Chronic Anticonvulsant Therapy Research Articles

941 PREVALENCE OF VITAMIN K DEFICIENCY IN NEWBORN INFANTS: INFLUENCE OF PERINATAL RISK FACTORS

Measurement of noncarboxylated prothrombin (PIVKA-II assay) was used to study 559 infants for vitamin K (vit K) deficiency. This test, performed by immunoelectrophoresis of plasma before and after BaCO3 precipitation, is sensitive to 0.03 u/ml PIVKA-II, has an intra- and inter-test coefficient of variation of 3-5%, and is negative in liver disease. Catagories of infants studied and results are as follows. As part of an ongoing study of 1,000 cord bloods, 534 cords were assayed and 2.6% were PIVKA-II positive (0.03-0.15 u/ml). The PT of the PIVKA-II positive samples ranged from 11.5-23 seconds and correlated inversely with prothrombin activities of 10-55%. SGA infants were at increased risk for K deficiency (14%); however, other groups were not (preterm, post-term, infants with fetal distress, and infants of mothers with hypertension or third trimester infection), Interestingly, of 16 infants born to mothers on chronic anticonvulsant therapy, only one showed PIVKA-II. Eight breast-fed infants who were given neonatal vit K did not develop a deficiency by two months of age. A K deficient infant given 1 mg vit K and then fed entirely by parenteral nutrition without supplemental vit K showed absence of PIVKA-II for five weeks. In summary, 2.6% of all newborns may be vit K deficient at birth. While most K deficient infants were born of normal pregnancies and deliveries, SGA infants were more likely to be PIVKA positive. Vit K is stored in newborns to an appreciable degree.

Febrile seizures: Emergency department diagnosis and treatment

Febrile seizures are a common problem. Simple febrile seizures usually occur in otherwise normal children and are brief, generalized, and relatively benign. First febrile seizures should be evaluated by a physician to rule out serious underlying disease. A careful history and thorough physical exam are essential. Routine laboratory evaluation of simple febrile seizures is seldom helpful. Other laboratory tests to determine the source of fever or cause of seizures should be obtained when specifically indicated. Although the threshold for performing a lumbar puncture should be low, it is not mandatory to obtain one in every case of simple febrile seizures. Treatment of most simple febrile seizures consists of fever control and parental counseling. Chronic anticonvulsant therapy should be limited to special circumstances.

Effect of serum albumin on free fractions of phenobarbital and valproic acid in patients with convulsive seizures

The free fractions of phenobarbital and valproic acid were assayed with Free-Level system I (Syva) and by an enzymatic immunoassay technique (EMIT) in 186 patients under chronic anti-convulsant therapy at precisely 2 hrs after they had taken the medicine at breakfast. The free fractions of PB ranged from 49 to 53% in monopharmacy and from 50 to 55% in polypharmacy. Those of VPA ranged from 10 to 12% in monopharmacy and from 8 to 11% in polypharmacy. The regression lines of the free fractions in PB monopharmacy and PB polypharmacy against serum albumin concentration indicated a negative correlation. There was no difference between the free fractions in PB monopharmacy and polypharmacy at the same albumin concentration. The regression lines of the free fractions in VPA monopharmacy and polypharmacy against serum albumin concentration indicated a negative correlation. The free fractions of VPA did not vary under a total VPA concentration of 80 micrograms/ml, while those of VPA above a total VPA concentration of 90 micrograms/ml increased with the total concentration, in the monopharmacy groups. On the other hand, free fractions of VPA in the polypharmacy groups did not vary with the total VPA concentration.

Effect of viloxazine on serum carbamazepine levels in epileptic patients.

The present study describes the interaction between carbamazepine (CBZ) and viloxazine, a recently synthesized antidepressant agent. Seven epileptic patients on chronic anticonvulsant therapy showed a significant (p less than 0.005) increase in steady-state serum CBZ levels (from 8.1 +/- 2.5 SD to 12.1 +/- 2.5 SD micrograms/ml) when viloxazine (300 mg/day) was added to the therapy. The effect was associated with the appearance of mild CBZ intoxication. The symptoms of this intoxication (i.e., dizziness, ataxia, fatigue, drowsiness) disappeared rapidly, and serum CBZ levels decreased to the basal values, when viloxazine administration was stopped.

Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment.

Alterations in vitamin D metabolism are generally thought to account for the hypocalcemia and osteopenia caused by long term treatment with anticonvulsant drugs. Regional variation in the incidence and severity of anticonvulsant drug-induced bone disease has been attributed to differences in sunlight exposure, with most reports coming from areas with limited sunshine or from institutionalized patients. Serum ionized calcium levels in 109 ambulatory adult epileptic outpatients receiving chronic anticonvulsant drug therapy in Georgia were decreased [4.73 +/- 0.02 (+/-SE) vs. 4.97 +/- 0.01 mg/dl; P less than 0.001). Immunoreactive PTH concentrations were increased (5.5 +/- 0.4 vs. 4.0 +/- 0.3 microliterEq /ml; P less than 0.005), while bone mineral content was reduced, averaging only 88.8% of the predicted normal values. Hypocalcemia and osteopenia occurred in spite of normal mean levels of serum 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D. The indirect relationship between serum concentrations of antiepileptic drugs and the serum ionized calcium level, and the lack of correlation with vitamin D metabolite levels suggested that hypocalcemia was independent of the effect of the drugs on vitamin D metabolism. Bone biopsies revealed increased osteoid but normal calcification front formation, accelerated mineralization rate, and decreased mineralization lag time indicative of increased skeletal turnover, rather than osteomalacia.

Persistence of Diminished Bone Mineral Content Following Renal Transplantation in Childhood

Bone mineral content (BMC) was measured in the nondominant arm of 18 children (aged 3 7/12 to 17 1/2 years) for a total 783 months after renal transplantation. Using photon absorptiometry, 89 measurements were made; 17 of the 18 patients had a functioning graft and one patient died. Significant demineralization, a BMC greater than -2 SD below appropriate control volumes, was found in 11 of 18 patients (62%) and 55 of 89 measurements (61%). Bone loss was progressive; among the 16 patients followed for more than 6 months, ten showed a decline of more than 0.5 SD in BMC, five had no change, and only one showed improvement. No relationship was found between BMC and the use of furosemide, type of transplant (15 living, seven cadaver), prior renal disease (six with glomerulonephritis, 11 tubulointerstitial), need for a second graft (five patients), chronic anticonvulsant therapy, or serum calcium and phosphate values. BMC was slightly correlated (P less than .05) with alkaline phosphatase values. BMC was more strongly correlated with serum creatinine (y = -0.48x + 1.25, r = -.042, P less than .001) and prednisone dose (mg/kg/d) (y = -0.65x + 0.481, r = -.543, P less than .001) in an inverse relationship. Patients whose serum creatinine value was less than 1 mg/dL had a BMC of -0.71 +/- 0.34 SD; those with serum creatinine value greater than 2 mg/dL had BMC of -3.32 +/- 0.31 SD, different at P less than .001. Patients receiving daily prednisone therapy had a significantly lower BMC than those receiving alternate-day therapy (-3.11 +/- 1.23 SD v -1.72 +/- 1.29 SD, P less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in circulating androgens during short term carbamazepine therapy.

Serum concentrations of testosterone, androstenedione, dehydroepiandrosterone sulphate (DHAS), sex hormone binding globulin (SHBG) and luteinising hormone (LH) were measured before, during and after 21 days treatment with carbamazepine (CBZ)400 mg daily in six healthy male subjects. Induction of hepatic microsomal enzyme activity was confirmed by an increase in antipyrine clearance (P less than 0.02) and a fall in circulating CBZ concentrations from the seventh to the fourteenth CBZ dose (P less than 0.05). Within 7 days of starting CBZ there was a rise in SHBG (P less than 0.05) and a fall in testosterone, free testosterone fraction, DHAS and androstenedione (P less than 0.05). Testosterone, free testosterone fraction and androstenedione levels rose towards baseline by the end of the treatment period while DHAS concentration remained low (P less than 0.05). The rise in SHBG and increased androgen catabolism is most likely to be secondary to induction of hepatic monooxygenase activity by CBZ. These changes may be implicated in the production of sexual dysfunction encountered in some epileptic patients on chronic anticonvulsant therapy.

