic acidosis, can sensitize and potentiate the effect of catecholamines, n,12 This may cause central nervous system depression and adversely affect myocardial performance and increase the potential for dysrhythmias. 5,6,11 Dysrhythmias, with resultant hypotension, may lead to cerebral hypoperfusion and anoxia, increasing the susceptibility to seizure. H y p e r t h e r m i a may play a role in the genesis of cocainerelated grand mal seizure. H y p e r t h e r m i a in cocaine use results from p e r i p h e r a l vasoconstriction, increased skeletal muscle activity, increased cardiac output, and central thermoregulatory dysfunction. 5 Attenuation of this h y p e r t h e r mic response in animal studies was associated with a lower incidence of seizures and decreased mortahty. The influence of patient t e m p e r a t u r e could not be measured in this study due to delay from cocaine-related grand mal seizure to presentation. H y p e r t h e r m i a was not a p r i m a r y concern of any patient in this review. 5,13 The pharmacologic kindling effect may be operative in the production of cocaine-related grand real seizure when repeated doses of cocaine are administeredA 4 This effect accounts for a greater susceptibility to seizure despite the development of tolerance. 13 The high hpid solubility of
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cocaine causes avid uptake in the b r a i n and may contribute to the kindling effect. Large initial plasma cocaine levels may lead to much higher central nervous system levels and, ultimately, seizure. 15 In addition, the psychologic effects of cocaine appear to be related to the rate of change rather than the absolute serum cocaine level. 13 Seizure may be prompted in a similar fashion. Subsequent equilibration keeps plasma levels high despite a decreasing euphoric effect. Seizures have been reported after IV, intranasal, freebase, oral, topical, rectal, and intravaginal cocaine use. lO.16-18 In this study, IV, intranasal, freebase, and oral routes of administration are reported, and the IV route is responsible for nearly half of those with cocaine-related grand mal seizure. The prevailing patterns of cocaine use in Denver during the study period are not known. Therefore, the relative risk of cocaine-related grand mal seizure according to route cannot be determined from our data. The effects of cocaine are numerous and depend on dosage (purity), route of administration, and form in which it is taken. It has a relatively rapid onset and a short duration of action. Peak" euphoria occurs 15 to 30 minutes after administration, with a serum half-life of 50 to 80 minutes. Although the elimination half-life remains constant, variability in absorption affects the clinical response. IV administration of cocaine provides a rapid rise in serum levels with significant physiologic effects. "Crack" cocaine, the alkaloid derivative of the hydrochloride salt, volatilizes when heated and t.hus is able to be inhaled. Rapid and efficient absorption occurs across the pulmonary capillary vasculature with an onset and intensity of effects approximating those of the IV route.15 I n t r a n a s a l cocaine use also may produce toxicity, but this route may create an absorptive b a r r i e r by mucosal vasoconstriction. 15 Furthermore, this n a t u r a l b a r r i e r may prolong the effects of cocaine due to continued absorption across the mucosa. Despite current misconceptions, cocaine taken by the oral route is readily absorbed across the gastric mucosa with adverse affects including intestinal ischemia and systemic toxicity. 19-2~ Classically, these cases involve "body packers" or "mules" attempting to smuggle cocaine. We did not find a statistically significant difference between patients who seized early (less than 15 minutes) and patients who seized late (two to eight hours) with regard to route of administration. This finding was unexpected and may be attributable to differences in exposure pattern, purity, or historical inaccuracies. The patients were categorized into three groups according to the elapsed time to seizure. These time intervals were constructed to differentiate acute seizures corresponding to the time to peak euphoria, a subacute interval approximating one serum half-life, and a more extended period to encompass any delay in effects. Generalized and focal seizures may result from a wide variety of toxic and metabolic disorders. Exposure to numerous medications and drugs, especially cyclic antide-
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pressants and theophylline, can lead to seizure. Withdrawal after chronic substance abuse, particularly ethanol and sedative hypnotics, also can produce seizure. Hypoglycemia is the most common cause of a metabolic-induced generalized seizure. Focal seizure most often is due to nonketotic hyperglycemia. Other less common causes of metabolic seizure include hypoxemia, hepatic encephalopathy, uremia, and various electrolyte disturbances. 22 When a toxic or metabolic etiology is solely responsible for the induction of a seizure, results of neurologic tests usually are unremarkable. Turnbull et al prospectively studied 136 patients to determine the usefulness of laboratory testing in the ED patient with new-onset seizure. 