Serum IgA, IgG, and IgM concentrations in patients with epilepsy and matched controls: a cohort-based cross-sectional study

Conflicting reports have been published on serum immunoglobulin (Ig) concentrations in patients with epilepsy. Serum IgA, IgG, and IgM concentrations were determined in a cohort of 958 patients and in a reference population of 581 subjects. Overall, 8.2% of patients with epilepsy and 1.9% of control subjects had low serum IgA concentrations. Low serum IgA levels were measured in 19.1% of patients currently on phenytoin therapy and in 11.9% of patients who had previously been treated with phenytoin, whereas only 3.8% of patients who had never been on phenytoin therapy had low serum IgA. In multivariate analysis low serum IgA concentrations were associated with phenytoin medication and female gender. No differences in serum IgG and IgM concentrations were observed between patients and control subjects. However, in patients with epilepsy, low serum IgG concentrations were associated with concomitant autoimmune diseases, and low IgM levels with older age at the onset of epilepsy, long duration of epilepsy, and autoimmune diseases. In conclusion, the prevalence of low serum IgA concentrations was increased in patients with epilepsy, but serum IgG and IgM concentrations were similar in patients with epilepsy and reference subjects. The low serum IgA concentrations were associated with phenytoin medication. In addition to current phenytoin medication, previous phenytoin therapy also was associated with low serum IgA concentrations. This implies that phenytoin medication may have permanent immunological effects in some patients.     

苯妥英钠和丙戊酸钠预防术后癫痫的对照研究

目的　对比苯妥英钠和丙戊酸钠预防术后癫痫的作用、毒副反应以及和血药浓度的关系。方法　采用随机前瞻对照性研究 ,选择幕上开颅手术病人 ,苯妥英纳组 72例 ,丙戊酸钠组 80例 ,术前术后分别规则服用苯妥英钠和丙戊酸钠 ,监测抗癫痫药物的血药浓度和术后癫痫及毒副反应发生情况。结果　两组共 15例术后发生早期癫痫 ,10例 (10 /15 )达到有效血浓度 ;其中 ,苯妥英钠组 6例 (8 3 % )发生早期癫痫 ,2例达到有效血浓度 ,丙戊酸钠组 9例 (11 3 % )发生早期癫痫 ,8例达到有效血浓度 ;远期癫痫发作 7例中丙戊酸钠组 5例 ,苯妥英钠组 2例。苯妥英钠组 11例 (15 3 % )及丙戊酸钠组2例 (2 5 % )出现了毒副反应。经χ2 检验 ,两组术后癫痫发生率无显著性差异 ,术后未发癫痫组和癫痫发作组间药物血浓度无显著性差异 (P >0 0 5 ) ,苯妥英钠组毒副反应发生率高于丙戊酸钠组。结论　苯妥英钠和丙戊酸钠预防控制术后癫痫无差别 ,苯妥英钠毒副反应较丙戊酸钠严重。     

CHANGES IN SERUM IMMUNOGLOBULIN LEVELS DURING PHENYTOIN TREATMENT of EPILEPSY

Immunoglobulin concentrations were determined by radial immunodiffusion in sera from 15 epileptic patients before and during phenytoin therapy. Three reaction patterns were recorded: Two patients developed IgA deficiency (<0.05 mg/ml) during the first 3–4 months of treatment. Both patients also had a decrease in serum IgG and IgM, but no significant fall or increase in serum IgE. the IgA deficiency state was apparently reversible, since normalization of serum levels occurred after withdrawal of phenytoin. Five patients developed a 35–80 per cent reduction in serum IgA. In these patients, the decline in serum levels of IgG and IgM was inconsistent. Eight patients showed no significant fluctuations in serum immunoglobulins during phenytoin treatment. When a fall in serum IgA occurred, it did not correspond to a fall in serum or in red cell folate. Mean serum IgG was lower (9.37 mg/ml) in epileptic patients who had taken phenytoin for < 1 year and had a low IgA, than in patients who had taken phenytoin for 10 years or more (11.50 mg/ml).     

Variability of phenytoin protein binding in epileptic patients

The variability of protein binding of phenytoin in epileptic patients was evaluated using a rapid ultrafiltration system. Thirty-one pairs of total and free (unbound) phenytoin plasma concentrations were reviewed. Filtered plasma for free phenytoin determination was obtained using an ultrafiltration membrane system. All samples were analyzed by an enzyme-multiplied immunoassay technique. A good correlation was obtained for total phenytoin concentration v free phenytoin concentration. Comparison of obtained and predicted free phenytoin values differed significantly. Of nine patients demonstrating toxic effects, six had total phenytoin concentrations within the accepted therapeutic range with free concentrations above the therapeutic range. The results of this study indicate a wide variation of phenytoin protein binding in chronic epileptic patients, implying that total phenytoin concentration must be interpreted cautiously, and use of free phenytoin concentration appears to be a more appropriate guide to therapy. The availability of a rapid method of ultrafiltration makes free phenytoin plasma levels readily available to the clinician.     

