Valproate Monotherapy Research Articles

Effect of chronic consumption of sodium valproate and melatonin on seizure activity in Krushinskii-Molodkina rats

Experiments on Krushinskii-Molodkina rats with hereditary predisposition to audiogenic seizures showed that chronic consumption of aqueous solution of melatonin (50 mg/liter) had no effect on the pattern of seizures induced by 20-fold acoustic stimulation. Sodium valproate (50 mg/liter) insignificantly decreased the seizure response. Combined treatment with sodium valproate and melatonin produced a potent anticonvulsant effect, i.e. increased the latency and decreased the severity of audiogenic seizures. However, myoclonus in animals receiving combined treatment with these drugs developed much more rapidly compared to rats receiving melatonin or sodium valproate monotherapy.

The Evaluation of Thyroid Functions, Thyroid Antibodies, and Thyroid Volumes in Children with Epilepsy during Short‐Term Administration of Oxcarbazepine and Valproate

The aim of this study was to evaluate the effects of short-term oxcarbazepine (OXC) and valproate (VPA) monotherapy on thyroid functions in children. Fifty-five newly diagnosed epileptic children with normal thyroid functions (confirmed with the thyrotropin releasing hormone stimulation test) participated in this study. VPA treatment was started in 30 patients and OXC in 25 patients. Serum thyroxine (T(4)), free thyroxine (fT(4)), triiodothyronine (T(3)), free triiodothyronine (fT(3)), reverse T3 (rT(3)), thyroid peroxidase antibodies (TPO-ab), and urine iodine levels were evaluated at baseline and at the third and sixth months of therapy. In the OXC group, serum T(4), fT(4), T(3), fT(3), and rT(3) levels were found to be decreased at the third and sixth months, the differences were significant compared to the baseline values except for fT(3) levels at the third month and fT(4) and rT(3) levels at the sixth month (p < 0.05). At the sixth month, serum T(4) level dropped below the normal reference value in 8 (32%), fT(4) in 5 (20%), T(3) in 4 (16%), and fT(3) in 3 (12%) patients. In the VPA group, mean T(4), fT(4), T(3), fT(3), and rT(3) levels at 3 and 6 months remained similar compared to the baseline values (p > 0.05). Mean serum thyroid stimulating hormone levels increased significantly at the sixth month compared to the baseline values in the VPA group (p < 0.05) while it remained unchanged in the OXC group (p > 0.05). There was no effect of either drug on urinary iodine excretion and serum TPO-ab levels remained in normal ranges throughout the study. In this prospective study, it is documented that children under short-term OXC or VPA therapy showed altered thyroid functions similar to the changes observed after long-term treatment. Although, the clinical significance of these results need to be evaluated with future studies, this observation of altered thyroid functions points out that thyroid functions may need to be monitored closely in children receiving antiepileptic treatment, even in the short-time interval.

Cingulate gyrus volumetry in drug free bipolar patients and patients treated with valproate or valproate and quetiapine

In patients with bipolar disorder, recent brain imaging studies have reported cingulate cortex volume change. We performed a volumetric magnetic resonance imaging (MRI) study to assess the subregions of the cingulate gyrus; left anterior cingulate (LAC), left posterior cingulate (LPC), right anterior cingulate (RAC), and right posterior cingulate (RPC). Our sample consisted of bipolar patients that are either unmedicated ( n = 10), on valproate monotherapy ( n = 10) or on valproate plus quetiapine ( n = 10) versus healthy comparisons ( n = 10). Thirty right-handed bipolar disordered patients were recruited. Of them, 10 were first-applying patients who never had taken any drug for this condition (medication-naive group), 10 were on valproate treatment (valproate group) and 10 were on valproate plus quetiapine treatment (valproate plus quetiapine group). Cingulate gyrus volumes included both cortex and white matter. Drug-free patients had significantly smaller LAC and LPC volumes compared with valproate and valproate plus quetiapine groups and healthy controls. In addition, in post hoc comparisons, a trend toward significant difference was found between valproate plus quetiapine group and valproate group in regard to only LAC. Our findings suggest that valproate and quetiapine may have neuroprotective effects.

