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Objective: Emerging evidence suggests that inflammatory cytokines are involved in pathophysiology of epilepsy. However, possible interaction between the cytokines and active epilepsy remains unclear. This study aimed to interictal and postictal plasma cytokines in active epilepsy patients., Materials and Methods: We enrolled 48 patients with active epilepsy and 30 healthy adults and measured postictal and interictal interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon gamma (IFN-γ), interleukin-10 (IL-10), and interleukin-17A (IL-17A) concentrations in peripheral blood by enzyme-linked immunosorbent assay (ELISA)., Results: We found postictal and interictal concentrations of IL-6, IL-17A, and IFN-γ were significantly elevated in epilepsy patients compared with healthy controls. There were no significant postictal and interictal alterations of IL-1β, IL-6, TNF-α, IFN-γ, IL-10, and IL-17A in patients with generalized seizures compared to those with partial seizures, in carbamazepine (CBZ)-treated patients compared to valproic acid (VPA)-treated patients or in temporal lobe epilepsy (TLE) patients compared to extra-temporal lobe epilepsy (eTLE) patients. Furthermore, multivariate linear regression analysis revealed that interictal IL-17A concentration positively correlated with National Hospital Seizure Severity Scale (NHS3) scores (B=0.092, P=.007) and seizure frequency (B=0.045, P=.000). Interictal IFN-γ concentration was also showed positively correlation with seizure frequency (B=0.019, P=.004)., Conclusions: Our data suggest that postictal and interictal various inflammatory cytokines are elevated in plasma of active epilepsy patients. Furthermore, interictal IL-17A and IFN-γ may predict seizure severity., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The objective of this study was to evaluate possible nonlinear lamotrigine (LTG) pharmacokinetics at elevated concentration. LTG is reported to have linear kinetics, so that elimination rate is linearly proportional to blood concentration and a change in dose is accompanied by a proportionate change in serum concentration. We encountered patients in whom LTG serum concentration increased dramatically in response to minor or no change in LTG dose. We studied this phenomenon in patients with LTG toxicity in one clinic., Materials and Methods: Using electronic medical records from 1997 to 2014, we identified patients who developed clinical LTG toxicity with LTG serum concentrations >20 mg/l, after tolerating lamotrigine at lower serum concentrations. We reviewed LTG dose change and other changes that preceded the episode of toxicity., Results: Twenty-two patients had at least one episode of LTG toxicity with levels higher than 20 mg/l (of 922 patients with available levels). The peak serum concentration varied from 21.1 to 40.3 mg/l (mean 28.7). The increase in level was explained in three patients (post-delivery in one, addition of valproate in two). In the 18 others, the increase was not explained or it was disproportionate to an increase in LTG dose., Conclusions: Spikes in LTG levels and associated clinical toxicity may occur unexpectedly, suggesting that elimination kinetics may be nonlinear in some individuals at serum concentrations in the upper range. Measurement and close monitoring of LTG levels is warranted for new symptoms that could be consistent with lamotrigine toxicity, particularly when the baseline serum concentration has been >10 mg/l., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To evaluate prospectively the influence of cyclic oral contraceptive (OC) use on lamotrigine (LTG) serum levels when used in combination therapy., Methods: Women with epilepsy using LTG in combination with valproate (VPA; n=7), carbamazepine (CBZ; n=3) or oxcarbazepine (OXC; n=1) were evaluated during two periods of 28 days cyclic OC use, monitoring antiepileptic drug (AED) levels every other day with