Withdrawal Of Valproate Research Articles

Morbidity and mortality risks associated with valproate withdrawal in young adults with epilepsy.

Valproate is the most effective treatment for idiopathic generalized epilepsy. Current guidance precludes its use in females of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to males. New guidance will limit use both in males and females aged <55 years, resulting in withdrawal of valproate from males already taking it, as occurs for females. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for males or females ON valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients' and clinicians' minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young males and females. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were males and females aged 16-54 years with ≥1 epilepsy disease or symptom code between 1 December 2017 and 1 December 2018, and ≥2 valproate prescriptions over the preceding 2 years (1 January 2015-30 November 2017). Five-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining ON versus withdrawn from valproate during the 1 December 2017-1 December 2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs). In total, 8991 males and 5243 females taking valproate were recruited. Twenty-eight per cent of males and 36% of females were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance [HRs overall: 1.236 (CI 1.159-1.319), males: 1.181 (CI 1.083-1.288), females: 1.242 (CI 1.125-1.371)], hospital admission [HRs overall: 1.160 (CI 1.081-1.246), males: 1.132 (CI 1.027-1.249), females: 1.147 (CI 1.033-1.274)], falls [HRs overall: 1.179 (CI 1.041-1.336), males: 1.298 (CI 1.090-1.546)], injuries [HRs overall: 1.095 (CI 1.021-1.174), males: 1.129 (CI 1.029-1.239)], burns [HRs overall: 1.592 (CI 1.084-2.337)] and new-onset depression [HRs overall 1.323 (CI 1.119-1.565), females: 1.359 (CI 1.074-1.720)]. The risk of these outcomes occurring was 1%-7% higher in those withdrawn from valproate than in those remaining ON valproate. Overall, valproate withdrawal was not associated with increased mortality. These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal.

An international study to investigate and optimise the safety of discontinuing valproate in young men and women with epilepsy: Protocol.

Valproate is the most effective treatment for idiopathic generalised epilepsy. Currently, its use is restricted in women of childbearing potential owing to high teratogenicity. Recent evidence extended this risk to men's offspring, prompting recommendations to restrict use in everybody aged <55 years. This study will evaluate mortality and morbidity risks associated with valproate withdrawal by emulating a hypothetical randomised-controlled trial (called a "target trial") using retrospective observational data. The data will be drawn from ~250m mainly US patients in the TriNetX repository and ~60m UK patients in Clinical Practice Research Datalink (CPRD). These will be scanned for individuals aged 16-54 years with epilepsy and on valproate who either continued, switched to lamotrigine or levetiracetam, or discontinued valproate between 2014-2024, creating four groups. Randomisation to these groups will be emulated by baseline confounder adjustment using g-methods. Mortality and morbidity outcomes will be assessed and compared between groups over 1-10 years, employing time-to-first-event and recurrent events analyses. A causal prediction model will be developed from these data to aid in predicting the safest alternative antiseizure medications. Together, these findings will optimise informed decision-making about valproate withdrawal and alternative treatment selection, providing immediate and vital information for patients, clinicians and regulators.

Epilepsy with Eyelid Myoclonia Complicated by Polycystic Ovary Syndrome: Valproate Withdrawal, Vagus Nerve Stimulation, and Seizure Reduction

Epilepsy with Eyelid Myoclonia Complicated by Polycystic Ovary Syndrome: Valproate Withdrawal, Vagus Nerve Stimulation, and Seizure Reduction

Acute Valproate-Induced Encephalopathy in Status Epilepticus: A Registry-Based Assessment.

Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with status epilepticus (SE) is, however, unknown. The aim of this study was to characterize the frequency and the clinico-biological characteristics of VIE in adult SE patients. We reviewed all patients included in our institutional SE registry who were treated for an SE episode between November 2021 and February 2023 and identified 39 patients who received valproate for their SE treatment. Acute VIE was defined by worsening of consciousness having led to the discontinuation of valproate, and improvement of consciousness within 96 hours after discontinuation of valproate during acute hospital treatment. Patients had a mean valproate intravenous loading dose of 34.5mg/kg and a mean maintenance dose of 15.3mg/kg/d (1078mg/d). Four out of 29 patients with measured ammonium had hyperammonemia. We identified four (10%) patients fulfilling acute VIE criteria. Median time from administration of valproate to the occurrence of VIE, and to resolution of VIE after cessation of valproate treatment, was 2 days for each. Three of the four VIE patients had no associated hyperammonemia. Patients who developed VIE more frequently had a history of liver disease (p=0.023), and tended to be younger, but other clinical variables did not differ significantly from patients without VIE, including valproate loading or maintenance doses, SE cause, duration or severity, other concomitant antiseizure medications (none received topiramate, phenobarbital, or primidone). Pending larger studies, VIE in SE seems relatively frequent and difficult to foresee; clinical alertness to symptoms is mandatory, even without hyperammonemia, and valproate withdrawal should be considered in suspected cases.