Effect of sodium valproate monotherapy on serum uric acid concentrations in ambulatory epileptic children: A prospective long-term study

Purpose Hyperuricemia has been shown to be related to cardiovascular morbidity and mortality. There is controversial data about the effect of sodium valproate (VPA) monotherapy on serum uric acid concentrations. The purpose of this study was to investigate by a long-term, prospective method, whether treatment with VPA monotherapy may alter serum uric acid concentrations and liver function tests in ambulatory epileptic children. Material and methods Serum uric acid concentrations were determined in 28 ambulatory epileptic children before and at 6, 12 and 24 months of VPA monotherapy. Serum concentrations of biochemical markers of liver and renal function, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase ( γ-GT) and creatinine (Cr) were also measured before and at 6, 12 and 24 months of VPA monotherapy. Serum VPA concentrations remained within the therapeutic range (50–100 mg/L) during the period of study. Results No statistically significant changes in serum uric acid concentrations were found at 6, 12 or 24 months of treatment. Serum ALT concentrations were significantly increased at 6 and 12 months of treatment, AST concentrations at 6 and 12 months of treatment and LDH concentrations at 12 months of treatment. Conclusions VPA monotherapy does not have a significant effect on serum uric acid concentrations in ambulatory epileptic children. Further studies are needed to definitively address whether it would be useful for physicians to routinely check for elevated serum uric acid levels in children treated with VPA.

Early effect of sodium valproate and carbamazepine monotherapy on homocysteine metabolism in children with epilepsy

Plasma total homocysteine (p-tHcy), serum folate (s-F), serum vitamin B-12 (s-B12) and plasma pyridoxal-5′-phosphate (p-PLP) were measured in epileptic children before and after a 20-week period of sodium valproate (group A, n = 32) and carbamazepine (group B, n = 20) monotherapy. P-tHcy significantly increased in both groups, s-F and s-B12 significantly increased in group A, while s-F and p-PLP significantly decreased in group B. Our study showed an early effect of antiepileptic drug treatment on homocysteine metabolism.

Evaluation of the Influence of Antiepileptic Therapy on Antioxidant Enzyme Activity and Lipid Peroxidation in Erythrocytes of Children With Epilepsy

The aim of this study was to evaluate the influence of antiepileptic therapy on antioxidant enzyme activity and lipid peroxidation in the erythrocytes of children with epilepsy. For this purpose, the activity of superoxide dismutase, glutathione peroxidase, and glutathione reductase and the malondialdehyde concentration in 61 healthy children and 90 children with epilepsy were measured. The activities of all of these enzymes were insignificantly higher, whereas the malondialdehyde concentration was significantly lower in the patients treated with carbamazepine monotherapy. In patients treated with valproate monotherapy, the activities of all enzymes were insignificantly lower, whereas the malondialdehyde concentration was insignificantly higher. In patients treated with polytherapy, the activity of superoxide dismutase was insignificantly lower, whereas the activity of glutathione peroxidase and glutathione reductase was insignificantly higher and the malondialdehyde concentration was lower. There were differences in glutathione reductase activity between the valproate monotherapy group and both the carbamazepine monotherapy and polytherapy groups and in malondialdehyde concentrations between the carbamazepine and valproate groups. The results indicate that the oxidant-antioxidant balance in children with epilepsy is modified by antiepileptic therapy.

Evaluation of the Influence of Antiepileptic Therapy on Antioxidant Enzyme Activity and Lipid Peroxidation in Erythrocytes of Children With Epilepsy

The aim of this study was to evaluate the influence of antiepileptic therapy on antioxidant enzyme activity and lipid peroxidation in the erythrocytes of children with epilepsy. For this purpose, the activity of superoxide dismutase, glutathione peroxidase, and glutathione reductase and the malondialdehyde concentration in 61 healthy children and 90 children with epilepsy were measured. The activities of all of these enzymes were insignificantly higher, whereas the malondialdehyde concentration was significantly lower in the patients treated with carbamazepine monotherapy. In patients treated with valproate monotherapy, the activities of all enzymes were insignificantly lower, whereas the malondialdehyde concentration was insignificantly higher. In patients treated with polytherapy, the activity of superoxide dismutase was insignificantly lower, whereas the activity of glutathione peroxidase and glutathione reductase was insignificantly higher and the malondialdehyde concentration was lower. There were differences in glutathione reductase activity between the valproate monotherapy group and both the carbamazepine monotherapy and polytherapy groups and in malondialdehyde concentrations between the carbamazepine and valproate groups. The results indicate that the oxidant-antioxidant balance in children with epilepsy is modified by antiepileptic therapy. (J Child Neurol 2006;21:558–562; DOI 10.2310/7010.2006.00115).