the dried blood spot sampling method. Results were compared with women on LTG monotherapy and OCs (n=12). Pharmacokinetic analysis was performed using NONMEM software., Results: Mean study population value of LTG clearance estimated by the final model was 3.17 l/h. Introduction of covariates for comedication (VPA, CBZ, OXC and OC) significantly reduced the between-subject variability. A significant influence of OC comedication on LTG clearance was seen in both LTG monotherapy (clearance with OC 4.02±0.38 l/h, OC-free week 3.03±0.39 l/h) and in LTG-CBZ combination (clearance with OC 4.95±0.15 l/h, OC-free week 4.15±0.26 l/h). No influence of OC was found in LTG-VPA combination (clearance with OC 0.99±0.16 l/h, OC-free week 0.90±0.15 l/h)., Conclusions: Adding OCs to LTG monotherapy or the combination LTG-CBZ significantly increased the LTG clearance and thus reduced LTG serum levels. In the combination LTG-CBZ, OCs had a non-significant effect on CBZ clearance. No significant influence of cyclic OC use on LTG or VPA clearance was found when these AEDs were used in combination., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The study was designed to evaluate the efficacy, safety, and tolerability of the ketogenic diet (KD) whether classic 4:1 formula or the modified Atkins diet (MAD) in intractable childhood epilepsy., Patients and Methods: Anthropometric measurements and serum lipid profile were measured upon enrollment and after 3 and 6 months in 40 patients with symptomatic intractable epilepsy. Fifteen were given MAD diet, ten were kept on classic 4:1 ketogenic liquid formula, and the rest were allowed to eat as desired., Results: The liquid ketogenic formula group showed significantly higher body mass index compared with those who did not receive KD after 6 months. The lipid profile of KD patients was within normal limits for age and sex during the study period. The rate of change of frequency and severity of seizures showed best improvement in ketogenic liquid formula patients followed by the MAD group than the patients on anti-epileptic medications alone., Conclusion: The KD whether classic 4:1 or MAD is a tolerable, safe, and effective adjuvant therapy for intractable symptomatic childhood epilepsy with limited adverse effects on the growth parameters and accepted changes in the lipid profile. The liquid ketogenic formula patients showed better growth pattern and significantly more seizure control., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To estimate the association between the prevalence of epilepsy and potential risk factors in three Burkina Faso villages., Methods: Three villages were selected based on local reports of high numbers of epilepsy cases and pig-rearing practices. One person aged 7 or older was selected at random from all households of selected concessions for epilepsy screening and blood sampling. Epilepsy was confirmed by a physician using the ILAE definition. The cross-sectional associations between epilepsy and selected factors and seroresponse to the antigens of Taenia solium were estimated using a Bayesian hierarchical logistic regression. Prevalence odds ratios (POR) and their 95% Bayesian Credible Intervals (95% BCI) were estimated., Results: Of 888 individuals interviewed, 39 of 70 screened positive were confirmed to have epilepsy for a lifetime prevalence of 4.5% (95% CI: 3.3; 6.0). The prevalence of epilepsy was associated with a positive reaction to cysticercosis Ag-ELISA serology (POR = 3.1, 95% BCI = 1.0; 8.3), past pork consumption (POR = 9.7, 95% BCI = 2.5; 37.9), and being salaried or a trader compared to a farmer or housewife (POR = 2.9, 95% BCI = 1.2; 6.4)., Discussion: Several factors were associated with prevalent epilepsy, with Ag-ELISA suggesting the presence of neurocysticercosis. The association between epilepsy and some occupations may reflect differences in local attitudes toward epilepsy and should be further explored., (© 2012 John Wiley & Sons A/S.)

