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Status Epilepticus as a Complication of Concurrent Electroconvulsive and Theophylline Therapy

      Status epilepticus that occurs after electroconvulsive therapy is a rarely reported event. Seizures associated with use of theophylline usually result from severe toxicity. We report a case in which status epilepticus occurred after electroconvulsive therapy in a patient who had a theophylline level above the accepted therapeutic range but below that generally associated with seizures. Caution should be exercised in the concurrent administration of electroconvulsive therapy and theophylline preparations.
      Status epilepticus is a rarely reported complication of electroconvulsive therapy; electrically induced seizures generally last less than 60 seconds.
      • Weiner RD
      • Volow MR
      • Gianturco DT
      • Cavenar Jr, JO
      Seizures terminable and interminable with ECT.
      As a manifestation of theophylline toxicity, seizures are usually seen with serum theophylline levels of more than 25 μg/ml.
      • Zwillich CW
      • Sutton Jr, FD
      • Neff TA
      • Cohn WM
      • Matthay RA
      • Weinberger MM
      Theophylline-induced seizures in adults: correlation with serum concentrations.
      Herein we report a case in which status epilepticus after electroconvulsive therapy was the first manifestation of a toxic level of theophylline.

      REPORT OF CASE

      A 71-year-old widow was admitted to our institution because of a 3-year history of depression, which had been treated intermittently with antidepressant medications. She had been unable to care for herself and had lived in a nursing home for the previous 2 years. She had a long history of severe corticosteroid-dependent asthma and had been hospitalized elsewhere 6 months previously, during which time she had required mechanical ventilation for 5 days. After that hospitalization, she had become more withdrawn, had slept and eaten poorly, and had lost 14 to 18 kg. No improvement was noted after treatment with doxepin, 150 mg/day, or trazodone, 150 mg/day. It was thought that electroconvulsive therapy might be of benefit. The patient had a history of nontransmural myocardial infarction 5 months previously with no evidence of congestive heart failure. Results of pulmonary function tests were consistent with mild to moderate obstructive lung disease. Serum chemistry studies indicated normal hepatic and renal function. She had no prior history of seizures. Mild cognitive impairment was noted.
      The patient was taking prednisone, 2.5 mg/day, and theophylline tablets (Slo-Phyllin), 250 mg twice daily. Her weight was 44 kg. The serum theophylline level at the time of admission was 5.5 μg/ml. In an effort to achieve a level in the range of 10 to 20 μg/ml, the medication was changed to a sustained-action preparation of anhydrous theophylline (Theo-Dur), and the dosage was increased to 300 mg twice daily. The serum level 5 days later was 7.1 μg/ml. The dosage was subsequently increased to 300 mg three times daily, and the serum level after 4 days was 6.6 μg/ml; finally, 300 mg of Theo-Dur was given four times daily.
      Three days later, nondominant unilateral electroconvulsive therapy was administered with a Mecta stimulus generator, and a pulse frequency of 70 per second, a pulse width of 0.75 second, and a duration of stimulus of 1.25 seconds were used. Premedication consisted of sodium pentothal (75 mg), atropine (0.4 mg), and succinylcholine (25 mg). Throughout the procedure, oxygenation was maintained with an oral airway and assisted ventilation with 100% oxygen by bag and mask. The induced seizure lasted 53 seconds. After a 20-second interval, a spontaneous generalized seizure occurred and persisted for 3 minutes. Five minutes later, a second spontaneous seizure began and responded to diazepam, 5 mg intravenously. Further generalized seizures occurred (a total of six episodes lasting up to 4 minutes each) and were managed with sodium pentothal (100 mg), succinylcholine (100 mg), endotracheal intubation, and mechanical ventilation. Phenytoin (500 mg intravenously) and phenobarbital (200 mg) were given, and the seizure activity abated during a period of 20 to 30 minutes.
      Serum electrolytes, glucose, calcium, and magnesium were within normal limits. The serum theophylline level determined approximately 3 hours before the procedure was 22.6 μg/ml. The level 9 hours after the procedure was 7.8 μg/ml. An arterial blood sample after the second seizure showed a high PaO2 (441 mm Hg) and moderately severe respiratory and metabolic acidosis (PaCO2 79 mm Hg and pH 6.97). A measurement of blood gases after intubation showed the following: PaO2 175mm Hg, PaCO2 36mm Hg, and pH 7.30.
      Electroencephalography done approximately 1 hour after the last physical seizure showed a burst-suppression pattern. Electroencephalographic recordings 1 and 4 days later showed a pattern of relatively normal sleep spindle activity alternating with higher amplitude slow activity, a considerable improvement from the previous recording. No underlying seizure disorder was identified. A computed tomographic head scan obtained several hours after the shock therapy showed mild generalized atrophy, which was thought to be a chronic change unrelated to the seizures. Although fully responsive, the patient remained lethargic.
      The subsequent course of the patient in the intensive care unit was complicated by poor mobilization of secretions, persistent bronchospasm, mucoid impaction, and recurrent lobar atelectasis, and repeated bronchoscopic suctioningwas necessary. After 5 weeks, she had persistent lethargy, anorexia, and residual radiographic evidence of left lower lobe atelectasis and was transferred to a nursing home. She was thought to show continued evidence of depression, withdrawal, and cognitive impairment and at times was confused and disoriented. The patient's family declined further psychiatric care.

