Valproic Acid Withdrawal Research Articles

Valproic acid induced Stevens–Johnson syndrome

A 27-year-old transgender female at the stage of gender transition with bipolar disorder for which she received valproic acid developed multiple petechial rashes on the chest, upper and lower extremities, local erythematous lesions with forming blisters, large-platelet peeling on the face, neck, chest and inguinal area, erosion on the oral mucosa. She was diagnosed with drug eruption, Stevens–Johnson syndrome. The diagnosis was verified on the basis of complaints, medical history, clinical picture, laboratory findings. Treatment included valproic acid withdrawal, dexamethasone, infusion therapy, vancomycin, cyclosporine A. Against the background of the therapy, skin condition was improved: there was the epithelization of ulcerative defects and the absence of new elements.

Withdrawal of valproic acid during pregnancy in women with epilepsy

Objective: to analyze the course of epilepsy in women after withdrawal of valproic acid (VA) during pregnancy. Material and methods. The study was conducted in the Center of paroxysmal conditions of Vitebsk Regional Clinical Diagnostic Center. The study included 58 women with epilepsy who gave birth in 2018–2020; a prospective analysis was also done using the Russian Register of Pregnancy and Epilepsy (RRPE) data. The study group included 112 women with epilepsy who were taking VA at the time of conception. In 16.1% of cases (n=18 out of 112) VA was discontinued in the first trimester (withdrawal group), in 83.9% of cases (n=94) VA therapy was continued. We analyzed the frequency of epileptic seizures depending on the use of VA during pregnancy for each trimester and for the entire pregnancy as a whole. Results. According to the Vitebsk Regional Clinical Diagnostic Center, 32 out of 58 (55.2%) patients took VA, all of them had generalized tonicclonic seizures in the structure of epileptic seizures. Seven of 32 patients (21.8%) received VA at a dose of <700 mg/day; 10 (31.3%) – 700–1000 mg/day, 15 (46.9%) – 1000–1500 mg/day. VA was canceled in two cases, in one of them a tonic-clonic seizure developed. According to the RRPE data, in 9 out of 65 (13.8%) cases VA was discontinued in the first trimester (withdrawal group), in 55 out of 65 (84.6%) cases the therapy with VA was continued, and in one case - the drug was changed. The number of women with epilepsy taking VA during pregnancy has decreased from 38.9% (275 out of 707) in 2017 to 24.9% (112 out of 450) by January 2023. According to the RRPE, the majority of patients continued VA therapy during gestation if pregnancy occurred while taking this antiepileptic drug. A high fraction of prescribing VA in patients with focal epilepsy was registered – 58.9% (66 out of 112) with continuation of VA therapy during pregnancy in 61.7% of cases. Among patients with generalized form of epilepsy, VA drugs were taken by 36.6% (41 out of 112). The majority of patients (35.1%; 33 of 94) continued to take VA throughout the entire gestation. About half of the patients took VA at a dose of >700 mg/day in the first trimester and throughout gestation. There were no statistically significant differences in the frequency of tonic-clonic and other types of epileptic seizures during pregnancy in patients who canceled VA and continued therapy, according to RRPE. Conclusion. Further prospective and controlled studies with large sample sizes are needed to determine the most effective and safe strategy for VA withdrawal.

A curious case of confusion

A curious case of confusion

Why do some women with epilepsy use valproic acid despite current guidelines? A single-center cohort study