Objective: The aim of this study was to assess how the ketogenic diet influences the blood levels of antiepileptic drugs in the first month of treatment in a pediatric population with drug-resistant epilepsy., Methods: The plasma concentrations of antiepileptic drugs were investigated in an open study on 36 consecutive children and adolescents (20 males), aged between 6 months and 16 years (mean age 4.7 years), who were put on the ketogenic diet because of medically refractory epilepsy. The plasma levels of antiepileptic drugs were determined 30 days and immediately before the diet and on days 8, 15, 22 and 29 after the start of the diet. The daily dose of each drug was not changed during the first month of treatment, while the daily dose of benzodiazepines was reduced by up to 30% if excessive sedation or drowsiness occurred., Results: While plasma concentrations of phenobarbital did not change in the first month on the ketogenic diet (mean increase of 2.3 mg/l ± 1.0), valproic acid showed a slight but not significant decrease (mean decrease of 6.7 mg/l ± 3.2), 2 weeks after the start of the diet., Conclusions: Adjustments in the daily dose of either drug before the start of the diet do not however appear to be justified., (© 2010 John Wiley & Sons A/S.)

Objective: To explore the reproductive conditions in women with epilepsy., Methods: Eighty-eight women were included; 37.5% and 62.5% had generalized and partial epilepsies, respectively. Ovarian sonogram, reproductive hormone and lipid profiles were assessed., Results: Compared with the control group and in accordance with our laboratory reference values, irregular menses and polycystic ovaries (PCO(s)) were reported in 70.5% and 39.8% versus 21.7% and 16.7% of controls. Abnormalities in leutinizing hormone (LH), follicle-stimulating hormone (FSH), LH-to-FSH ratio, testosterone (T) and prolactin (PRL) were identified. High values of FSH, LH and FSH-to-LH ratio were common with carbamazepine while that of T and PRL were common in untreated patients and with valproate. Low levels of high-density lipoprotein cholesterol was identified in approximately 59% but neither associated with duration and type of antiepileptic drugs nor patients' age, hormonal profile or PCO(s). Significant correlation was identified between menatrual irregularities, T, PRL, hormonal, lipid profile alterations, PCO(s) and seizure frequency but neither with epilepsy type nor focus., Conclusion: This is the first study in our country that aimed at evaluation of reproductive conditions in women with epilepsy. This study indicates that reproductive dysfunction is common, hence, characterization of seizure-associated neuroendocrine adverse effects is important while managing women particularly during choice of antiepileptic medications as initial step and during patients' follow-up.

Objectives: The present study aimed to investigate the levels of the biochemical markers of apoptosis (soluble Fas and Bcl-2) in the sera of children and adolescents with idiopathic epilepsy., Materials and Methods: The study included 30 children and adolescents (mean age 8.03 +/- 4.49 years) with idiopathic epilepsy, 16 of them were newly diagnosed, and 15 clinically healthy control subjects. Of the included patients, 22 had focal seizures and eight had generalized seizures. In addition to laboratory and radiological investigations needed for diagnosis and follow-up, soluble Fas (s.Fas) and Bcl-2 were assayed in sera of patients and controls by enzyme-linked immunosorbent assay technique., Results: Serum levels of s.Fas and Bcl-2 were significantly higher in the patients group than in the control group; however, their levels were comparable in patients with different seizure types. Levels of s.Fas correlated positively with seizure severity and negatively with the duration from the last attack. Bcl-2 levels were positively correlated to each of the duration of epilepsy, the severity of seizures and its frequency. There was a significant positive correlation between serum levels of s.Fas and that of Bcl-2 and both were significantly increased in patients with uncontrolled epilepsy., Conclusion: The present data demonstrate that markers of apoptosis, both the proapoptotic Fas and the anti-apoptotic Bcl-2, were proportionately elevated in sera of patients with idiopathic epilepsy, and their levels were related to the seizure severity and frequency.

Objective: To assess whether serum S100B levels could reflect a glial response in patients with epilepsy secondary to neurocysticercosis (NCC) and with idiopathic epilepsy., Subjects and Methods: Serum S100B levels were measured using an immunoluminometric assay in 20 patients with focal epilepsy related to chronic NCC (NCC group), and 19 patients with focal epilepsy (EPI group), matched by epidemiological and clinical data. Epileptic patients were compared with 20 healthy controls (CON group) matched by age and sex., Results: No difference was observed in S100B levels among NCC, EPI and CON groups (P>0.39). Serum S100B levels were not affected by antiepileptic drugs, frequency and type of seizures. Preliminarily, significantly higher levels of S100B were observed in patients with bilateral electroencephalographic (EEG) findings than in patients with unilateral and normal EEG findings (P<0.05)., Conclusion: Serum S100B is normal in patients with focal epilepsy related or not to chronic NCC.

