Chronic Valproate Therapy Research Articles

Valproate induced Gynecomastia: A case report

Epilepsy is a common health problem and affects any group patients. Valproate is indicated in all seizure disorders. It has wide range of pharmacokinetic properties with a narrow therapeutic range. Long term use can cause many side effects including gynecomastia. So we describe a case of valproate induced gynecomastia in patient on chronic valproate therapy.

Polypharmacy: a risk factor to consider in valproate‐induced hyperammonaemic encephalopathy

AbstractBackgroundValproate is commonly prescribed as part of combination therapy in antiepileptic or mood stabilising regimens. Although generally well tolerated, valproate has potential to cause serious adverse effects, one of which is valproate‐induced hyperammonaemic encephalopathy (VHE). The risk of developing VHE is rare; however, this can increase when valproate is used in conjunction with other medications.AimThis report aims to highlight the importance of early diagnosis of VHE and emphasise the potential deleterious effects of polypharmacy and certain hazardous drug combinations.Clinical detailsA 58‐year‐old woman with a 1‐week history of increasing lethargy, confusion and drowsiness presented to the emergency department. Blood tests showed a raised ammonia level and liver function test (LFT) derangement. She had been on a long‐term antiepileptic regimen which included sodium valproate. The only recent change to her medications was the introduction of atorvastatin. A diagnosis of VHE was made and valproate was discontinued. Atorvastatin was also stopped on account of its likely role in LFT derangement.OutcomesAfter discontinuation of both agents attributed to her presentation, serum ammonia and LFTs returned to within normal range. The patient also gradually resumed her usual level of alertness and functional state.ConclusionThis report describes a case of VHE and emphasises the detrimental role of polypharmacy associated with this presentation. This illustrates the potentially complex pharmacy issues that must be considered in the management of a patient on chronic valproate therapy.

Valproate-Induced Non-Hepatic Hyperammonaemic Encephalopathy: A Rare Complication of Chronic Valproate Therapy

Valproic acid can sometimes produce encephalopathy secondary to hyperammonemia without hepatic dysfunction, termed as valproate-induced hyperammonaemic encephalopathy (VHE). VHE is characterized by acute onset of impaired consciousness, lethargy, confusion, headache, vomiting, seizures and focal neurological deficits. Known risk factors include therapy with multiple antiepileptic drugs, presence of underlying inborn errors of metabolism, febrile states, and insufficient nutritional intake. We hereby, describe a case of VHE in a 10-year-old male child on long-term VPA therapy and no history of underlying liver disease. Encephalopathy reversed on withdrawal of VPA and L-carnitine therapy. We emphasize the need for early recognition, investigation, and treatment of this potentially life-threatening condition. doi:10.4021/ijcp33w

Quantitative analysis of motor performance in epilepsy patients treated with valproate

Purpose The aim of our study was to detect objective signs of deterioration of motor performance in epilepsy patients treated with chronic valproate therapy. Methods We examined 14 controls and 15 epilepsy patients receiving chronic valproate monotherapy, who had no subjective complaints related to motor function. Regularity and maximum frequency of repetitive hand and finger movements, and simple reaction time were measured. Intensity and frequency characteristics of resting and postural tremor were assessed using accelerometry. Data were statistically evaluated. Results Repetitive hand and finger movements were significantly more irregular and the maximum frequency of repetitive movements was significantly lower in the valproate group than in controls. Resting tremor peak frequency and motor reaction time of the two cohorts did not differ. Conclusions This is the first study, which quantitatively assesses motor performance of patients with epilepsy on chronic valproate therapy. The results suggest significant irregularity of repetitive hand movements and finger tapping even in patients with no motor complaints. Objective methods might help to recognize valproate-induced motor performance deterioration.

Clinical Outcomes and Low-Dose Levocarnitine Supplementation in Psychiatric Inpatients With Documented Hypocarnitinemia: A Retrospective Chart Review