An International Cohort Study Assessing the Morbidity and Mortality Risks of Valproate Withdrawal in Men and Women Aged 16–54 Years with Epilepsy

An International Cohort Study Assessing the Morbidity and Mortality Risks of Valproate Withdrawal in Men and Women Aged 16–54 Years with Epilepsy

Valproate-induced hypothyroidism in schizoaffective disorder

IntroductionValproate is widely used in the treatment of maniac and mixed episodes and is well known to be safe with side effects being mostly related to hepatic disorders and psychomotor retardation.ObjectivesRaising attention to valproate-induced hypothyroidism that despite the increasing evidence tends to be neglected.MethodsHere, we report a case of a 55-year-old woman, with a previous diagnosis of schizophrenia, treated for many years with 200mg of zuclopenthixol triweekly and 2mg of risperidone daily. Patient developed a maniac episode characterized by elevated mood, sense of grandiosity, increased energy and psychomotor activity, disinhibition and insomnia. No laboratory abnormalities were detected and inpatient treatment was initiated with paliperidone up to 12mg/day and valproate 1000mg/day.ResultsPatient showed progressive clinical recovery attaining full remission within 2 weeks. Despite the absence of clinical side effects and the valproate serum levels of 74.9μg/mL (range 50–100μg/mL), laboratory testing found progressive reduction F-T4 down to 0.45ng/dL (range 0.8–1.5 ng/dL) and a concomitant upregulation of TSH to 73.99mUI/L (range 0.55–4.8mUI/L). Thyroid autoantibodies and thyroid echography were negative. Considering that patient was previously medicated with risperidone, it was suspected that her hypothyroidism was caused by valproate. Normalization of thyroid function was observed after 21 days valproate withdrawal. Patient is currently being treated with 150 mg paliperidone (monthly) with no recurrence of mood or psychotic episodes and maintain normal thyroid function.ConclusionsOur case emphasizes the need for extended laboratory testing upon prescription of new pharmacological medications as severe analytic alterations can take place in the absence of immediate clinical manifestation.DisclosureNo significant relationships.

Predictors of successful valproate withdrawal in women with epilepsy

ObjectiveValproate (VPA) use was restricted due to its teratogenic risks in women with epilepsy (WWE). We aimed to assess the outcome and predictors of treatment decisions of withdrawal/switch or continuation of VPA in WWE. MethodsWe included 214 consecutive WWE with a follow-up time of 9.57 ± 7.04 years, who have used (n = 142) or are still using VPA (n = 72) during their reproductive ages. The demographic, clinical, and electroencephalography (EEG) properties of WWE who could withdraw (successful withdrawal; n = 142) and could not withdraw VPA (unsuccessful withdrawal; n = 36) were compared statistically. ResultsThe main reasons for still using VPA were high risk of seizure recurrence (63.9%), cognitive impairment (27.8%), and no pregnancy prospect (8.3%). In the successful withdrawal group, 67 (47.1%) patients maintained remission after VPA withdrawal and 26 of them (38.8%) had relapse during the follow-up. The rate of side effects related to the new drugs (levetiracetam and lamotrigine) was 52/142 (36.6%). The unsuccessful withdrawal rate was 13.9% in focal epilepsy whereas it was 86.1% in generalized epilepsy (p = 0.002). Co-occurrence of three types of seizures and anti-seizure medication (ASM)-resistance was related to unsuccessful withdrawal in genetic generalized epilepsy (GGE) (p = 0.02 for both). ConclusionsAlthough women with focal epilepsies are more ASM-resistant and more likely to have continuing seizures, they do not usually deteriorate after VPA discontinuation, therefore posing them to teratogenic risk is often unnecessary. In GGE, certain predictors such as previous ASM-resistance and the presence of three seizure types must be taken into account, before a withdrawal attempt of VPA treatment.