Effects of phenobarbitone and phenytoin on folate catabolism in the rat

The effects of phenobarbitone and phenytoin on the catabolism of oral [2- 14C] and [3′,5′,7,9- 3H] folic acid were investigated. Normal rats were found to excrete an excess of 3H-labelled compounds into the urine and 14C-labelled compounds into the faeces. Phenytoin abolished this urinary 3H imbalance and also delayed and prolonged the overall excretion of radioactive material. Phenobarbitone appeared to increase the amounts of urinary scission products in the first 24 hr but over the 0–72 hr period both anticonvulsants decreased folate polyglutamate catabolism. As the anticonvulsants used in these experiments decreased folate catabolism in the rat it is unlikely that the megaloblastic anaemia caused by chronic anticonvulsant therapy is due to induction of the enzymes responsible for folate breakdown in vivo.

The effect of chronic anticonvulsant therapy on serum lipids and lipoproteins in epileptic children.

We measured serum lipids and lipoproteins in 33 epileptic children who were treated with phenobarbital, valproate, and carbamazepine. High-density lipoprotein cholesterol (HDL-c) was significantly higher in the epileptic children than in two control groups: healthy nonepileptic children, and epileptic children before starting anticonvulsant therapy. Our findings indicate that anticonvulsant drugs should be added to the list of substances that affect serum HDL-c.

Serum dihydroxyvitamin d metabolite concentrations in patients on chronic anticonvulsant drug therapy: Response to pharmacologic doses of vitamin D 2

We examined the effects of chronic anticonvulsant drug administration on the serum concentrations of dihydroxy-vitamin D metabolites and the response of these metabolite levels to short-term treatment with pharmacologic doses of vitamin D 2. Twelve patients maintained on chronic combined diphenylhydantoin and phenobarbital therapy were studied before and after the administration of vitamin D 2, 75,000 units/week for 6 weeks. Prior to vitamin D 2 administration, the patient group demonstrated decreased serum calcium ( P < 0.01) and increased serum iPTH ( P < 0.02) concentrations relative to 18 matched controls. Serum 250HD and 24,25(OH) 2D concentrations in the patient group were reduced by 38% and 75% ( P < 0.001), while serum 1,25(OH) 2D concentration was increased by 27% ( P < 0.05) relative to control values. After vitamin D administration serum calcium and iPTH concentrations in the patient group were restored to values that were not significantly different from control levels. Serum 250HD and 24,25(OH) 2D concentrations were increased by 4.6-and 6.3-fold, respectively, to supranormal levels. Serum 1,25(OH) 2D concentration exhibited an unexpected further 30% increase over pretreatment values, resulting in a return of the serum 1,25(OH) 2D/24,25(OH) 2D concentration ratio to a normal value. These data indicate that in patients treated chronically with anticonvulsant drugs, serum 250HD concentration responds appropriately to vitamin D2 administration, but regulation of renal dihydroxy metabolite formation may be altered.

OSTEON CROSS‐SECTIONAL SIZE IN THE ILIAC CREST

Cross-sectional osteon size was measured in undecalcified stained sections of iliac crest bone specimens from normal individuals (n = 68) and from patients with spinal osteoporosis (n = 27), primary hyperparathyroidism (n = 23), epilepsia (receiving chronic anti-convulsant therapy) (n = 11), acromegaly (n = 18), and hypothyroidism (n = 12). In each individual the shortest osteon diameter (D) and the corresponding Haversian canal diameter (d) were measured in a minimum of 20 completed secondary osteons by means of a micrometer eyepiece. Among normal males the areas of bone resorbed and formed increased with age (p less than 0.01), owing to an increase in the thickness of bone resorbed (p less than 0.01) and an unchanged thickness of bone formed. Among the females, both the areas of bone resorbed and formed decreased with age (p less than 0.05), owing to a reduction in the thickness of bone resorbed (p less than 0.05) as well as formed (p less than 0.001). Resorbed and formed areas were reduced in the epileptic (p less than 0.01) and acromegalic (p less than 0.01) groups but increased in the hypothyroid group (p less than 0.01) compared to sex- and age-matched controls. Neither the osteoporotic nor the hyperparathyroid group showed any alterations in osteon size. The Haversian canal diameter was slightly increased in the epileptic group but normal in the other patient groups. The observed changes reflect variations in the amount of work performed by osteoclasts and osteoblasts during bone remodelling and may be explained by variations in cellular activity and bone turn-over rates.