Oxcarbazepine (OCBZ) is a new antiepileptic drug with a chemical structure similar to carbamazepine. We investigated the daily fluctuations of 10-OH-carbazepine (monohydroxy derivative, MHD), the clinically relevant metabolite of OCBZ, in patients with or without comedication. Twenty-two profiles of (total) serum concentrations of MHD from 18 epileptic patients on a b.i.d. OCBZ regimen were determined at 8.00, 11.00, 14.00, 17.00, 20.00 h (and 22.00 h/23.00 h). A patient was only considered twice if his comedication or OCBZ dosage had been changed. The maximal MHD concentrations were about 33% +/- 14% higher than the minimal MHD concentrations during the day. The free MHD concentrations were determined in 17 profiles. The mean free fraction of MHD was 56.7% +/- 5.5%. In combination with valproic acid the free fraction (64.0% +/- 1.4%) was slightly, but significantly higher (p < 0.05) than in monotherapy (52.3% +/- 0.9%) or in combination (58.0% +/- 2.6%) with other antiepileptic drugs (2 x phenobarbital, 2 x methsuximide, 1 x sulthiame). Further studies are necessary to clarify if the observed fluctuations of MHD are of clinical importance.

The effects of Viloxazine (VLX, 100 mg b.i.d. for 10 days) on the steady-state plasma concentrations of Oxcarbazepine (OXC), its active metabolite 10, 11-dihydro-10-hydroxy-carbazepine (MHD) and the corresponding diol (DHD) were studied in a randomized, double-blind cross-over placebo-controlled trial in 6 epileptic patients stabilized on a fixed dosage of OXC. Administration of VLX resulted in an 11% increase in the plasma concentration of MHD (p = 0.003) associated with a 31% fall in DHD levels (p = 0.0001). Plasma concentrations of unchanged OXC were unaffected by VLX. No changes in seizure frequency nor signs of drug toxicity were observed during the study. Although VLX may inhibit the conversion of MHD to the inactive diol, the interaction is unlikely to be of clinical significance.

Increase in the red blood cell mean corpuscular volume (MCV), and mean corpuscular haemoglobin (MCH) values in patients receiving Valproate as mono or polytherapy was noted. To investigate this situation 41 epileptic patients were studied on Valproate alone (Group 1) and 20 patients on Valproate added to another antiepileptic drug (AED), (Group 4), and compared with 19 patients on carbamazepine (CBZ) (Group 2) and 12 patients on phenytoin (PHT), (Group 3). The results showed significant rise in MCV values in Groups 1 and 4. The peripheral blood smear and other tests including reticulocyte counts of the patients with abnormal values ruled out macrocytic anemias. We postulate a generalized effect which is the result of alteration in erythrocyte membrane phospholipids.

Efficacy and tolerability of the new antiepileptic drug oxcarbazepine, was evaluated in a retrospective multicentre study. The records of all 947 epilepsy patients treated with oxcarbazepine in the eight participating centres from 1981 through 1990 were examined. The median daily dose of oxcarbazepine was 30 mg/kg in children, 18 mg/kg in adults, and 15 mg/kg in elderly patients, given b.i.d. or t.i.d. The mean plasma levels of the main active metabolite of oxcarbazepine was 88, 79, and 68 mumol/l in children, adults, and elderly, respectively. In patients shifted to oxcarbazepine treatment, seizure frequency was unchanged in 51-66%, 32-48% had a decrease, and 1-10% an increase in seizure frequency, considering the individual seizure types separately. Adverse events were reported in one third of patients, most frequently affecting the CNS (dizziness: 6%; sedation: 6%; fatigue: 6%). Rash was reported in 6% of patients, half of these patients had previously had an allergic reaction to carbamazepine. Hyponatremia was found in about a quarter of the patients from whom data were available. No congenital malformations were seen in nine live-born, first trimester oxcarbazepine-exposed children.