23 When a metabolic etiology of seizure was discovered, computed tomography was u n r e m a r k a b l e in all cases. In all except two cases, both hypoglycemia, there were clues from the history and physical examination that would have raised suspicion of the laboratory abnormalities that were discovered subsequently.23 Ramirez-Lassepas et al retrospectively studied the value of CT after first seizure in 148 adults. 24 Sixteen patients (11%) were thought to have a metabolic etiology responsible for their seizures. Nine of these patients (56%) exhibited focal or partial complex symptomatology, but CT scan evaluation revealed no abnormalities in any of these patients. Longterm anticonvulsant therapy was not instituted unless a primary central nervous system lesion was demonstrated or epileptiform changes were seen on EEG. 2a Occult vascular or structural central nervous system pathology may exist and contribute to the precipitation of toxic-metabolic-related seizures in a subset of patients. 15,25 Earnest et al studied 259 patients with suspected first alcohol withdrawal seizure. 26 Sixteen of his patients (6.2%) had intracranial pathology, and further intervention was required in eight (3.2%). Significantly, the presence or absence of intracranial pathology could not be predicted from the patient's presenting neurologic examination. The presence of an u n r e m a r k a b l e neurologic workup in patients with cocaine-related grand real seizure has been noted by other investigators. Bettinger described one patient with status epileticus after massive oral cocaine ingestion. 2° After resolution of his seizures, the patient's examination normalized. Subsequent diagnostic evaluation, including CT scan and cerebral angiography, was negative, and the patient was discharged from the hospital without neurologic impairment. Seaman and Gushee report two cases of cocaine-related grand real seziure in which investigation revealed unsuspected b r a i n tumors. 25 Both of these patients, however, had persistent focal neurologic deficits at presentation. Ernst and Sanders described four cases of cocaine-related grand real seizure in children. 27 Despite recurrent seizures and focal features in one child, all had an u n r e m a r k a b l e diagnostic workup, including CT scan and blood chemistries. Pascal-Leone et al studied the risk factors a n d confounding variables associated with cocaine-related grand mal seizure. 2a
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Of the 13 first-time cocaine users with seizure, only a patient with subarachnoid hemorrhage had an a b n o r m a l CT scan. Of the 19 patients with habitual cocaine use, 52.6% were noted to have diffuse cerebral atrophy. Neurologic examination of these patients was not documented. Choy-Kwong and Lipton reported four of 283 patients with a history of cocaine abuse who presented to the ED with cocaine-related grand mal seizure. 29 Focal and generalized seizures were observed in this group. However, neurologic examination and CT scan did not reveal underlying structural b r a i n lesions. These reports and our data suggest that neurologic workup, including CT scan, for the patient with an uncomplicated generalized seizure associated with cocaine intoxication may not be necessary. Patients with an uncomplicated cocaine-related grand real seizure, ie, without focality, a prolonged course, or persistence of neurologic abnormalities are unlikely to have underlying i n t r a c r a n i a l pathology. Management should attend ongoing toxic or metabolic concerns. Acute anticonvulsant t h e r a p y and institution of chronic anticonvulsant medication are not indicated in this setting. Rhabdomyolysis, a recently described complication of cocaine abuse, was seen in one of our patients. Although seizure alone has been implicated in causing rhabdomyolysis, this condition is associated with cocaine use in the absence of tonic-clonic activity. Suggested pathophysiologic mechanisms arc vasoconstriction within the skeletal muscle with subsequent ischemia and loss of cell m e m b r a n e integrity and a direct toxic effect to the muscle cell. Previous studies have documented a 33% incidence of acute renal failure associated with rhabdomyolysis, including cases caused by cocaine exposure. 1,30 This did not occur in the single episode in our series. Limitations of our study included its retrospective n a t u r e , the unknown reliability of historical data, and the small number o f cases. The eight-hour time limit used in this study also may underestimate the incidence of cocaine-related grand mal seizure due to disparate absorption and solubility between plasma and central nervous system tissue. In fact, cocaine-related grand real seizure have been r e p o r t e d as long as 12 hours after cocaine use.14 Finally, the potential exists that undetected adulterants or an idiopathic seizure disorder complicated the cocaine use. CONCLUSION Patients described in this study experienced a single uncomplicated generalized seizure temporally related to cocaine use with either historical or l a b o r a t o r y c o r r o b o r a tion of cocaine exposure. Our limited d a t a suggest that patients with cocalne-related grand real seizure who r e t u r n to their baseline neurologic status do not have their management altered by the performance of any diagnostic study. We emphasize that these observations are not applicable to patients with complicated seizures.
