Hyponatremia due to sodium valproate

Here, we report a familial spinocerebellar ataxia (FSCA), which has clinical features similar to Friedreich's ataxia, an ataxia with isolated vitamin E deficiency, and ataxia telangiectasia. However, the serum levels of creatine kinase, γ-globulin, and α-fetoprotein were elevated, and biochemical and genetic analyses ruled out diagnosis of these three ataxias as well as other FSCAs. Thus, this family is thought to have a new type of FSCA.     

Tremor due to sodium valproate.

Four patients developed postural tremor after ingestion of sodium valproate. The tremor was recorded by a variable-capacitance transducer and was of the "benign essential" type. The dosages of sodium valproate varied between 1000 mg and 2000 mg daily and serum levels were between 34.9 microgram per milliliter and 154.3 microgram per milliliter. Tremor was ameliorated in two cases when the dosage was reduced. In only one case was the serum level in the toxic range for our laboratory. The pharmacology of essential tremor is unknown; production of a similar tremor by a drug could serve as a biochemical model.     

How to replace lamotrigine with valproate

If lamotrigine (LTG) has to be replaced with valproate (VPA), this exchange may be complicated by adverse events that result from the complex interaction of both drugs. We report on two cases in which such problems occurred in spite of a cautious switch considering the VPA induced LTG serum increase. The satisfying outcome after a sudden and complete withdrawal of LTG in both cases encouraged us to perform the switch from LTG to VPA systematically by discontinuing LTG abruptly and building up the VPA maintenance dosage very rapidly in the following five consecutive patients who required this exchange. We recommend our abrupt dosage change-over strategy as an easy, safe and cost-effective option.     

Conversion from delayed-release sodium valproate to extended-release sodium valproate: initial results and long-term follow-up

OBJECTIVE: The goal of our study was to evaluate clinical and serum valproic acid concentration changes in patients following overnight conversion from delayed-release sodium valproate (VPA-DR) to the same daily dosage of extended-release sodium valproate (VPA-ER). METHODS: Epilepsy patients on VPA-DR were offered the chance to convert to VPA-ER. Thirty patients were converted to twice-daily dosing and 11 were converted to once-daily dosing. Trough levels of valproic acid were measured prior to the change and 2 weeks after conversion. Short-term and long-term clinical data were evaluated. RESULTS: Patients successfully converted from VPA DR to VPA-ER. No significant difference in percentage change in serum trough valproic acid level was observed when comparing dosing frequency of VPA-DR, total daily dosage of VPA, conversion to once-daily versus twice-daily VPA-ER, or presence of enzyme-inducing agents. Mean seizure count per month prior to conversion was 3.35 versus 3.29 following conversion. Improvements in tremor, weight gain, and nausea/vomiting were noted. CONCLUSIONS: Overnight conversion to VPA-ER was well tolerated by all patients. Long-term results were favorable, with 77.5% of patients remaining on drug. Seizure counts and adverse events remained the same or were improved in both short-term and long-term evaluations. Dosing of VPA-ER either once-daily or twice-daily is acceptable.     

Encephalopathy induced by levetiracetam added to valproate

Background –  We report on the manifestation of a levetiracetam (LEV)-induced encephalopathy.
Findings –  A 28-year-old man suffering from idiopathic epilepsy with generalized seizures was treated with LEV (3000 mg) added to valproate (VPA) (2000 mg). Frequency of generalized tonic-clonic seizures increased from one per 6 months to two per month. Neuropsychological testing showed impaired word fluency, psychomotor speed and working memory. The interictal electroencephalogram (EEG) showed a generalized slowing to 5 per second theta rhythms with bilateral generalized high-amplitude discharges.
Outcome –  Following discontinuation of LEV, EEG and neuropsychological findings improved and seizure frequency decreased.     

卡马西平 托吡酯与丙戊酸钠治疗脑炎继发癫痫的疗效分析

目的观察卡马西平、托吡酯与丙戊酸钠治疗脑炎继发癫痫的疗效。方法选取60例脑炎继发癫痫患者为研究对象,随机分为A、B、C 3组,每组20例,A组给予卡马西平治疗,B组给予丙戊酸钠治疗,C组给予托吡酯治疗。对3组疗效进行评价;对3组患者治疗期间不良反应的发生情况进行观察。结果 3组临床有效率分别为70%、70%和75%,差异无统计学有意义(P0.05),且3组各项疗效评价结果差异均无统计学意义(P0.05);3组治疗期间不良反应的发生率分别为55%、45%和15%,A组或B组不良反应发生率显著高于C组(P0.05),A组皮疹发生率显著高于B组与C组(P0.05)。结论卡马西平、丙戊酸钠、托吡酯治疗脑炎继发癫痫的疗效基本相当,但托吡酯的不良反应较少,有助于提高患者的依从性。     

Possible valproate teratogenicity

The teratogenic risk of maternal valproic acid therapy and the prenatal effects on growth and morphogenesis have been difficult to determine, in part, because of the small number of epileptic women who receive valproic acid as the sole anticonvulsant therapy. An increased incidence of open neural tube defects has been suggested and other isolated case reports have noted the presence of certain dysmorphic features. We present a patient whose defects in morphogenesis appear to be associated with valproic acid exposure only, and suggest a clinical phenotype that our patient shares with other children exposed to prenatal valproic acid therapy. Features described previously include dysmorphic facies with hypertelorism, prominent forehead, low flat nasal bridge, low-set or odd-shaped ears, and micrognathia with growth deficiency of prenatal or postnatal onset. A striking and perhaps unique feature in our patient consists of hypoplasia of the lateral margins of the zygomatic arches. We discuss the pharmacokinetics of valproic acid in pregnancy and in the neonatal period.     