Effect of Cimetidine on Phenytoin Serum Levels

Cimetidine, 300 mg p.o. four times a day, was administered for 5 days to nine epileptics who were stabilized while receiving phenytoin. Five patients had statistically significant increases in phenytoin serum levels, including two who became clinically toxic. One patient had a statistically significant decrease in phenytoin serum concentration. A relationship was not found between cimetidine levels and change in phenytoin serum levels. Cimetidine can cause significant changes in phenytoin serum levels which may be manifested clinically.     

Incidence of seizures with phenytoin toxicity

Among 50 patients with phenytoin intoxication, 14 had seizures during the episode. Seizures in 9 of these 14 patients probably resulted from poor seizure control despite high phenytoin levels, but in 5 cases, attacks were attributed to phenytoin toxicity. The only factor that seemed to correlate with seizures was a serum phenytoin level over 30 micrograms/ml. No demographic, metabolic, neuropsychiatric, or therapeutic variables were predictive; nor were any other symptoms of toxicity particularly likely to be found in association with seizures. Seizures are an occasional manifestation of phenytoin toxicity, particularly when levels are high.     

Interference of oral phenytoin absorption by continuous nasogastric feedings

Inhibition of phenytoin absorption by continuous nasogastric tube feeding was studied in 20 neurosurgery patients and 5 normal subjects. Ten patients receiving phenytoin suspension 300 mg per day coadministered with continuous nasogastric feedings had a mean phenytoin serum concentration of 2.59 micrograms per milliliter. When the feedings were discontinued, the average concentration rose to 10.22 micrograms per milliliter in 7 days. In 10 other patients stabilized on phenytoin suspension 300 mg per day, the average serum concentration decreased from 9.80 microgram per milliliter to 2.72 microgram per milliliter in 7 days when continuous tube feedings were started. Five normal subjects received a single oral dose of phenytoin suspension alone and while drinking a nasogastric tube feeding preparation orally at a rate of 100 ml per hour; phenytoin serum levels decreased an average of 71.6% when the tube feeding was taken concurrently.     

Phenytoin dosage in ambulant epileptic patients.

Ambulant patients with recently diagnosed generalised or psychomotor seizure disorders or both were randomly assigned to two dosage regimens of phenytoin. Drug compliance was evaluated with subsequent blood phenytoin levels four to eight weeks after initial enrollment into the study. Although the two groups had similar mg-kg daily dosages of phenytoin, the mean blood levels were statistically different between the two groups, favoring the simplified dosage regimen. Once or twice a day dosage regimens of phenytoin had a beneficial effect on drug compliance when compared to more frequent regimens as measured by phenytoin blood levels.     

Characterization of glucose homeostasis and lipid profile in adult,seizure‐free,epileptic patients in Asian population

Background and purpose: The most common prescribed antiepileptic drugs (AEDs), phenytoin and valproate, are potent enzyme inducers and inhibitors of the cytochrome P450 system, which interfere with lipid profile and glucose homeostasis. Studies on this topic have suffered from inadequate assessment of confounders and have rarely included glucose homeostasis and lipid profile as well as both enzyme inducers and inhibitors in the same study. We sought to determine whether these drugs had an effect on lipid profile and glucose homeostasis in Thai epileptic patients. Methods: We recruited 98 patients with epilepsy (45 taking phenytoin, 27 taking valproate, and 26 not taking any AED). Fasting blood samples were obtained to measure serum lipid, and glucose homeostasis was evaluated via the oral glucose tolerance test. We calculated the homeostasis model assessment index for each patient. Results: Our study revealed that CYP450 was induced by AEDs, and that patients on phenytoin had an increased mean value of serum total cholesterol, serum total triglycerides, and serum LDL cholesterol when compared with patients with epilepsy taking valproate and those taking no AEDs. No statistical significant difference was observed between patients taking valproate and patients taking no AEDs. In addition, patients with epilepsy taking phenytoin had higher fasting plasma glucose levels at fasting state than both those taking valproate and those taking no AEDs. Thirty percent of the patients taking phenytoin exhibited insulin resistance. We have found a negative correlation between log insulin sensitivity and log TG, but not high‐density lipoprotein (HDL). Conclusion: CYP450‐induced phenytoin produces significant amelioration in several serologic markers of atherosclerosis. These findings suggest that phenytoin may substantially increase the risk of vascular events.     

Prophylactic effect of phenytoin in bipolar disorder: a controlled study

Objective:  Phenytoin is an effective anticonvulsant that has not previously been studied prophylactically in bipolar (BP) patients. Thus a study of phenytoin prophylaxis was undertaken and is herein reported.
Method:  Bipolar patients were studied who had at least one episode per year in the previous 2 years despite ongoing prophylaxis. Patients were stable for a mean of 4 months (range 1–13) before entering the study. Phenytoin or placebo was added to their current therapy in a double-blind cross-over design for 6 months in each phase. Thirty observation periods of 6 months each were studied for 23 patients.
Results:  Three patients had relapse on phenytoin and nine had relapse on placebo. There was a significant prophylactic effect of phenytoin in BP disorder [Cox's F -test for comparing survival in two groups: F ( 6 , 18 ) = 3.44, p = 0.02].
Conclusions:  This study suggests prophylactic effects of add-on phenytoin in BP illness. However, the number of patients was small and confirmation is necessary.