Roald E. Strandjord

Influence of carbamazepine on serum thyroxine and triiodothyronine in patients with epilepsy

Hypothyroidism induced by anti‐epileptic drug treatment gave rise to thyroid function test studies in patients treated with carbamazepine (CBZ) only.

Hypothyroidism induced by anti-epileptic therapy

Two patients on long‐term anti‐epileptic treatment, one with both phenytoin and carbamazepine, the other with carbamazepine, developed clinical hypothyroidism. Laboratory assays verified the diagnosis. Both patients became euthyroid and the thyroid hormone assays were normal after withdrawal of the drugs.

The effect of carbamazepine on serum immunoglobulin concentrations

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 < 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.

Serum concentrations of immunoglobulins in patients with epilepsy treated with carbamazepine

The concentrations of IgA, IgG and IgM were determined in sera of 16 patients, all of whom had partial epilepsy and had received CBZ as the only drug since the beginning of therapy. Fifty‐three healthy subjects served as controls. Serum concentrations of IgA and IgG were significantly higher in patients than in controls (IgA: P= 0.05; IgG: P= 0.01). The concentration of IgM was not significantly different from that of the controls (P= 0.1). The IgG serum levels in the controls were lower with increasing age. Furthermore, IgG serum levels were higher with increasing CBZ concentrations.

Clonazepam in the treatment of epileptic seizures.

Clonazepam (Ro 5‐4023) has been used in the treatment of epileptic seizures since December 1968. Fourty‐four hospitalized patients (20 girls, aged 6–15 years and 24 boys aged 3–25 years) with long‐lasting epilepsy of early onset were given the drug in addition to previous medication. At the date of assessment 30 patients were on clonazepam treatment. Seven of these patients had been treated for less than 1 year (a minimum of 3 months), in 18 patients the duration of treatment was from 1 to 3 years and in 5 patients more than 3 years (mean 22 months). In 11 patients with excellent clinical effect the duration of treatment was from 18 to 39 months (mean 28) and the dosage from 0.1 to 0.5 mg per kg body weight (mean 0.2). Lasting excellent or good seizure control was obtained in 20 of 44 patients in whom all other available anti‐epileptic drugs had failed. Clonazepam had effect in partial as well as in generalized seizures. Clonazepam was withdrawn in 14 patients; due to lack of clinical effect (3 patients), because absences were associated with loss of bladder control (2 patients), due to increased frequency of grand mal seizures (2 patients), to confusion, restlessness and anxiety (2 patients), and due to symptoms of intoxication in 5 patients, who received clonazepam (less than 0.065 mg per kg body weight) in addition to barbiturates (4 patients) and to carbamazepine and nitrazepam (1 patient). Individual dose adjustment were necessary. Some pharmacokinetic points of view are discussed. A method for routine determination of serum levels is desirable.

Respiratory Disease in Patients with Epilepsy on Single-Drug Therapy with Carbamazepine or Phenobarbital

IgA, IgG and IgM concentrations were determined in sera and nasal washings from 20 patients with epilepsy on single-drug treatment with carbamazepine, in 20 patients on single-drug treatment with phenobarbital and in 26 healthy subjects. There were no significant differences in immunoglobulin concentrations between the groups of patients and the controls. Symptoms of respiratory tract disease were recorded daily during 6 months both in patients and in controls. The mean number of days with symptoms from the respiratory tract was 38.5, 36.6 and 27.9 in the patients on carbamazepine, phenobarbital and the controls, respectively. The differences were not statistically significant. The individuals with the lowest immunoglobulin concentrations did not have more frequent symptoms of respiratory disease than those with higher immunoglobulin concentrations.

LACK OF EFFECT OF CLONAZEPAM, ON SERUM LEVELS OF DIPHENYLHYDANTOIN, PHENOBARBITAL AND CARBAMAZEPINE

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 66 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.

Anticonvulsant drug therapy in human pregnancy: Effects on serum concentrations of vitamin D metabolites in maternal and cord blood

Serum concentrations of the main vitamin D metabolites and of calcium, phosphate, and alkaline phosphatase were determined in each of the three trimesters of pregnancy and in simultaneously obtained maternal and cord blood at delivery in 22 epileptic women treated with diphenylhydantoin or carbamazepine alone or with a combination with one other drug. The results were compared with similarly obtained data from 22 normal pregnancies. Women in both groups received supplements of 400 IU vitamin D3 per day. All the women had 25-hydroxyvitamin D levels within the normal range for healthy adults (greater than 12 ng/ml) throughout pregnancy. The epileptic women had, however, significantly (p less than 0.05) lower median 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels and higher median 25,26-dihydroxyvitamin D values than the reference group. The 24,25-dihydroxyvitamin D concentrations did not differ significantly, but the median ratio of 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D was higher in the epileptic women at the end of pregnancy (p = 0.05). The respective differences in cord serum concentrations reflected those of the mothers at delivery. Serum calcium tended to be lower during epileptic pregnancy, but none were hypocalcemic. The alkaline phosphatase and phosphate values did not consistently differ from those of the reference women. The median alkaline phosphatase level of cord serum was slightly higher in the epileptic group, but the calcium and phosphate levels were similar to the reference values. The various biochemical parameters of the carbamazepine-treated women tended to be intermediate between those of the healthy and diphenylhydantoin-treated groups. Antiepileptic drug therapy appears to affect vitamin D metabolism and calcium homeostasis during pregnancy. The derangements may not be of major clinical significance, however, in vitamin D-supplemented and normally functioning women on long-term low-dose therapy.

Salivary immunoglobulin concentrations in patients with epilepsy treated with carbamazepine

Various anti‐epileptic drugs may affect the immune system. An IgA‐depressing effect of carbamazepine has been proposed, but only serum concentrations have been studied. IgA constitutes a small fraction of the serum immunoglobulins, while it is the predominating one in external secretions. In the present study the concentrations of IgA, IgG and IgM in unstimulated saliva were determined by single radial immunodiffusion in 34 patients with partial epilepsy, and being treated with carbamazepine alone. Median salivary IgA concentration in the patients was 208 × 10‐3 g/l, compared to 150 × 10‐3 g/l in 41 healthy controls. Salivary IgG and IgM concentrations were also somewhat higher in the patients than in the controls, while the albumin concentrations were similar in the two groups. However, the differences in the immunoglobulin concentrations between patients and controls were not significant at a 5 % level. There was no significant correlation between the concentrations of IgA in saliva and serum.

REQUIREMENT AND METABOLISM OF VITAMIN D IN PREGNANT EPILEPTIC WOMEN

Chronic anticonvulsant therapy has been associated with osteomalacia and rickets, and it has been suggested that drug induced hepatic degradation of vitamin D with subsequent vitamin D deficiency may be the pathogenetic factor (1). During pregnancy the need for intestinal absorption of calcium (Ca) and phosphorus ( P ) is increased to meet the requirements of the growing fetus. This is reflected in elevated serum concentratiods of 1,25-dihydroxyvitamin D (1,25(OH)2D), which is the main active vitamin D metabolite, and probably in increased requirements for vitamin D (2). The purpose of the present study was to compare the vitamin D requirement and vitamin D metabolism of pregnant women with and without epilepsy.