ObjectiveCurrent guidelines and regulations strongly discourage the use of valproic acid (VPA) in women of childbearing age because of the risk of congenital malformations and neurodevelopmental disability in children exposed to VPA in utero. Our goal was to establish the reasons for continued use of VPA in a cohort of women with epilepsy (WWE) and to characterize the subgroup of WWE who do not consent to withdraw VPA despite potential risks. Material and methodsThe study included consecutive adult premenopausal WWE who visited an outpatient epilepsy clinic between April 2017 and March 2018. Data on demographics (age, age at onset of epilepsy), characteristics of epilepsy (types and frequency of seizures), and its treatment were collected from medical records and seizure diaries. All WWE taking VPA were regularly informed about VPA-related risks and had the opportunity to discuss the withdrawal of VPA. ResultsThe study involved 353 WWE (mean age: 31.7 years). Focal epilepsy was diagnosed in 244 (69.1%) patients; 180 (51.0%) women had no seizures during last 12 months before the study visit, and 228 patients (64.6%) were on monotherapy. A total of 146 (41.3%) patients used VPA in the past, and 98 (27.8%) never used VPA. Of women who were currently on VPA (n = 109, 30.9%), 30 had concurrent severe disabilities that would make future pregnancy extremely unlikely, in further 15 patients, VPA was recommenced because of failure of alternative treatment and 64 women did not accept the plan of VPA withdrawal. Women currently on VPA were more likely to have genetic generalized epilepsy and to be on monotherapy (both p ≪ 0.001). Among 64 WWE who decided to continue therapy with VPA, 35 (55.5%) had generalized epilepsy and 35 (55.5%) were in remission, 27 (42.2%) had at least one child, 9 (14.1%) planned to have a child in the near future but only 15 (23.4%) used effective contraception. ConclusionTreatment with VPA is unavoidable in many WWE of childbearing age despite recent regulations. About 60% of WWE currently treated with VPA do not consent to withdraw VPA treatment after thorough consideration of potential risks and other 40% use VPA because pregnancy is highly unlikely and/or other treatments failed.

Valproic acid withdrawal ameliorates impairments of hippocampal-spatial working memory and neurogenesis.

Valproic acid (VPA), an agent that is used to treat epileptic seizures, can cause spatial memory impairment in adults and children. This effect is thought to be due to the ability of VPA to inhibit neurogenesis in the hippocampus, which is required for learning. We have previously used an animal model to show that VPA significantly impairs hippocampal-spatial working memory and inhibits neuronal generation in the sub-granular zone of the dentate gyrus. As there are patient reports of improvements in memory after discontinuing VPA treatment, the present study investigated the recovery of both spatial memory and hippocampal neurogenesis at two time points after withdrawal of VPA. Male Wistar rats were given intraperitoneal injections of 0.9% normal saline or VPA (300 mg/kg) twice a day for 10 d. At 1, 30, or 45 d after the drug treatment, the novel object location (NOL) test was used to examine spatial memory; hippocampal cell division was counted using Ki67 immunohistochemistry, and levels of brain-derived neurotrophic factor (BDNF) and Notch1 were measured using western immunoblotting. Spatial working memory was impaired 1 and 30 d after the final administration, but was restored to control levels by 45 d. Cell proliferation had increased to control levels at 30 and 45 d. Both markers of neurogenesis (BDNF and Notch1 levels) had returned to control levels at 45 d. These results demonstrate that memory recovery occurs over a period of six weeks after discontinuing VPA treatment and is preceded by a return of hippocampal neurogenesis to control levels.

Valproic acid withdrawal

Valproic acid withdrawal

Valproic Acid Improves Porcine Parthenogenetic Embryo Development Through Transient Remodeling of Histone Modifiers

Background/Aims: Parthenogenetic embryos are useful in many applications, such as being an alternative source of embryonic stem cells that would avoid ethical problems. Aberrance in epigenetic reprogramming is considered the major reason for the developmental failure of parthenogenetic embryos. Many histone deacetylase inhibitors have been shown to improve the reprogramming of stem cells and embryos. Here, the relationship between histone modification and parthenogenetic embryonic development was explored. Methods: Valproic acid (VPA) treatment was applied during the culture of parthenogenetic embryos. The abundance of histone modifiers was examined by immunofluorescence and quantified by Image-pro software. Results: The acH3K9 level in in vitro fertilized embryos was significantly higher than parthenogenetic embryos. VPA treatment improved both the blastocyst formation rate and the acH3K9 level in parthenogenetic embryos. The signal intensities of acH4K5 and H3K4me2 were also enhanced in VPA treated embryos. The H3K27me2 level was decreased in the VPA treated embryos at the 2-cell stage. However, the enhancement in the acH3K9, acH4K5 and H3K4me2 level, or the decrease in the H3K27me2 level disappeared shortly after VPA withdrawal. Conclusion: Optimizing histone modifications for a short time following activation was sufficient to enhance the in vitro development of parthenogenetic embryos.

