Richard W. Fincham

Bradycardia and syncope as manifestations of partial epilepsy

Although transient increases in heart rate typically occur, bradycardia has infrequently been noted in association with partial seizures. Five patients with temporal lobe epilepsy are described in whom sinus bradyarrhythmias and syncope were prominent manifestations of seizure activity. Partial improvement occurred in one of two patients in whom a permanent pacemaker was implanted before a diagnosis of epilepsy was established. Treatment with phenytoin or carbamazepine resulted in nearly complete resolution of symptoms in all five patients. Because pacemaker implantation does not prevent recurrent symptoms, but anticonvulsant therapy does, this experience underscores the importance of considering the diagnosis of partial epilepsy in selected patients with sinus bradyarrhythmias and syncope.

Carotid-cavernous sinus thrombosis caused by Aspergillus fumigatus: magnetic resonance imaging with pathologic correlation - a case report.

The authors describe a case of aspergillosis with carotid-cavernous sinus thrombosis diagnosed by use of magnetic resonance imaging (MRI). MRI may aid in early detection of intracranial fungal infection and potentially help decrease morbidity and mortality through the institution of early medical and surgical therapy.

Effect of charcoal and sorbitol-charcoal suspension on the elimination of intravenous phenobarbital

The effects of two different oral charcoal suspensions on the elimination of a 200 mg/70 kg, 1 h intravenous (i.v.) infusion of phenobarbital and the tolerances of the two regimens were determined in a randomized crossover study in six healthy male volunteers. Phenobarbital was given i.v. alone or together with 105 g of oral activated charcoal suspension or with 105 g of a commercially available sorbitol-charcoal suspension over a 36-h period. A 13–34% decrease in the area under the serum concentration time curve (AUC) for 0–60 h occurred with the administration of the activated charcoal, and a 19–52% decrease occurred with the commercial sorbitol-charcoal regimen. The mean apparent systemic clearance of total phenobarbital increased from 0.089 ± 0.019 ml/min/kg to 0.141 ± 0.029 and 0.146 ± 0.036 ml/min/kg with the charcoal and sorbitol-charcoal treatments, respectively. No significant change in the fraction of phenobarbital bound to protein was detected. The charcoal regimen caused constipation in one subject. All subjects taking the sorbitol-charcoal preparation experienced diarrhea: there were no changes in electrolytes with either charcoal suspension. All subjects preferred the sorbitol-charcoal preparation.

Phenytoin Pharmacokinetics: Before and After Folic Acid Administration

Summary: Phenytoin (PHT) exhibits linear and Michaelis‐Menten pharmacokinetics. PHT decreases serum folate; the vitamin folk acid (FA) is hypothesized to be a cofactor in the metabolism of PHT. The depletion of serum folate may explain the unpredictability of measured total serum PHT concentrations and time to steady state as compared with the Michaelis‐Menten predictive calculations. We examined PHT pharmacokinetics before and after FA supplementation in 13 healthy male volunteers. The study was divided into two phases. Phase 1 determined Vmax (mg/day) and Km (μg/ml) of PHT to calculate PHT doses needed for the second phase. Phase 11 was a four‐way cross‐over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 μg/ml less and 5 μg/ml greater than the subjects Km, K−1, and Km+5, respectively. Predicted versus measured total serum PHT concentrations, t90% (days to steady state), and the effect of FA were calculated for Km−1, and Km+5 before and after 1 or 5 mg FA. The measured total serum PHT concentration was always greater than the calculated concentration (p < 0.05), and t90% was always longer than the calculated t90% (p < 0.05) for Km−1, before FA (all subjects decreased serum FA); the same was observed for Km+5. If folate is assumed to be a cofactor in PHT metabolism, these results are expected, because depletion of the vitamin would indicate less folate to drive the metabolism of PHT, resulting in higher total serum PHT concentrations and longer time to reach steady state. Even though steady‐state criterion was satisfied, “pseudo‐steady state” could have occurred, making the time to steady state longer and possibly increasing total serum PHT further. When FA was added, the same results were obtained. Neither was there any difference in total serum PHT concentration before and after either 1 or 5 mg FA. These latter results may be explained by the fact that depletion of FA had to be corrected first before the role of FA as a cofactor in PHT metabolism could be used. Therefore, the interdependence of PHT and FA may explain the pseudo‐steady state observed for PHT and the deviations from the Michaelis‐Menten predictive calculations. Perhaps FA supplementation should be recommended when PHT therapy is initiated.

Decrease of serum folates in healthy male volunteers taking phenytoin.