Pharmacokinetics of diazepam in epileptic patients and normal volunteers following intravenous administration.

1 The pharmacokinetics of diazepam following intravenous administration have been investigated in six normal volunteers and nine epileptic patients receiving chronic antiepileptic drug therapy. 2 After intravenous administration, serum diazepam levels declined biexponentially in all subjects. The elimination half-life was significantly shorter and the plasma clearance significantly higher in the patients than in the normal volunteers. 3 Serum N-desmethyldiazepam levels were higher and the time to peak serum concentration was earlier in the epileptic patients than in the controls. 4 It is suggested that the metabolism of diazepam is induced in patients treated with enzyme inducing antiepileptic drugs, although a protein binding interaction between valproic acid and diazepam may contribute to the higher plasma clearance in the epileptic patients taking sodium valproate.

Effect of anticonvulsant drugs on the rate of folate catabolism in mice.

An increase in folate catabolism has been suggested as the cause of the folate deficiency observed in many clinical conditions, including chronic anticonvulsant therapy. Previous studies have shown that the radioactive catabolites, excreted after an equilibration period of 3 d, consisted exclusively of folates that had been cleaved to produce pteridines and p-aminobenzoylglutamate, most of which was excreted as acetamidobenzoylglutamate. We have developed an experimental animal model using mice to determine the rate of catabolism of [3H]pteroylglutamate (folic acid) by the quantitative estimation of [3H]p-aminobenzoylglutamate and [3H]acetamidobenzoylglutamate in urine. Administration of diphenylhydantoin at three different doses (0.5, 20, and 50 mg/kg) significantly increased the rate of catabolism as measured by an increase in both the mean daily excretion and the cumulative excretion of these catabolites. Administration of intramuscular phenobarbitone on the other hand, did not affect the rate of catabolism, when compared with controls.

Decreased serum 24,25-dihydroxy vitamin D concentrations in children receiving chronic anticonvulsant therapy.

Serum 24,25-dihydroxy vitamin D (24,25(OH)2D) and 25-hydroxy vitamin D (25-OHD) concentrations and the ratio between the two were measured in 31 Israeli children and adolescents receiving long-term treatment with phenobarbitone or phenytoin and in controls. 24,25 (OH)2D concentrations were significantly depressed in the patients, although the 25-OHD concentrations were similar to those in the healthy controls. In four patients with radiological evidence of osteopenia very low serum 24,25(OH)2D concentrations and serum 24,25(OH)2D: 25-OHD ratios were recorded. The findings suggest that 24,25(OH)2D deficiency may play an important part in the pathogenesis of osteomalacia in patients treated with anticonvulsant drugs and provide further indirect evidence that 24,25(OH)2D is important for normal bone structure.

Antiepileptic Drugs and Vitamin D Supplementation

The incidence of biochemical signs of vitamin D deficiency and the effects of vitamin D supplementation were investigated in 83 children and 95 adults on chronic antiepileptic therapy and 40 mentally retarded controls living under comparable conditions. Low 25-hydroxyvitamin D and serum calcium, and elevated immunoreactive parathyroid hormone and alkaline phosphatase was a common finding in all groups, but in patients on antiepileptic drugs, signs of vitamin D deficiency were recorded more frequently. Supplementation of 125 microgram or 250 microgram vitamin D3 per week for 9 months normalized the laboratory findings in most patients; the effect of 37.5 microgram/week only slightly exceeded the influences of season observed in the controls and in epileptic patients without vitamin D. It is suggested that a dose between 37.5 and 125 microgram vitamin D3/week might be most suitable to avoid biochemical signs of vitamin D deficiency in children and adults on antiepileptic drugs.

The frequency of bone abnormality in patients on anticonvulsant therapy

Biochemical and bone morphometric measurements were evaluated in 12 patients who were on long-term anticonvulsant therapy with barbiturates. Half of the patients had no symptomatic bone disease, and half presented with bone disease and pain. Serum biochemical values were normal except for a few patients who had an elevated serum level of parathyroid hormone; the concentration of serum 25-hydroxy vitamin D was decreased in the majority of patients in whom it was measured. Bone absorptiometric values were normal but proved to be misleading: the Singh Index and videodensitometric measurements indicated that bone mass was below normal in all patients. Bone morphometric data indicated that bone resorption was 3 times greater than normal, and there was no evidence of osteomalacia. Vitamin D and possibly calcium have been suggested as potentially useful agents in the treatment of the bone disease associated with chronic anticonvulsant therapy.