Valproic Acid Induced Isolated Thrombocytopenia after Acute Respiratory Infection

Valproic acid is the most used antiepileptic drug in children. Thrombocytopenia is one of known adverse effects of valproic acid. Acute respiratory infections are the most frequent acute infections in children. We present eleven cases of resistant thrombocytopenia in children on valproic acid therapy within therapeutic levels. Thrombocytopenia (without clinical signs) appeared after a short febrile episodes and signs and symptoms of acute respiratory infection, presenting with only few petehial skin spots. It does not respond to intravenous immunoglobulin’s, nether to corticosteroids. Thrombocytopenia responded dramatically to withdrawing of valproic acid. Complete platelet normalization after valproic acid withdrawal proved known adverse drug reaction between valproic acid and the thrombocytopenia this association.

Valproic acid-associated low fibrinogen and delayed intracranial hemorrhage: case report and mini literature review

A 41-year-old male had suffered from gradual hearing loss in his right ear for 2 years. Head computed tomography and magnetic resonance imaging scans showed a neoplasm in the cerebellopontine angle region, which was confirmed by the diagnosis of acoustic neurilemmoma by pathological findings after surgery. Following surgery, he routinely received valproic acid (VPA) to prevent seizures. However, the patient presented with hypofibrinogenemia and cerebral hemorrhage after taking VPA for 12 days. The hypofibrinogenemia recurred when VPA was re-administered. After withdrawal of VPA, his fibrinogen concentration rose to normal within several days. As far as we are aware, this is the first case of cerebral hemorrhage due to VPA to have been reported. Herein, as well as reporting on this case, a mini review of the relevant literature is also presented.

Valproic acid withdrawal

Valproic acid withdrawal

Hallucinations after Valproic Acid Withdrawal

Child psychiatrists and neurologists in Utrecht, The Netherlands report case histories of 2 girls, ages 4 and 12 years, with a history of epilepsy who developed hallucinations after withdrawal of valproic acid (VPA).

Hallucinations After Withdrawal of Valproic Acid

We report 2 children with a history of epilepsy in whom valproic acid (VPA) withdrawal was identified as a potential cause of hallucinations. After a restart of VPA, the hallucinations disappeared. We suggest mechanisms for the occurrence of the hallucinations and a possible control of a predisposition to hallucinations by VPA.

Hyperammonemic encephalopathy related to valproate, phenobarbital, and topiramate synergism

We present a woman with epilepsy secondary to a lesion in the left frontal lobe. She developed episodes of disorientation and behavioral changes. She was taking valproic acid (1500mg/day), topiramate (200mg/day), and phenobarbital (100mg/day). During an episode, the EEG revealed moderate encephalopathy and ammonia levels were increased (195μg/dL, reference range: 11–60μg/dL). Episodes ceased after withdrawal of valproic acid.

Neonatal episodic hypoglycemia: A finding of valproic acid withdrawal

The treatment of epilepsy during pregnancy is a worldwide problem. Drugs need to be used to control seizures in the mothers. In utero, exposure to valproic acid (VPA) and phenytoin (PH) may cause congenital malformations and also withdrawal symptoms such as irritability, jitteriness and symptoms of hypoglycemia. We present here a newborn with episodic hypoglycemia due to in utero exposure to VPA and PH. The mother was diagnosed as having complex partial epilepsy and was treated with PH (200 mg/day) and VPA (600 mg/day). The offspring developed jitteriness on the second day of life. The infant was hypoglycemic (32 mg/dl). These findings were accepted as withdrawal symptoms, since serum levels of VPA and PH were 37.8 μg/ml (50−100 μg/ml) and 6.37 μg/dl (10−20 μg/ml), respectively. Measurement of blood glucose is important and should be carefully monitored in infants exposed to antiepileptics in utero.Conflict of interest:None declared.