Based on a case history of fetal haemorrhage due to maternal antiepileptic treatment and a review of 40 previously described similar cases, it is recommended that epileptic mothers receive vitamin K tablets throughout the month before delivery and intravenously during labour. It is further recommended that phytomenadione should be administered intravenously to the infant immediately after birth. Cord blood specimens should be submitted for immediate clotting studies and if diminished vitamin K-dependent factors are found, fresh frozen plasma should be given at a dose of 20 ml/kg over a period of 1-2 h. Alternatively, the drug treatment of women with epilepsy during pregnancy could be changed from liver enzyme inducing drugs to clonazepam, which is a benzodiazepine without liver enzyme-inducing properties. Further, no malformations have been reported in connection with this drug.

The effects of dextropropoxyphene on the steady-state kinetics of oxcarbazepine and its metabolites were investigated in eight patients with epilepsy or trigeminal neuralgia. One patient dropped out of the study, presumably due to side-effects of dextropropoxyphene. Dextropropoxyphene did not affect the plasma levels of the principal active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. Since dextropropoxyphene is known to increase the plasma levels of carbamazepine, leading to toxicity, the findings of this study suggest that oxcarbazepine is a useful alternative to carbamazepine when concomitant dextropropoxyphene therapy is required.

Serum lipids, lipoproteins and apolipoproteins A and B were measured in 101 epileptic patients receiving chronic treatment with valproic acid, carbamazepine or phenobarbital and in 75 age- and sex-matched control subjects. In relation to controls, subjects treated with valproic acid showed significantly lower values of total and LDL-cholesterol levels; subjects treated with carbamazepine showed significantly higher values of HDL-cholesterol and apolipoprotein A concentrations and subjects treated with phenobarbital showed significantly higher values of total cholesterol, HDL-cholesterol, apolipoprotein A and apolipoprotein B levels. The total cholesterol/HDL-cholesterol ratio was significantly lower in patients receiving valproic acid or carbamazepine but not in the phenobarbital-treated group. Changes in serum lipids profile did not correlate with drug plasma concentrations nor the duration of the treatment.

Taltrimide was compared with valproate and placebo in 17 patients with intractable epilepsy being on carbamazepine monotherapy. Taltrimide (400 mg/day), valproate (1000 mg/day) or placebo were added to the treatment for periods of 3 months using a randomized cross-over design. Serum carbamazepine concentrations remained within the therapeutic range throughout the trial. Thirteen patients completed the study. In partial epilepsy of 7 the seizure frequency was reduced by 27% during valproate (p less than 0.05), compared with placebo, while no improvement was found during taltrimide. In 6 with primary generalized epilepsy, the number of seizures was reduced by 49% during taltrimide and by 38% during valproate, but neither effect was significant, compared with placebo. Headache was reported by 3 patients while on taltrimide. One with hypersensitivity history developed petecchiae and nasal bleeding during taltrimide and, therefore, the treatment was stopped. The three other interruptions were independent of taltrimide. Thus, the only statistically significant effect in this study was that of valproate in partial epilepsy.

111 pregnancies of epileptic women on phenytoin therapy were observed in a prospective study. Maternal serum phenytoin concentrations were measured monthly or bi-weekly during pregnancy, labor and puerperium. The concentration decreased towards the end of pregnancy and was lowest at delivery. In 48% of the patients the drug dosage had to be increased to combat the increased seizure frequency.

Due to the metabolic changes induced, e.g. in the liver by anti-epileptic drugs, the significance of high serum triglyceride and cholesterol in epileptics was studied and the plasma HDL cholesterol level was compared in 190 epileptic patients with elevated or normal triglyceride and cholesterol, with the corresponding values in 43 healthy subjects. One-third of the epileptic patients showed elevated plasma HDL cholesterol levels. Female epileptics had higher plasma HDL cholesterol than the normolipidemic healthy subjects. Epileptics with elevated triglyceride or a combination of elevated triglyceride and cholesterol had a lower plasma HDL cholesterol level than normolipidemic patients with epilepsy. HDL cholesterol level in epileptics with high serum cholesterol did not diverge from the level in epileptics with normal serum triglyceride and cholesterol. The results show significant differences of plasma HDL cholesterol between epileptic patients and normolipidemic healthy controls on one hand, and between epileptics with altered and epileptics with normal serum lipid levels on the other. The findings suggest that the increase of plasma HDL cholesterol level in epileptics undergoing anticonvulsant treatment is influenced by endogenous triglyceride metabolism.