Summary: The effect of phenytoin (PHT) on serum folate and the effect of additional oral folic acid (FA) on serum folate during continued treatment with PHT were studied in 13 healthy male subjects 20–35 years of age. The study was divided into two phases: Phase I determined Vmax (mg/kg/day) and Km (μg/ml) of PHT in order to calculate the PHT doses needed for the second phase. Phase II was a four‐way cross‐over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 μg/ml less and 5 μg/ml greater than the subjects Km, Km‐1 and Km+ 5, respectively. Both phases examined the effect of PHT on serum folate. In Phase I, serum folate decreased by a mean and standard deviation of 42.15 ± 21.44% after an average of 24.15 ± 5.63 days of PHT administration, with a mean steady‐state total serum PHT concentration of 8.45 ± 2.70 μg/ml. Mean percentage decreases in serum folate before the addition of 1 and 5 mg FA in Phase II were 12.80 ± 31.45% and 23.24 ± 21.24% for Km‐1 and Km+5, respectively. The average numbers of days of PHT administration and total serum PHT concentrations before FA administration were 9.52 ± 3.34 and 15.84 ± 7.02 days, and 2.60 ± 2.18 and 8.64 ± 3.44 μg/ml, for Km‐1 and Km+5, respectively. The percentage increases in serum folate after taking FA while continuing PHT in Phase II were as follows: 38.78 ± 72.84%, Km‐1 (1 mg FA): 81.38 ± 72.75%, Km+5 (1 mg FA); 138 ± 93.43%, Km‐1 (5 mg FA); and 169.67 ± 69.67%, Km+5 (5 mg FA). Five milligrams FA increased the serum folate more than the 1‐mg dose. The higher total PHT concentration was associated with a greater decrease in the serum folate. Therefore, serum folate may decrease early with PHT therapy and should be monitored at that time.

Folic Acid improves Phenytoin Pharmacokinetics

Phenytoin (PHT) therapy to control seizures decreases serum folate levels in half of epileptic patients, thus increasing the risk of folate depletion. Supplementation with folic acid prevents deficiency but also changes PHT pharmacokinetics. Kinetic monitoring of PHT when folic acid is provided as a supplement has not been reported in women of child-bearing age. This study of six fertile women examined the interdependence of PHT and folic acid in a randomized crossover study of two treatments: treatment 1 consisted of 300 mg sodium PHT per day and treatment 2 consisted of 300 mg sodium PHT plus 1 mg folic acid per day. Dietary folic acid intake was calculated daily. During treatment 1, serum folate level decreased 38.0 +/- 18.6% (mean +/- standard deviation) and serum PHT concentration was in the low therapeutic range (43.92 +/- 14.52 mumol/L). During treatment 2, serum folate level increased 26.0 +/- 33.4%, and serum PHT level (39.04 +/- 14.16 mumol/L) was similar to that in treatment 1. Only one subject attained PHT steady state during treatment 1, but four subjects achieved steady state during treatment 2. Dietary folate intakes during treatments 1 and 2 were not significantly different. This study suggests an interdependence between PHT and folic acid and supports the observation that fertile women treated with PHT require folic acid supplementation to maintain a normal serum folate level.

Parkinsonism—Drug Treatment: Part I

The purpose of this two-part review is to explain current drug treatment in part I and discuss investigational drug therapy and miscellaneous drugs in the management of parkinsonism in part II. The medical approach to this disease is still based on the imbalance between a deficiency of dopamine and a functional increase in acetylcholine. Anticholinergic agents are used to treat the tremors in the early stages of the disease.

Parkinsonism Treatment: Part III—Update

OBJECTIVE: The purpose of this review is to update clinicians with recent advances in the management of parkinsonism, including drug therapy, transplantation, and diet. DATA SOURCES: Pertinent articles were obtained from an English-language literature search using MEDLINE (1970–1991), Index Medicus (1987–1991), Current Contents (1990), and bibliographic reviews of review articles. Index terms included parkinsonism, selegiline, pergolide, vitamin E, and transplantation. Fifty-five articles (representing 85 percent of the complete literature search) were selected by multiple reviewers for their contribution to the stated purpose. Emphasis was placed on double-blind, placebo-controlled, and randomized studies. Data from cited articles were examined by multiple reviewers for support of their stated hypothesis and were included as background for justification of major points in this article; critical studies were abstracted in more detail. RESULTS: New therapeutic measures have been added to the treatment of parkinsonism. Selegiline, a monoamine oxidase inhibitor type B, has shown beneficial results, especially in early stages. Pergolide, a dopamine agonist, may be an efficacious alternative to bromocriptine resistance or intolerable adverse effects. Vitamin E may have protective antioxidant properties, but very few clinical data are available. Fetal tissue transplantation needs continued research and remains very controversial. Diet modification may maximize the results of therapy with exogenous dopamine therapy. CONCLUSIONS: Clinicians should familiarize themselves with new alternatives for the management of parkinsonism in order to be reliable consultants for both professional and lay persons.

Postictal Depression following Subtle Seizures.

We describe a woman with stereotypic recurrent episodes of severe depression with suicidal ideation that follow series of simple partial seizures. Her seizures were not clinically recognized for many years. When her seizures are effectively treated with antiepileptic drug therapy, her depressive episodes remit.

Effect of Three Charcoal Preparations on Oral and Intravenous Phenobarbital

AbstractThe purpose of this randomized, controlled study was to determine which of the three commercially available activated charcoals (Actidose, Charcoaid and SuperChar) was the best to clear 200 mg of either oral or intravenously administered phenobarbital from healthy male volunteers, 20–40 years of age. Twenty subjects were recruited; 13 and 14 volunteers were used for the analysis of the oral and intravenously administered phenobarbital, respectively. Cpmax, Tmax, the AUCs for designated time intervals, Clp, and the mean ratios of AUC for charcoal treatment/AUC for no charcoal treatment were calculated. There was no significant difference (p<0.05) in Cpmax and Tmax values for oral phenobarbital with and without charcoal. There was no significant difference (p<0.05) with and without charcoal, between Cpmax values for the intravenous route. For oral phenobarbital, the AUC values for Superchar and Actidose showed a significant decrease (p<0.10) from no charcoal treatment throughout all of the time int...