Early and persistent increase in serum lipoprotein (a) concentrations in epileptic children treated with carbamazepine and sodium valproate monotherapy

Purpose The aim of this study was to investigate by a prospective, self-controlled method, whether treatment with carbamazepine (CBZ) and sodium valproate (VPA) monotherapy may alter serum lipoprotein (a) [Lp(a)] concentrations in epileptic children. Methods Serum Lp(a) concentrations have been determined in 18 epileptic children before and at 6, 12 and 24 months of treatment with CBZ monotherapy and in 30 epileptic children before and at 6, 12 and 24 months of treatment with VPA monotherapy. Serum total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoproteins A-I and B concentrations and serum concentrations of biochemical markers of liver and renal function were also measured in the study participants. Results Serum Lp(a) concentrations were significantly increased at 6, 12 and 24 months of CBZ and VPA monotherapy. There were no significant correlations between serum Lp(a) and serum lipids, lipoproteins, apolipoproteins, concentrations of biochemical markers of liver and renal function or antiepileptic-drugs concentrations. Conclusions Children who receive CBZ or VPA monotherapy may have significant and persistent increase in serum lipoprotein (a) concentrations, occuring early in the course of therapy. It may be useful to measure serum Lp(a) concentrations routinely in epileptic children taking these antiepileptic drugs, especially in those that are already at higher atherosclerotic risk.

Carbamazepine and valproate for the treatment of bipolar disorder: a review of the literature

There are an increasing number of pharmacologic therapies for bipolar disorder. Two of these agents, the anticonvulsants carbamazepine (CBZ) and valproate (VPA), were first developed over 30 years ago for the treatment of epilepsy, and subsequent studies demonstrated that they are also effective in the treatment of acute mania and suggest efficacy as maintenance therapy in bipolar disorder. Because VPA and CBZ have been in use for many years, the psychiatric community is familiar with the adverse event profiles of these agents. A review of the clinical data evaluating VPA and CBZ monotherapy for the treatment of acute mania suggests that VPA and CBZ are similarly effective in acute mania. However, when their respective adverse event profiles are considered, VPA may be more tolerable than CBZ for short-term use, while CBZ may be better suited for long-term therapy. Controlled and direct comparative studies, both short and long term, are needed to further clarify the differences between VPA and CBZ.

Quantitative EEG effects of carbamazepine, oxcarbazepine, valproate, lamotrigine, and possible clinical relevance of the findings

Quantitative EEG (QEEG) effects of therapeutic doses of carbamazepine (CBZ), oxcarbazepine (OXC), valproate (VA) and lamotrigine (LA) monotherapy were investigated in patients with beginning epilepsy. Baseline waking EEG (EEG1) was recorded in the untreated state, the second EEG (EEG2) was done after 8 weeks of reaching the therapeutic dose. Left occipital data were used for analysis. QEEG target parameters were absolute band-power (delta: AD, theta: AT, alpha: AA, beta: AB), and alpha mean frequency (AMF). Group effects (untreated versus treated condition in the CBZ, VA, OXC, LA groups) were computed for each target parameter. One group with benign rolandic epilepsy remained untreated for clinical reasons and served to estimate the QEEG test–retest differences. In addition, the individual QEEG response to each drug was calculated as (EEG2 − EEG1). Results: statistically significant ( p < 0.05) group differences indicated the QEEG domain systematically affected by the drugs. CBZ caused AT increase and AMF decrease. OXC caused AMF decrease. VA and LA did not decrease AMF (LA even increased it), but reduced broad-band power. Individual power and AMF changes showed considerable variability in each group. >0.5 Hz AMF decrease (that was reported to predict cognitive impairment in prior studies) occurred in 10/41 patients in the CBZ group but never in the OXC, VA, LA groups. The results may be utilized in planning further studies addressing the relationship between antiepileptic drugs and their CNS effects. In addition, the relationship of AED-related cognitive impairment and AMF changes was discussed.