Serum lipids and the cholesterol concentration in the high density lipoprotein (HDL) fraction were measured in epileptic patients taking either carbamazepine or phenytoin as single drug treatment. There was a significant increase in HDL-cholesterol levels in patients taking both phenytoin and carbamazepine. Serum total-cholesterol concentrations in patients taking both drugs did not differ significantly from those of controls. The ratio of HDL-cholesterol/total cholesterol was increased in both drugs and the increase reached significance in patients taking phenytoin. There was a significant increase in serum triglycerides in females taking carbamazepine.

Ninety-three, previously untreated epileptics were subjected to clonazepam monotherapy. The plasma clonazepam concentrations were monitored to achieve optimal therapeutic effects of the drug. Within a mean duration of follow-up of 32 months, 57 (61.3%) of the 93 cases became seizure-free. The drug showed a high efficacy for complete seizure control of more than 80% for both simple partial seizures and primary generalized tonic clonic ones. The mean plasma level of clonazepam giving complete seizure control was 14.7 ng/ml (range: 3.0-34.6 ng/ml) in cases of generalized epilepsy, and 15.6 ng/ml (range: 4.5-42.3 ng/ml) in cases of partial epilepsy. There was a high correlation between the plasma level and the dose, but no correlation between the plasma level and the clinical effect of the drug. The variable therapeutic range and great interindividual differences in the optimal plasma clonazepam level imply that individually tailored regimens are necessary to achieve optimal therapeutic effects of the drug.

Studies investigating the influence of antiepileptic drugs on thyroid hormones usually have compared patients chronically treated with antiepileptic drugs to controls. To date, this type of designs has produced divergent results both with regard to individual drugs and individual thyroid hormones. The present study comprised 31 patients with newly diagnosed epilepsy, commencing treatment with either carbamazepine or valproate. T3, T4, FT4, FT3, rT3, TSH, T3 resin uptake and blood folic acid, were determined before and during antiepileptic monotherapy, thus making the patient his own control. During treatment with carbamazepine, a significant decrease in T4, FT4, FT3, rT3 and TBG was observed. Valproate caused a decrease in T4, FT4 and T3. Neither of the drugs caused any changes in blood folic acid concentrations or persistent increases in the TSH values. None of the patients developed overt symptoms of hypothyreoidism. Conceivable mechanisms underlying these hormonal changes are reviewed.

Thirty-one patients suffering from progressive myoclonus epilepsy, (also called Unverricht-Lundborg's disease) without Lafora bodies, were examined to check the findings reported in literature and to chart out the main abnormalities in routine laboratory findings. Many alterations could be pointed out, but a high proportion of them were due to factors which are secondary to the syndrome of progressive myoclonus epilepsy: continuous anticonvulsive medication; immobilization; frequent infections; and the patient's poor nutritional condition. The most remarkable finding, and the only one which supported the abnormality reported earlier, was the raised excretion of indican which could not be explained by fermentation in the bowels. The urinary 5-hydroxyindoleacetic acid excretion was a little low, but still within the normal range. The tryptophan and 5-hydroxytryptamine metabolism deserves further investigation in attempting to discover the aetiology of progressive myoclonus epilepsy.

Calcium metabolism was examined in 30 adult epileptic outpatients on carbamazepine monotherapy. The patients had a normal bone mass, evaluated both on the forearm (100 +/- 13 of normal) and on the total skeleton (102 +/- 15), and normal serum concentrations of 25OHD. The serum calcium was decreased (P less than 0.001) and the serum alkaline phosphatase increased (P less than 0.001). The clinical significance of our study is that monotherapy with carbamazepine does not have the side effects on bone metabolism known as "anticonvulsant osteomalacia". Our results further question the connection between liver enzyme induction and anticonvulsant osteomalacia, since carbamazepine possesses the same potency of liver enzyme induction as phenytoin. Further studies on epileptic outpatients will be necessary in order to elucidate the connection between treatment with anticonvulsant drugs and anticonvulsant osteomalacia.