Valproate but not levetiracetam slows the EEG alpha peak frequency – A pharmaco-EEG study

ObjectiveStudies of the effect of valproate (VPA) on the background EEG have shown varying results. Therefore, we compared the effect of VPA and levetiracetam (LEV) on the EEG alpha peak frequency (APF). MethodsWe retrospectively examined the APF in resting-state EEG of patients undergoing inpatient video-EEG monitoring (VEM) during withdrawal of VPA or LEV. We assessed APF trends by computing linear fits across individual patients’ APF as a function of consecutive days, and correlated the APF and daily antiseizure medication (ASM) doses on a single-patient and group level. ResultsThe APF in the VPA-group significantly increased over days with falling VPA doses (p = 0.005, n = 13), but did not change significantly in the LEV-group (p = 0.47, n = 18). APF correlated negatively with daily ASM doses in the VPA-group (average of r = −0.74 ± 0.12 across patients, p = 0.0039), but not in the LEV-group (average of r = −0.17 ± 0.18 across patients, p = 0.4072). ConclusionsOur results suggest that VPA treatment slows the APF. This APF reduction correlates with the daily dose of VPA and is not present in LEV treatment. SignificanceOur study identifies a VPA-related slowing of the APF even in patients without electroencephalographic or overt clinical signs of encephalopathy.

Valproate-associated Movement Disorder: A Literature Review.

Valproate (VPA) was first synthesized in 1882, but it was only in the early 1960s that its anticonvulsant properties were discovered. The aim of this literature review is to evaluate the clinical epidemiological profile, pathological mechanisms, and management of VPA-associated movement disorder (MD). Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 138 reports containing 362 cases of subjects who developed a MD secondary to VPA were reported. The MD identified were parkinsonism (PKN) (252), myoclonus (MCL) (54), dystonia (DTN) (17), dyskinesia (DKN) (16), stutters (4), tics (3), akathisia (AKT) (1). In the not clearly defined group, 15 extrapyramidal symptoms, 3 AKT, 2 DTN, 1 rigidity, 1 unstable gait were assessed. The mean and median age was 55.8 (SD: 16.58) and 61 years (range: 4-87 years). The most common VPA-indication was epilepsy, and 51.36% were males. The mean and median time from the VPA start to the MD onset was 32.75 (SD: 30.05) and 21.15 months (range: 1 day - 20 years). The mean and median time from the VPA withdrawal until the MD recovery was 2.89 (SD: 2.79) and 3 months (1 day - 12 months). The most common management was drug withdrawal. A complete recovery was obtained in 80.61%. VPA-associated MD was extensively reported in the literature. PKN was the most well-described. Future studies need to clearly report the clinical history of the patient, considering the full investigation of other adverse events during their entire life.

Valproate-associated foetal malformations-Rates of occurrence, risks in attempted avoidance.

To gain insight into the main advantages and disadvantages that might result from valproate being unavailable for women who intend to become pregnant. Analysis of data from the Australian Pregnancy Register concerning pregnancies exposed to valproate (N=501) and pregnancies where previous valproate intake had been ceased before pregnancy (N=101). The risk of foetal malformation associated with valproate exposure during pregnancy was dose-related, and there was a tendency for the more major malformations, including those often managed by therapeutic abortion, for example spina bifida, to occur at higher valproate doses. Had there been no exposure to valproate during pregnancy, some 80% of the foetal malformations that occurred might have been avoided. Cessation of previous valproate therapy before pregnancy was associated with an increased hazard of seizure-affected pregnancy. This was particularly the case for women with generalized epilepsies, in whom the incidence of seizure-affected pregnancy was increased by 50% to nearly 100%. Avoiding valproate intake during pregnancy is likely to reduce the incidence of foetal malformation, but at a cost of worsened maternal epilepsy control. Individualization of treatment is particularly important in considering withdrawal of valproate in the light of the fact that it is much more widely used in generalized epilepsy, there being fewer alternative drugs than for focal epilepsy and withdrawal is not without risk for both mother and baby. This study may provide a quantitative basis for assessing the balance between benefit and disadvantage for individual women with valproate-treated epilepsy who are considering pregnancy.

Valproate overdose and withdrawal

Valproate overdose and withdrawal

Status epilepticus in pregnant women with epilepsy after valproate adjustment: A case series

PurposeValproate is an effective wide-spectrum anti-epileptic drug that is also known to be teratogenic. Its administration in epileptic women remains controversial. This report aims to draw more attention to valproate adjustment before and during pregnancy. MethodsWe collected medical records of pregnant women with epilepsy at West China Hospital in Chengdu, China who developed status epilepticus during pregnancy after valproate withdrawal or reduction in dose from January 2013 to July 2015. ResultsA total of 281 pregnancies in patients with epilepsy were examined; 6 episodes of status epilepticus occurred during these pregnancies. Four patients with status epilepticus took long-term valproate before pregnancy. Among them, 2 patients stopped taking valproate 3 months prior to pregnancy, and 2 patients discontinued valproate or reduced their valproate dose when pregnancy was confirmed. All 4 suffered from a convulsive status epilepticus; 3 experienced an increased frequency of seizures. One child was diagnosed with neonatal asphyxia, hypoxic-ischemic encephalopathy, and neonatal pneumonia. ConclusionValproate adjustment prior to or during pregnancy may result in deterioration of seizure control, which may include resultant status epilepticus. Valproate during pregnancy increases the risk of major congenital malformations, but the significance of maintaining seizure control in pregnant women should be also taken into consideration. Open and careful discussion with every pregnant woman with epilepsy should discuss the risk-benefit ratio of epilepsy medications.