Serum total amylase, pancreatic amylase and lipase activities in epileptic children treated with sodium valproate monotherapy

To investigate by a prospective, self-controlled method, whether early treatment with sodium valproate (VPA) monotherapy has some effect on serum total amylase and particularly on its pancreatic isoenzyme and lipase activities in epileptic children. Serum total amylase, pancreatic amylase and lipase activities have been evaluated in 23 epileptic children, before and at 6 and 12 months of VPA monotherapy. All children remained without clinical symptoms of pancreatitis during the period of study. Serum pancreatic amylase activities were significantly decreased at 6 and 12 months of treatment with VPA, whereas serum total amylase and lipase activities did not show any significant changes at 6 or 12 months of treatment. Non-pancreatic isoenzyme activities of amylase were significantly higher at 6 and 12 months of treatment. Three patients (13%) had slightly elevated serum total amylase levels at 6 and 12 months of treatment. There was no significant correlation of serum pancreatic amylase levels or non-pancreatic isoenzyme levels of amylase with serum VPA levels at 6 and 12 months of treatment. Non-pancreatic amylase activities, probably derived from salivary glands, may be increased in children treated with VPA monotherapy. Measurement of serum pancreatic amylase and/or serum lipase activities is indicated in patients with increased serum total amylase levels but without clinical symptoms of pancreatitis and, furthermore, in patients with symptoms suggesting dysfunction of pancreas, in order to avoid unnecessary discontinuing of VPA.

Insulin-related metabolic changes during treatment with valproate in patients with epilepsy

Weight gain is a known side effect of valproate (VPA) therapy, which is associated with hyperinsulinemia and polycystic ovary-like syndrome and unfavorable lipid changes in women. Hyperinsulinemia has also been observed in male and lean subjects as well. Hyperinsulinemia is associated with several health risks, such as cardiovascular diseases and the metabolic syndrome. The purpose of this study was to evaluate whether VPA-related hyperinsulinemia is associated with other metabolic changes and whether there is any association between weight gain, other adverse effects related to VPA, and the metabolic syndrome. Fifty-one patients under VPA monotherapy and 45 healthy control subjects participated in the study. They were interviewed and clinically examined, and, after an overnight fast, blood samples were taken to evaluate fasting serum insulin, lipid, free fatty acid, and uric acid levels. Incidence of the metabolic syndrome was determined as well. Compared with control subjects, VPA-treated patients had higher circulating insulin concentrations relative to body mass index, higher uric acid and triglyceride levels, and lower high-density lipoprotein cholesterol concentrations. There was no significant difference in the frequency of the metabolic syndrome between the VPA-treated patient group and the control group. In conclusion, valproate therapy, especially if started at a young age, is associated with increased circulating insulin concentrations relative to body mass index, indicating that the high insulin levels are not a consequence of obesity. Although the frequency of the metabolic syndrome did not differ between VPA-treated patients and control subjects, VPA-treated patients had higher concentrations of triglycerides and uric acid and lower levels of high-density lipoprotein cholesterol than control subjects.

Detecting Vigabatrin Toxicity by Imaging of the Retinal Nerve Fiber Layer

To quantify retinal nerve fiber layer thickness (RNFLT) and macular thickness (MT) in patients exhibiting vigabatrin-attributed visual field loss (VAVFL) and to determine the efficacy of these measures as markers of the retinal damage associated with vigabatrin. This was a prospective cross-sectional observational study involving five groups: Group I, 13 patients exhibiting VAVFL; Group II, 8 patients exposed to vigabatrin but with normal fields; Group III, 14 patients receiving carbamazepine monotherapy; Group IV, 20 normal individuals; and Group V, 7 patients receiving sodium valproate monotherapy. At one of two visits, the right eye of each participant underwent two digital imaging modalities: ocular coherence tomography (OCT; StratusOCT; Carl Zeiss Meditec, Dublin, CA) and scanning laser ophthalmoscopy (SLO; Heidelberg Retinal Tomograph; Heidelberg Engineering GmbH, Heidelberg, Germany). At the other visit, participants underwent three-zone, age-corrected suprathreshold perimetry of the whole field and threshold perimetry of the central field (Humphrey Field Analyzer 750; Carl Zeiss Meditec). The order of the visits was randomized. The group mean RNFLT in Group I was attenuated relative to that of the remaining groups (all P < 0.001). At 100% specificity, based on the 95% confidence limits derived from Group IV, OCT exhibited 100% sensitivity and SLO 77% sensitivity for an attenuated RNFLT in patients with VAVFL. All participants manifested an MT within the normal range derived from Group IV. OCT of the RNFL can efficiently identify vigabatrin-induced damage and will be useful for adults and children unable to perform perimetry and when the perimetric outcome is equivocal.