Immunological effects of carbamazepine (CBZ) were examined by studying 10 previously untreated epileptic patients before and during CBZ therapy. The mean number of leukocytes were reduced from 7020/mm3 to 5500/mm3, whereas no significant changes in the proportion of active and total T lymphocytes, B lymphocytes, Fc gamma receptor- and C3b receptor-positive cells, and phagocytizing cells were observed in peripheral blood. Mononuclear blood cells were stimulated to the same extent before and during CBZ treatment by the mitogens PHA, ConA and PWM. Accordingly, the mild IgA and IgM reducing effect of CBZ previously reported was not paralleled by changes in the mononuclear blood cells as examined in this study.

The influence of clonazepam on steady-state serum levels of diphenylhydantoin, phenobarbital and carbamazepine was studied in 22 patients with epilepsy receiving one or two of these drugs. Clonazepam was given in slowly increasing doses for 2 weeks until a maximum dose of 4-6 mg per day was reached; thereafter the dose was kept constant. The serum levels of diphenylhydantoin, phenobarbital and carbamazepine were determined once a week for at least 6 weeks. During clonazepam medication in ordinary doses the serum levels of the drugs in question were unaltered. Thus, it is unlikely that the antiepileptic effect of clonazepam in these patients even partly may be due to increased serum levels of these other drugs mentioned.

Serum IgA, IgG and IgM concentrations were determined in 30 patients with partial epilepsy before and during carbamazepine therapy. None of them had received anti-epileptic drugs prior to the study. The IgA and IgM concentrations decreased significantly during the 1st month of treatment (P less than 0.0001). No further decrease was observed during the subsequent 3 months. 15 patients were followed for 8-30 months. The IgA concentrations remained low, while the IgM concentrations tended to increase. However, the IgM concentrations did not reach the levels which were found before carbamazepine was started. Carbamazepine had no influence on the mean IgG serum concentration. There was no relationship between the IgA and IgM concentrations in serum and the serum concentrations of carbamazepine.

Six menstrual cycles and three 1-month periods were studied in seven patients with epilepsy. The patients all had had anti-epileptic treatment for a long time. In each case, the dosages had been costant for at least 1 month prior to the start of the investigation. Blood samples were taken every second day. Phenytoin, phenobarbital, carbamazepine, estradiol and pregesterone were analyzed. The serum levels of the anti-epileptic drugs were correlated to the plasma hormone concentrations. No correlations were obtained between the plasma hormone concentrations and the serum levels of the anti-epileptic drugs. There is, therefore, no evidence that the relationship between the seizure frequency and plasma hormone concentrations, shown in a previous study (Bäckström 1976)) was related to a change in serum levels of the anti-epileptic drugs.

The possibility (based on the recognised existence of anticonvulsant osteomalacia), of an osteomalacic origin of a number of subjective symptoms in epileptics (back pain, tiredness, sleepiness, irritability, and giddiness) was tested during a controlled therapeutic trial in 226 outpatients. There was no correlation between subjective symptoms and objective pathological indices of osteomalacia, and group treated with vitamin D (2000 international units daily for 3 months) showed no amelioration of subjective symptoms above that seen in the placebo group. The findings do not support the view that all epileptic patients on anticonvulsant therapy should be treated prophylactically with vitamin D.

The serum concentrations of the vitamin D metabolites 25-hydroxyvitamin D (25OHD), 24,25-dihydroxyvitamin D (24,25(OH)2D), and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in 18 epileptic patients and 10 controls. The patients were divided according to the anti-convulsant treatment they had been receiving for at least 1 year: 9 patients had received phenytoin and 9 patients carbamazepine, as the sole anti-convulsant therapy. The serum 25OHD was decreased in the patients on phenytoin (P less than 0.01), whereas the other serum vitamin D metabolites were normal. Moreover, serum alkaline phosphatase was increased (P less than 0.001) and serum calcium was decreased (P less than 0.001) in this patient group. In the patient group treated with carbamazepine (a negligible, liver inductor), changes in serum 25OHD and serum alkaline phosphatase were less pronounced (P less than 0.05), but the same degree of hypocalcaemia (P less than 0.001) was present. Our data suggest that liver induction in epileptic patients on anti-convulsant drugs cannot explain the pathophysiology behind anti-convulsant osteomalacia.