Neurotoxicity following addition of intravenous valproate to lamotrigine therapy

Reversible neurotoxic symptoms were observed in three adult patients with absence status epilepticus on lamotrigine (LTG) therapy after administration of an IV bolus followed by oral valproic acid (VPA). Neurotoxicity was likely related to elevated serum LTG levels, as improvement correlated with discontinuing or reducing LTG dosage.     

Growth hormone response to sodium valproate in chronic schizophrenia

The hypothesis of a gamma-aminobutyric acid (GABA) involvement in the pathophysiology of schizophrenia has been recently proposed but not confirmed. As GABA has been shown to affect basal growth hormone (GH) secretion in humans, the assessment of plasma GH response to a GABAergic drug, such as sodium valproate (SV), in schizophrenic subjects might be a tool with which to investigate central GABA activity in this illness. For this purpose, we administered orally 800 mg of SV or placebo to 13 chronic schizophrenics and to 10 normal controls, and measured plasma GH levels before and after the drug administration. SV enhanced basal GH secretion in healthy male volunteers, but not in chronic schizophrenics. These results suggest a defect of the endogenous GABA system in chronic schizophrenia. Whether the reduced responsiveness observed represents a primary defect or a secondary alteration of the GABA system in schizophrenia is as yet unknown.     

Neuroprotective properties of valproate

Neuropsychiatric disturbances are extremely common in Alzheimer’s disease (AD), and represent integral features of the illness, as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or some other mechanism, is a useful therapeutic agent to modify disease progression in AD.     

Encephalopathies caused by valproate

Valproic acid (VPA)-induced encephalopathy is a rarely considered side effect, with somnolence, reduced motor activity and severe deterioration of cognitive and behavioural abilities. In accordance with the increasing clinical importance of valproate clinical symptoms, causes and possibilities of treatment are reviewed by reporting on two cases of valproate-induced encephalopathy. In comparison to VPA intoxication, which is associated to increased VPA blood levels, the mechanisms of encephalopathy may include interactions of the hepatic enzymes, a direct toxic effect on the cerebral receptors, as well as drug interactions, a paradoxical epileptogenic effect and metabolic interactions. In most cases withdrawal of VPA produces regression of the symptoms within a few days; the role of L-carnitin or citrullin supplementation in clinical treatment remains unclear.     

Cognitive effects of valproate

The effects of valproate on cognition are usually considered to be minimal, but few formal neuropsychological studies are available. We studied the psychomotor performances of 20 seizure-free epileptics during fixed valproate monotherapy and after its withdrawal. Our findings suggest some adverse effects of valproate which appear to be completely reversible after withdrawal.     

Favorable response of ADHD with giant SEP to extended-release valproate

We treated three boys with attention deficit/hyperactivity disorder (ADHD) associated with giant somatosensory evoked potentials (SEP). All responded well to extended-release valproate (EVA), a gamma-aminobutyric acid (GABA) enhancer. Improvement particularly involved hyperactivity and impulsivity. When methylphenidate previously was administered to two patients, symptoms worsened. EVA therefore may be preferable for ADHD with giant SEP.     

Teratogenesis of sodium valproate

PURPOSE OF REVIEW: Sodium valproate has been a first-line antiepileptic drug for 40 years. A recent multicentre study conducted in the UK (Standard and New Antiepileptic Drugs) has confirmed what most practising neurologists had long suspected--that sodium valproate is the most effective drug in the treatment of idiopathic generalized epilepsy and juvenile myoclonic epilepsy. RECENT FINDINGS: Knowledge of the drug's unsurpassed efficacy has intensified the dilemma faced by neurologists treating people with epilepsy, and in particular young women. Recent data from pregnancy registers has not only confirmed that sodium valproate is teratogenic but also that it may be associated with neurodevelopmental delay and autistic spectrum disorders in the children of women exposed to the drug during pregnancy. Thus physicians have to balance the undoubted benefits of seizure freedom for their female patients with the potential long-term consequences for the infants of these patients. SUMMARY: There is undoubtedly a phamacogenetic component to sodium valproate's teratogenic and neurodevelopmental effects. Future research may enable us to identify those women whose offspring may be affected. Research now underway will help quantify the precise risk of neurodevelopmental delay in the offspring of women exposed to the drug, although it will be some years before results become available.