REFERENCES 1. Roth D, Alarcon FJ, FernandezJA, et al: Acute rhabdomyolysis associated with cocaine intoxication. N EnglJ Med 1988;319:673-677. 2. Derlet RW: Emergency department presentation of cocaine intoxication. Ann Emerg Med1989;18:182-186. 3. Buchanan J P: Cocaine intoxication: A review of the presentation and treatment of medical complications. HaspPhys1988;24:24-35. 4. Cregler LL, Mark H: Medical complications of cocaine abuse. NEnglJMed 1986;315:1495-1500. 5. Catravas JD, Waters IW: Acute cocaine intoxication in the conscious dog: Studies on the mechanism of lethality. JPharmaco/Exp Ther1981;217:350-356. 6. Jonosson S, O'Meara M, Young JB: Acute cocaine poisoning, Am J Med 1983;75:1061-1064. 7. Klonoff DC, Andrew BT, Obana WG: Stroke associated witll cocaine use. Arch Neural 1989;46:989-993. 8. Levine SR, Welch KMA, Brust JCM: Cerebral vesculitis associated with cocaine abuse or subarachnoid hemorrhage. JAMA 1988;259:1648. 9. Mody CK, Miller BL, Mclntyre HR, et al: Neurologic complications of cocaine abuse. Neurology1988;38:1189-1193. 10. Wetli CV, Wright RK: Death caused by recreational cocaine use. JAMA 1979;241:2519-2522. 11. Drake TR, Henry T, Marx J, et al: Severe acid-base abnormalities associated with cocaine abuse. J EmergMed 1990;8:331-334. 12. Ford GD, Clinte WH Jr, Fleming WW: Influence of lactic acidosis on cardiovascular response of sympathomimetic amines. Am JPhysio/1968;215:1123-1129. 13. Zaccara G, Muscas GC, Messori A: Clinical features, pathogenesis and management of drug-induced seizures. DrugSafety1990;5:109-151. 14. Lowenstein DH, Massa SM, Rowbatham MC, et al: Acute neurologic and psychiatric complications associated with cocaine abuse, Am J Med1987;83:841-846. 15. Van Dyke C, Byck R: Cocaine. SciAm 1982;248:128-141. 16. Difazio C: Local anesthetics: Action, metabolism, and toxicity. OtolaryngolC/in NorthAm 1981;14:515-519, 17. Ettinger TB, Stine RJ: Sudden death temporally related to vaginal cocaine abuse. Am J EmergMed 1989;7:129-136. 18. Myers JA, Earnest MP: Generalized seizures and cocaine abuse. Neurology 1984;34:675-676, 19. Gerkin RD Jr: Cocaine, in Tintinalli JE, Krome RL, Ruiz E (eds): EmergencyMedicine: A ComprehensiveStudyGuide,ed 2. New York, McGraw-Hill Book Co, 1988,p 711-712. 20. Bettinger J: Cocaine intoxication: Massive oral overdose. Ann EmergMed 1980;9:429-480. 21. Nalbandian H, Sheth N, Dietrich R, et al: Intestinal ischemia caused by cocaine ingestion: Report of two cases. Surgery1985;97:374-376. 22. Berkovic SF, Johns JA, Bladin PF: Focal seizures and systemic metabolic disorders. Aust N Z J Med 1982;12:620-623. 23. TurnbuffTL, Vanden HookTL, EisnerRF: Utility of laboratory studies in the emergency department patient with a new-onset seizure.Ann EmergMed 1990;19:373-377. 24. Ramirez-LessepasM, Cipolle RJ, Morillo LR, et al: Value of computed tomogrephic scan in the evaluation of adult patients after their first seizure.Ann Neure/1984;15:536-543. 25. Seaman M, Gushee D: Investigation of cocaine-related seizures showing unsuspected brain tumors. Ann EmergMed 1990;19:733-734. 26. Earnest MP, Feldman H, Marx JA, et al: Intracranial lesions shown by CT scans in 259 cases of first alcohol related seizure. Neurology1988",38:1561-1565. 27. Ernst AA, Sanders WM: Unexpected cocaine intoxication presenting as seizures in children. Ann EmergMed1989;18:774-777. 28. Pascal-Leone A, Dhuna A, Altafullah I, et al: Cocaine-induced seizures. Neurology 1990;40:404-487. 29. Choy-Kwong M, Lipton RB: Seizures in hospitalized cocaine users. Neurology 1989;39:425-427. 30. Gabow P, Kaehny WD, Kelleber SP: The spectrum of rhabdomyolysis. Medicine 1982;61:141-152. Address for reprints: John A Marx, MD, FACEP, Carolinas Medical Center, Department of Emergency Medicine, PO Box 32861, Charlotte, North Carolina 28232.
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