      DISCUSSION

      Electroconvulsive therapy is only rarely associated with prolonged seizures, and these episodes are reportedly more common with the multiple monitored technique, in which several seizures are induced during one period of anesthesia under continuous monitoring.
      • Weiner RD
      • Volow MR
      • Gianturco DT
      • Cavenar Jr, JO
      Seizures terminable and interminable with ECT.
      • Weiner RD
      ECT-induced status epilepticus and further ECT: a case report.
      The seizures in the patient described in this report were induced with a single stimulus from a Mecta apparatus. Continuous oxygenation during electroconvulsive therapy has also been implicated as a factor that may prolong the duration of seizures, and hyperoxia was observed in this case. Use of supplemental oxygenation, however, is generally thought to be necessary to avoid the greater risks of hypoxemia; despite this standard practice, status epilepticus after electroshock therapy remains extremely rare.
      • Weiner RD
      • Volow MR
      • Gianturco DT
      • Cavenar Jr, JO
      Seizures terminable and interminable with ECT.
      • Posner JB
      • Plum F
      • Van Poznak A
      Cerebral metabolism during electrically induced seizures in man.
      In this patient who was taking theophylline, electroconvulsive therapy was complicated by status epilepticus. She had been taking no other medications that could be implicated as a cause of seizures because of either toxicity or withdrawal. Despite attention to dosage and repeated measurement of theophylline levels, a high serum concentration was observed. With a dosage of 1,200 mg/day, or 27.3 mg/kg, a relatively high serum level might have been expected, although such relationships are difficult to predict.
      • Jacobs MH
      • Senior RM
      • Kessler C
      Clinical experience with theophylline: relationships between dosage, serum concentration, and toxicity.
      Our patient was receiving no medications associated with prolongation of the theophylline half-life and had no evidence of an underlying disease, such as congestive heart failure or hepatic dysfunction, that might have delayed drug metabolism.
      • Van Dellen RC
      Theophylline: practical application of new knowledge.
      Although blood levels were not measured frequently enough to estimate drug elimination accurately in this patient, a greater than 50% reduction in the serum level was observed after 9 hours. Therefore, the half-life was presumably within the broad range of 2.9 to 12.8 hours that has been reported in adults who have asthma.
      • Van Dellen RC
      Theophylline: practical application of new knowledge.
      Spontaneous theophylline-induced seizures are most often seen when serum levels of the drug are more than 50 μg/ml but have been reported at a serum level of 25 μg/ml.
      • Zwillich CW
      • Sutton Jr, FD
      • Neff TA
      • Cohn WM
      • Matthay RA
      • Weinberger MM
      Theophylline-induced seizures in adults: correlation with serum concentrations.
      • Van Dellen RC
      Theophylline: practical application of new knowledge.
      Recently, Nakada and associates
      • Nakada T
      • Kwee IL
      • Lerner AM
      • Remler MP
      Theophylline-induced seizures: clinical and pathophysiologic aspects.
      described three elderly patients in whom seizures developed when theophylline levels were 17, 20.5, and 24 μg/ml, respectively. In each of these patients, a substantially decreased serum albumin level was noted, and the authors suggested that because theophylline is approximately 53 to 65% protein bound, decreased serum proteins resulted in increased levels of the free drug. In our patient, the serum albumin was only slightly decreased at 3.42 g/dl (normal range, 3.5 to 5.0 g/dl) and should not have affected the drug levels appreciably. The prolonged seizures in our patient occurred at a relatively low serum theophylline concentration but with the external stimulus of electroconvulsive therapy. Although theophylline may lower the seizure threshold, the mechanism is not well understood.
      • Nakada T
      • Kwee IL
      • Lerner AM
      • Remler MP
      Theophylline-induced seizures: clinical and pathophysiologic aspects.
      Side effects other than seizures may occur when the serum theophylline concentration is within the recommended therapeutic range of 10 to 20 μg/ml but more commonly represent early signs of toxicity.
      • Jacobs MH
      • Senior RM
      • Kessler C
      Clinical experience with theophylline: relationships between dosage, serum concentration, and toxicity.
      • Van Dellen RC
      Theophylline: practical application of new knowledge.
      In depressed, lethargic, or obtunded patients, symptoms such as nausea, anorexia, and headache may be difficult to ascertain; thus, toxicity might not be suspected.
      As noted, status epilepticus induced by electroconvulsive therapy is exceedingly rare, and we know of no data on which to base a recommendation for a “safe” level of theophylline in patients who are scheduled to undergo this procedure. Physicians who evaluate the status of patients before electroconvulsive therapy should be aware of the potential risk of the concomitant use of theophylline, particularly with serum levels of the drug above the accepted therapeutic range.

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        Theophylline-induced seizures in adults: correlation with serum concentrations.
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        Cerebral metabolism during electrically induced seizures in man.
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        Theophylline: practical application of new knowledge.
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