Valproic acid-induced abnormal behavior

A 12-year-old female was admitted to hospital with complaints of abnormal behavior. She was on valproic acid 200mg twice daily and clobazam 5mg at night for the past 13 weeks for her complex partial seizures with secondary generalized seizures. On day 60 of the treatment with valproic acid she developed behavioral disturbances and initiated treatment with tablet chlorpromazine, olanzapine and risperidone. During the present hospitalization, as there was no improvement in abnormal behavior, antipsychotics were discontinued and she was on observation for five days. On day 6, valproic acid was replaced with carbamazepine. Patient started recovering gradually from the abnormal behavior three days after the withdrawal of valproic acid and completely recovered after three months. Causality of valproic acid-induced abnormal behavior was ‘possible’. Behavioral disturbances associated with valproic acid are rare and is reversible upon discontinuation of the drug. There is a need for vigilance on abnormal behavioral effects in patients receiving valproic acid.

Nonalcoholic fatty liver disease during valproate therapy

Valproic acid (VPA) is effective for the treatment of many types of epilepsy, but its use can be associated with an increase in body weight. We report a case of nonalcoholic fatty liver disease (NAFLD) arising in a child who developed obesity during VPA treatment. Laboratory data revealed hyperinsulinemia with insulin resistance. After the withdrawal of VPA therapy, our patient showed a significant weight loss, a decrease of body mass index, and normalization of metabolic and endocrine parameters; moreover, ultrasound measurements showed a complete normalization. The present case suggests that obesity, hyperinsulinemia, insulin resistance, and long-term treatment with VPA may be all associated with the development of NAFLD; this side effect is reversible after VPA withdrawal.

Valproate-associated reversible encephalopathy in a 3-year-old girl with Pallister-Killian syndrome

Valproic acid (VPA) is considered to be a drug of first choice for the therapy of generalized and focal epilepsies, including special epileptic syndromes. The drug is usually well tolerated, rare serious complications may occur in some patients, including hemorrhagic pancreatitis, coagulapathies, bone marrow suppression, VPA-induced hepatotoxicity and encephalopathy. We report a case of VPA-associated encephalopathy without hyperammonemia in a 3-year-old girl with Pallister-Killian-Syndrom, combined with a mild hepatopathy and thrombopathy. After withdrawal of VPA, the clinical symptoms and the electroencephalography-alterations vanished rapidly.

Valproic acid induced encephalopathy – 19 new cases in Germany from 1994 to 2003 – A side effect associated to VPA-therapy not only in young children

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well-tolerated. Rare serious complications may occur in some patients, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity and VPA-induced encephalopathy. The typical signs of VPA-induced encephalopathy are impaired consciousness, sometimes marked EEG background slowing, increased seizure frequency, with or without hyperammonemia. There is still no proof of causative effect of VPA in patients with encephalopathy, but only of an association with an assumed causal relation. We report 19 patients with VPA-associated encephalopathy in Germany from the years 1994 to 2003, none of whom had been published previously.

Valproic acid withdrawal

Valproic acid withdrawal

Obesity and Plasma Concentrations of Alpha-Tocopherol and Beta-Carotene in Epileptic Girls Treated with Valproate

To investigate whether epileptic patients who become obese after valproic acid (VPA) therapy can have a high risk of atherosclerosis related to the oxidation of low-density lipoprotein, we prospectively studied the plasma concentrations of lipid-soluble antioxidant vitamins in a group of 20 epileptic girls and 20 controls. After 1 year of VPA treatment, epileptic patients who gained weight had decreased plasma concentrations of α-tocopherol and α- and β-carotene, the main lipid-soluble antioxidants. Moreover, 5 patients who gained weight were reevaluated 6 months after withdrawal from VPA therapy and showed normal body mass indices and normalized plasma levels of antioxidants. In conclusion, the data suggest that epileptic patients who gain weight after VPA therapy have reduced plasma concentrations of antioxidant vitamins and that these reductions are reversible after VPA withdrawal.