Metabolic encephalopathy is one of the crucial manifestations of carnitine deficiency. In psychiatric patients, low serum carnitine levels may result from chronic valproate therapy. Despite the widespread use of valproate in psychiatry, neither carnitine deficiency nor supplementation has been studied in a psychiatric population. To describe clinical outcomes in hospitalized psychiatric patients with documented hypocarnitinemia who were receiving oral levocarnitine supplementation. Retrospective chart review. In 38 patients with hypocarnitinemia, a low-dose oral levocarnitine supplementation, in association with comprehensive psychiatric therapy, did not result in any adverse psychiatric or medical outcomes, and was associated with overall improved behavioral, cognitive, and motor functioning. Initially all patients had some degree of cognitive impairment, but after correction of carnitine serum levels, scores on the Mini-Mental State Examination (MMSE) improved in most of the patients (mean improvement 5.5 points, P <0.0001), and normalized in 11 cases. This allowed a correction of the diagnosis in 8 of 14 patients who had initially been diagnosed with dementia. African-American patients achieved significantly lower serum carnitine levels and MMSE scores than Caucasian patients with comparable therapy. We hypothesize that correction of carnitine depletion, either by levocarnitine supplementation or by valproate dose reduction, may enhance recovery from hypocarnitinemia-associated encephalopathy in psychiatric patients. Our findings also suggest that ethnic traits may affect carnitine bioavailability as well as cognitive outcomes in this clinical context. Further studies of carnitine metabolism and supplementation in psychiatric patients are warranted.

PO18-WE-42 Salivary testosterone and 8-OHDG levels in epileptic patients under chronic valproate therapy

and hypertensive encephalopathy 18%. With rectal diazepam, the mean time to control seizure was 5 minutes and was effective in all patients with clinical response seen in 0.5–9 minutes. Intravenousl Midazolam mean time to control was recorded at 7 minutes and 33 seconds. This was effective in 14 of 15 (93%) subjects with clinical response noted within 5 seconds up to 10 minutes. The buccal route responded similarly with the intravenous Midazolam group with cessation of seizures in 12 of 13 (92%) children. Comparing seizure duration with time to control the attack using the Pearson Correlation found to be not significant. Also noted was the increased recurrence of seizures using intravenous midazolam. Conclusion: Buccal Midazolam is safe, effective in seizure control It is easily administered with fewer seizure recurrence. However, there was no statistical significance in seizure termination between the three treatment group.

Valproate Enhances Neuropeptide Y Expression: Modulating the Modulators

Chronic Valproic Acid Treatment Triggers Increased Neuropeptide Y Expression and Signaling in Rat Nucleus Reticularis Thalami. Brill J, Lee M, Zhao S, Fernald RD, Huguenard JR. J Neurosci 2006;26:6813–6822. Valproate (VPA) can suppress absence and other seizures, but its precise mechanisms of action are not completely understood. We investigated whether VPA influences the expression of neuropeptide Y (NPY), an endogenous anticonvulsant. Chronic VPA administration to young rats (300–600 mg · kg–1 · d–1 in divided doses over 4 d) resulted in a 30–50% increase in NPY mRNA and protein expression in the nucleus reticularis thalami (nRt) and hippocampus, but not in the neocortex, as shown by real-time PCR, radioimmunoassay, and immunohistochemistry. No increased expression was observed after a single acute dose of VPA. Chronic treatment with the pharmacologically inactive VPA analog octanoic acid did not elicit changes in NPY expression. No significant expression changes could be shown for the mRNAs of the Y1 receptor or of the neuropeptides somatostatin, vasoactive intestinal polypeptide, and choleocystokinin. Fewer synchronous spontaneous epileptiform oscillations were recorded in thalamic slices from VPA-treated animals, and oscillation duration as well as the period of spontaneous and evoked oscillations were decreased. Application of the Y1 receptor inhibitor N2-(diphenylacetyl)- N-[(4-hydroxyphenyl)methyl]-d-arginine-amide (BIBP3226) enhanced thalamic oscillations, indicating that NPY is released during those oscillations and acts to downregulate oscillatory strength. Chronic VPA treatment significantly potentiated the effect of BIBP3226 on oscillation duration but not on oscillation period. These results demonstrate a novel mechanism for the antiepileptic actions of chronic VPA therapy.

Distribution of Spatial Complexity of EEG in Idiopathic Generalized Epilepsy and Its Change After Chronic Valproate Therapy

The objective of this study was to investigate the global and regional spatial synchrony of the EEG background activity, and to assess the effect of chronic valproate therapy on spatial synchrony. 15 idiopathic generalized epilepsy (IGE) patients were examined and compared to 16 normal controls. Resting EEG with 19 channels was investigated before and during chronic administration of valproate (VPA). Omega, a single-valued measure of spatial covariance complexity, was calculated to assess the degree of spatial synchrony of EEG. Furthermore, a new parameter was defined to characterize the distribution of spatial synchrony (Antero-Posterior Complexity Ratio, APCR). Global Omega complexity was significantly lower in IGE compared to controls, while regional complexity showed significant differences only in the anterior region: the IGE group showed lower complexity. APCR was significantly lower in IGE. VPA therapy (1) lowered the global complexity, (2) increased regional complexity in the anterior region, but decreased it in the posterior region, and (3) increased APCR. In IGE lower complexity, i.e. enhanced spatial synchrony, was found, especially in the anterior cortical area. VPA modified the distribution of spatial synchrony in IGE patients towards that of normal controls, although the effect is not identical with full normalization of cortical bioelectric activity. Whether the observed change of spatial synchrony distribution may reflect the normalizing effect of valproate on the brain state is worth further investigation.