Immunoglubulin 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 (less than 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 less than 1 year and had a low IgA, than in patients who had taken phenytoin for 10 years or more (11.50 mg/ml).

This study concerns the distribution of T-cell subsets as determined by specific monoclonal antibodies in 50 individuals with complex partial seizures (31) and primary generalized tonic-clonic seizures (19), and in 30 healthy controls. The epileptic group had significantly fewer circulating T4 "helper" lymphocytes and significantly greater number of T8 "suppressor" lymphocytes than the controls. The T4/T8 ratio was consistently significantly lower in the epileptic group. There was no relation between lymphocyte subsets or T4/T8 ratio and antiepileptic medication. The results suggest a derangement of cell-mediated immunity in individuals with epilepsy.

The sexual behaviour and hormonal profiles in 97 patients with chronic epilepsy from an epilepsy centre were studied. Sexual behaviour relating to numbers of sexual contacts, orgasms, spontaneous erections, and early morning erections, whether there was difficulty in obtaining or maintaining an erection, or in ejaculation, was assessed at interview. Hormonal profiles consisted of LH, FSH, prolactin, total testosterone, free testosterone, and SHBG. Information was obtained relating to type of seizure, seizure frequency, age of onset, likely pathology, IQ, and medication. The study showed that this patient group was profoundly hyposexual and had a high level of sexual dysfunction. Serum free testosterone levels were low, and it is suggested that the high level of sexual dysfunction and lack of sexual interest may well have a hormonal basis. The reasons for this are discussed.

Treatment of alcoholics with phenytoin and disulfiram (DI) simultaneously is complicated and inexpedient because of the marked drug interaction. The aim of this study was to investigate whether an interaction exists between DI and carbamazepine (CBZ). The serum levels of CBZ and the metabolite CBZ-10, 11-epoxide were measured by high-pressure liquid chromatography in seven out-patients with epilepsy, on monotherapy with CBZ, before and during two weeks administration of DI. Five patients completed the investigation. None were alcoholics. The changes in the serum levels were insignificant, i.e. without clinical important. Moreover, uncontrolled clinical experience has not indicated any interaction between DI and CBZ. Thus the influence of DI on the metabolism of CBZ is probably negligible. CBZ is suggested, therefore, when anticonvulsive therapy is needed by alcoholics in treatment with DI.

In a controlled therapeutic trial, serum calcium and serum alkaline phophatase levels were measured levels were measured during treatment with different doses of vitamin D2 in 45 epileptic inpatients. The results demonstrate that, in spite of the curative effect of vitamin D2 with regard to total body calcium, this vitamin has no effect on serum calcium or serum alkaline phosphatase in anticonvulsant osteomalacia.

Serum concentrations of vitamin D metabolites were measured in 30 epileptic outpatients on monotherapy with carbamazepine before and during treatment with either vitamin D2 or vitamin D3, 4000 IU per day for 24 weeks. Vitamin D2 treatment increased the serum concentration of 25OHD2, but a corresponding decrease in 25OHD3 resulted in an unchanged serum value of total 25OHD. Vitamin D3 treatment increased the serum concentration of 25OHD3. The resulting serum level of 25OHD was consequently twice the level of that in the D2-treated group. The serum concentrations of the dihydroxy metabolites showed a similar difference between the 2 treatment groups. We conclude that treatment with vitamins D2 and D3 in the same doses produces considerably different serum concentrations of vitamin D metabolites. If the present findings can be extrapolated to normal subjects, it is important to consider more carefully which D-vitamin should be used, both with regard to therapy and supplementation.