The use of anticonvulsants in the aftermath of mania

This paper reviews the evidence for the efficacy of anticonvulsants in the continuation and maintenance phases of treatment of bipolar disorder, when there has been an episode of mania (Bipolar-I disorder). The evidence to be considered is primarily that arising from randomized controlled trials. A literature search was performed to identify all randomized controlled trials of anticonvulsants used as maintenance treatment for bipolar-I disorder. Placebo-controlled studies were preferred, however there have been relatively few of these and clinical practice must therefore be guided by evidence carrying a lower level of conviction. Valproate monotherapy lacks a convincing evidence base. The view that valproate is more effective than lithium in rapid cycling has not been borne out. Lamotrigine is effective in preventing depression after an episode of mania. As monotherapy, lithium appears superior to carbamazepine in bipolar patients not previously treated with either drug. The combination of lithium and carbamazepine may be superior to either drug alone, in certain treatment-resistant patients, but is associated with increased side effects. Other anticonvulsants lack evidence supporting their use in bipolar disorder except in treating co-morbid alcohol dependence, anxiety and bulimic symptoms. Valproate continues to be recommended by most current guidelines despite the lack of evidence.

Embriopatía por ácido valproico con malformaciones graves del sistema nervioso central

Embryogenetic disorders are one of the most serious problems in the life of an epileptic. Over the last few decades many antiepileptic drugs, including valproic acid, have been shown to have teratogenic properties. Embryopathy due to valproate, also known as fetal valproate syndrome, is a well-known and documented example of these conditions. We report the case of a preterm newborn infant who, at birth, exhibited a syndrome characterised by facial dysmorphia, gingival hyperplasia, neurological hyperexcitability and multiple malformations, the most striking of which was the presence of predominantly temporal atrophy in the left brain hemisphere. The most significant event in the medical history of the case was the mother's taking valproate in monotherapy throughout the entire period of gestation as treatment for generalised idiopathic epilepsy that was diagnosed during adolescence. Screening precluded the most common metabolic, hereditary or infectious causes that can cause embryopathies. The mother's history of taking valproic acid and the specific findings that coincided in the peculiar embryopathy of this patient enabled us to link them.

Acute Hyperammonemic Coma with Chronic Valproic Acid Therapy

To report a case of dose-related hyperammonemic coma without liver failure in a patient receiving chronic valproate therapy. A 56-year-old woman with poorly controlled epilepsy, receiving valproate at subtherapeutic levels for 6 years, developed a life-threatening hyperammonemic coma following a moderate dosage increase. Hyperammonemic coma without associated liver failure is an extremely rare complication of valproate therapy, described primarily in patients with inborn errors of metabolism and occurring idiosyncratically during initial stages of therapy. In our case, family history was suggestive of an X-linked disorder, raising the possibility that our patient may have been an asymptomatic carrier of a urea cycle enzyme deficiency unmasked by valproate therapy. To our knowledge, as of October 24, 2005, only one prior case of hyperammonemic coma in the context of chronic valproate monotherapy has been described. Application of the Naranjo probability scale score suggests that a causal relationship between valproic acid and hyperammonemic coma was probable. The widespread use of valproic acid emphasizes the need to maintain a high degree of suspicion with respect to this rare but potentially fatal adverse effect at all times, regardless of therapy duration.