Rational management of alcohol withdrawal seizures.

Phenytoin has traditionally been used for both prophylaxis and acute treatment of alcohol withdrawal seizures. With the exception of a well defined subgroup of withdrawing patients, this may not be appropriate. Chronic anticonvulsant therapy is not indicated without evidence of another underlying seizure diathesis.

Interaction of Diphenylhydantoin (Phenytoin) and Phenobarbital with Hormonal Mediation of Fetal Rat Bone Resorption In Vitro

Chronic administration of high doses of anticonvulsant drugs frequently produces classic osteomalacia with bone histologic changes characteristic of increased parathyroid hormone (PTH) effect in man. However, several reports have documented defects in calcified tissue metabolism suggestive of an end-organ resistance to PTH after chronic anticonvulsant drug therapy. To examine the direct action of anticonvulsant drugs on bone resorption, we investigated the effects of diphenylhydantoin (phenytoin) (DPH) (100-200 mug/ml) and phenobarbital (10-400 mug/ml) on basal and hormonally mediated resorption 5-day cultures of fetal rat forelimb rudiments. In this system both drugs significantly inhibited basal and PTH-stimulated (45)Ca and [(3)H]hydroxyproline release, as well as 1,25-dihydroxyvitamin D(3)-stimulated (45)Ca release. The effects of DPH and phenobarbital were additive, with DPH exhibiting a several-fold more potent inhibitory effect than phenobarbital. Whereas DPH exhibited a striking synergism with the inhibitory effects of human calcitonin (HCT) on PTH-induced resorption, the effect of phenobarbital was merely additive to that of HCT. PTH and PTH plus HCT-induced increases in bone cyclic AMP (cAMP) content were significantly inhibited by DPH but not by phenobarbital. However, in contrast to effects on (45)Ca release, DPH inhibition of cAMP generation was not accentuated in the presence of HCT. It is concluded that: (a) both DPH and phenobarbital can directly inhibit basal and hormonally stimulated bone resorption, with DPH being much more potent in this regard; (b) DPH appears to inhibit bone resorption via a cAMP-independent mechanism and has an additional suppressive effect on PTH-induced cAMP generation; and (c) the synergistic interaction of DPH and HCT in inhibiting (45)Ca release occurs at a site independent of cAMP generation.

The effects of diphenylhydantoin and Vitamin D deficiency on developing teeth in the rat

The effects of short-term (21 days) and long-term (116 days) treatment with oral diphenylhydantoin (DPH, 6 g/kg diet) on the development of rat teeth was investigated. Long-term DPH reduced the size of the incisors and of all the molars except the upper first. There was also a reduction in tooth weight and both changes were shown to be independent of body weight. Short-term DPH reduced the size of the incisors and upper third and second molars only. The relationship of these lesions to the shortened tooth roots found in epileptics on chronic anticonvulsant therapy and the stunted root development seen in hypoparathyroidism is discussed. It is suggested that DPH may induce a state of “pseudohypoparathyroidism” by inhibiting the action of parathyroid hormone on bone and tooth. This complication would appear to be additional to the so-called “anticonvulsant-induced osteomalacia”.

Multiple Vitamin Deficiencies in Association With Chronic Anticonvulsant Therapy

Tolman et al. (Pediatrics 56:45, July 1975) and Crosley et al. (Pediatrics 56:52, July 1975) described rickets and osteomalacia complicating chronic anticonvulsant therapy. We recently cared for a 28-month-old black girl who not only developed the physical and roentgenographic stigmata of rickets while receiving long-term anticonvulsants, but who also demonstrated clinical evidence of cardiac beriberi and subclinical ascorbic acid deficiency. The patient was receiving acceptable doses of phenobarbital, Dilantin, and Mysoline for infantile myoclonic seizures, was allegedly fed a full diet in the nursing home in which she was cared for, but did not receive vitamin supplementation.