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.

Mood stabilizers in Alzheimer’s disease: symptomatic and neuroprotective rationales

Objective: This paper provides a case study of ‘reverse translational research’, in which empirical clinical trials focused on relieving psychopathological symptoms of Alzheimer’s disease (AD) ultimately led to mechanism-based trials addressing aspects of the underlying pathophysiology of Alzheimer’s disease. AD is multi-dimensional in nature, characterized not only by cognitive and functional decline but by neuropsychiatric symptoms that develop commonly and are associated with considerable morbidity. There have been a large number of empirical trials of various pharmacological agents to reduce these symptoms, such as agitation. Although antipsychotics are used most frequently for agitation, the usual effect size is modest, and there is a range of tolerability and/or safety issues, leading to the hope that alternatives can be found. Furthermore, most clinical trials addressing psychopathology have not been mechanism-based and none have attempted an alternative approach, namely, to delay or prevent the emergence of psychopathology. Findings: The evidence of clinical trials is reviewed regarding the safety, tolerability, and apparent efficacy of the mood stabilizers carbamazepine and valproate for agitation associated with AD. Possible mechanisms of action of valproate are reviewed, leading to the surprising conclusion that neuroprotective properties may account for some of its clinical effects. These mechanisms (including activation of wnt-dependent signaling and upregulation of bcl-2, among others) may be particularly relevant for long-term treatment of AD. Conclusions: These clinical and mechanistic findings were combined in the development of a novel clinical trial examining whether chronic valproate therapy can attenuate the clinical progression of AD, which will be implemented by the Alzheimer’s Disease Cooperative Study. The design addresses valproate’s potential to delay or prevent the onset of agitation in patients lacking agitation to begin with, as well as to slow progressive decline in cognition and daily functioning.

Abnormal metabolism of carnitine and valproate in a case of acute encephalopathy during chronic valproate therapy

We analyzed the urinary metabolic profiles of valproate (VPA) and carnitine metabolism in an epileptic patient who died of acute encephalopathy during VPA therapy. On admission, the serum free carnitine level was greatly decreased and gas chromatographic mass spectrometric analysis of organic acids in urine showed a complete lack of beta-oxidation metabolites of VPA, while omega-oxidation was markedly increased. After administration of L-carnitine, the levels of acylcarnitine in both serum and urine, and of serum free carnitine increased, and the metabolites of beta-oxidation appeared in urine, while there was no improvement in the liver and renal functions. This is not a typical case of VPA-induced hepatotoxicity and the main cause of the disease is not clear. But the results show that the mitochondrial beta-oxidation of VPA was greatly disturbed in this patient, which may be related to the carnitine deficiency induced by the chronic VPA-therapy.

‘Perming’ effects associated with chronic valproate therapy

International Journal of Clinical PracticeVolume 42, Issue 2 p. 75-77 Case Report ‘Perming’ effects associated with chronic valproate therapy A K Gupta MB BS, MD, Corresponding Author A K Gupta MB BS, MD Consultant in Clinical Neurophysiology n/[email protected] Dudley Road Hospital, BirminghamAddress correspondence to Dr A K Gupta, EEG Department, Dudley Road Hospital, Birmingham, B18 7QH.Search for more papers by this author A K Gupta MB BS, MD, Corresponding Author A K Gupta MB BS, MD Consultant in Clinical Neurophysiology n/[email protected] Dudley Road Hospital, BirminghamAddress correspondence to Dr A K Gupta, EEG Department, Dudley Road Hospital, Birmingham, B18 7QH.Search for more papers by this author First published: 01 February 1988 https://doi.org/10.1111/j.1742-1241.1988.tb08516.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume42, Issue2February 1988Pages 75-77 RelatedInformation

Valproylcarnitine: a novel drug metabolite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry

Urine samples from three children at different stages of chronic valproate therapy were partially purified using a cation exchange column. A signal consistent with either valproylcarnitine or octanoylcamitine was observed in one of these extracts by direct fast atom bombardment-mass spectrometry analysis. These isomeric acylcarnitines were synthesized, separated and characterized by thermospray high performance liquid chromatography-mass spectrometry. This new technique was then employed to positively identify intact valproyl-camitine in the patients' urine samples. The implications of this finding with regard to a mechanism to account for carnitine deficiency in patients receiving valproate are discussed.