Idiopathic Generalized Epilepsies: A Review and Modern Approach

Idiopathic Generalized Epilepsies: A Review and Modern Approach

Children exposed to valproate in utero—Population based evaluation of risks and confounding factors for long-term neurocognitive development

Purpose: To evaluate neurological and cognitive functioning of school-aged (≥6 years) children exposed to valproate monotherapy in utero in a population based, evaluator-blinded, controlled study. Methods: Studied children ( N = 39, aged 6.6–13.4 years) and their mothers were identified through a population based pregnancy registry. Mothers with carbamazepine monotherapy and mothers with epilepsy but without antiepileptic drug (AED) treatment during pregnancy and their age and gender matched children served as controls. Hospital records were reviewed and neurological examination (Touwens test), intelligent quotients (IQ) of mothers (WAIS), and children (WISC-III) and neuropsychological assessment of children (NEPSY) were performed evaluator-blinded. Results: The prevalence of low intelligence (FIQ < 80) was 19% (4/21) and the prevalence of exceptionally low intelligence (FIQ < 70) 10% (2/21) in valproate (VPA) monotherapy exposed children. Children exposed to carbamazepine (CBZ) and children of women with epilepsy but without AED exposure during pregnancy had all at least low average intelligence. The mothers using valproate scored significantly lower ( p < 0.05) in FIQ, VIQ and PIQ tests and had also significantly lower ( p = 0.035) educational level. Altogether 21% (8/39) of the children had minor neurological dysfunctions. Conclusions: In a population based setting inheritance and cumulating environmental factors may partly explain the increased prevalence of neurocognitive symptoms in children exposed to valproate in utero although concern about the possible long-term effects of intrauterine valproate exposure does exist.

Visual function in epilepsy patients treated with initial valproate monotherapy

To investigate whether initial valproate (VPA) monotherapy for the treatment of epilepsy causes visual field defects and visual dysfunction. In a cross-sectional study, visual fields were examined with the kinetic Goldmann and automated Humphrey perimeters, contrast sensitivity function with the Pelli-Robson letter chart and colour vision with the Standard Pseudoisochromatic Plates Part 2 (SPP 2) and Farnsworth-Munsell 100 Hue test (FM 100) in eighteen epilepsy patients (aged 18--50 years, 30.2.+/-10 years, mean+/-S.D.) treated with initial valproate monotherapy for 2--20 years (8.4+/-5.1 years). None had vigabatrin-type, concentric visual field defect with the kinetic Goldmann or automated Humphrey perimetries. In the Humphrey perimetry, the mean deviation for the group was within normal limits varying from -2.53 to 0.59 dB (-0.74+/-0.80 dB) in the right eye and from -2.66 to 0.67 dB (-0.78+/-0.82 dB) in the left eye. In the FM 100 test, acquired colour vision deficiency was found in two out of 18 patients (11%, 95% CI: 0--25%). However, the mean total error score was lower in the patient group than in the control group. All patients had normal contrast sensitivity function. The use of VPA in the treatment of epilepsy is not associated with visual field defects similar to vigabatrin, but may induce abnormalities in colour vision.

What can we say to women of reproductive age with epilepsy?

It is not yet established which antiepileptic drugs (AEDs) are most likely to allow an uncomplicated pregnancy and delivery of a baby who develops normally. Two recent studies of the risk of major malformations, a national birth registry1 and a prospective single experience,2 consisted mainly of carbamazepine (CBZ) or valproate (VPA) exposed pregnancies. Both suggested that first semester exposure to VPA monotherapy carried a higher risk of fetal malformation than exposure to CBZ monotherapy. There is an increased risk3 for abnormalities in infants exposed in utero to phenobarbital, a drug that not long ago was the recommended drug for pregnant women with epilepsy (WWE). In this and a future issue of Neurology , three birth registries are reported. Cunnington et al.4 report results from the lamotrigine (LTG) registry and Wyszynski et al.5 report results from VPA-exposed pregnancies. Both reports track major birth defects evident by ultrasound or inspection within the first few days of life. Artama et al.6 report on the rate of malformations in offspring of WWE after exposure to several AEDs in monotherapy and polytherapy compared to offspring of untreated WWE. Cunnington et al.4 report a 2.9% incidence of major defects in the infants of 414 WWE treated with LTG monotherapy. When LTG was used in polytherapy, there was a 12.5% incidence if it was used with VPA (88 exposures) and a 2.5% incidence with other AEDs (182 exposures). This multinational registry (12 years of observations) enrolled patients voluntarily by physician report, with postpartum physician information. Wyszynski et al.5 report results …