Psychotic disorders induced by antiepileptic drugs in people with epilepsy.

Antiepileptic drug treatment can induce psychosis in some patients. However, there are no agreed definitions or diagnostic criteria for antiepileptic drug-induced psychotic disorder in the classification systems of either epileptology or psychiatry. In this study we investigated the clinical spectrum of antiepileptic drug-induced psychotic disorder in patients with epilepsy. The medical records of all patients with epilepsy who were diagnosed by a neuropsychiatrist as having a psychotic disorder at the Royal Melbourne Hospital from January 1993 to June 2015 were reviewed. Data were extracted regarding epilepsy and its treatment, psychotic symptoms profile and outcome. The diagnosis of epilepsy was established in accordance to the classification system of the International League Against Epilepsy while that of psychotic disorder was made according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition and the proposal on neuropsychiatric disorders in epilepsy. Patients with antiepileptic drug-induced psychotic disorder were compared to those with psychotic disorders unrelated to antiepileptic drugs assessed over the same period (non-antiepileptic drug induced psychotic disorder group). Univariate comparisons were performed and variables with a value of P < 0.1 were selected for the multivariate logistic regression analysis. The records of 2630 in-patients and outpatients with epilepsy were screened, from which 98 (3.7%) with psychotic disorders were identified. Among these, 14 (14.3%) were diagnosed to have antiepileptic drug-induced psychotic disorder. Excluding one patient who developed psychosis after valproate withdrawal, 76.9% in the antiepileptic drug induced psychotic disorder group were female and the percentage of temporal lobe involvement was higher in the antiepileptic drug induced psychotic disorder group (69.2% versus 38.1%, P < 0.05). Current use of levetiracetam was higher in antiepileptic drug-induced psychotic disorder group (84.6% versus 20.2%, P < 0.01) while use of carbamazepine was higher in the comparator group (15.4% versus 44.0%, P < 0.05). Multivariate logistic regression confirmed four factors associated with antiepileptic drug-induced psychotic disorder: female gender, temporal lobe involvement and use of levetiracetam, and a negative association with carbamazepine. Disorganized behaviours and thinking were more common in the antiepileptic drug-induced psychotic disorder group (100% versus 72.6% and 76.9% versus 38.1%, respectively; P < 0.05). The percentage of continuous treatment with antipsychotic drugs was lower in the antiepileptic drug-induced psychotic disorder group (15.4% versus 66.7%, P < 0.01). No patients experienced a chronic course in antiepileptic drug-induced psychotic disorder group whereas 40.5% did in non-antiepileptic drug induced psychotic disorder (P < 0.05). Our findings indicated that one in seven patients with epilepsy who developed psychosis had antiepileptic drug-induced psychotic disorder. In these patients, female gender, temporal lobe involvement and current use of levetiracetam were significantly associated with antiepileptic drug induced psychotic disorder compared to other types of psychosis, while carbamazepine had a negative association. Disorganized behaviours and thinking were predominant in antiepileptic drug-induced psychotic disorder. Patients with antiepileptic drug-induced psychotic disorder differed from non-antiepileptic drug-induced psychotic disorders in having better outcome.

Technical aspects of pediatric epilepsy surgery: Report of a multicenter, multinational web-based survey by the ILAE Task Force on Pediatric Epilepsy Surgery.

Surgical techniques may vary extensively between centers. We report on a web-based survey aimed at evaluating the current technical approaches in different centers around the world performing epilepsy surgery in children. The intention of the survey was to establish technical standards. A request was made to 88 centers to complete a web-based survey comprising 51 questions. There were 14 questions related to general issues, 13 questions investigating the different technical aspects for children undergoing epilepsy surgery, and 24 questions investigating surgical strategies in pediatric epilepsy surgery. Fifty-two centers covering a wide geographic representation completed the questionnaire. The median number of resective procedures per center per year was 47. Some important technical practices appeared (>80% of the responses) such as the use of prophylactic antibiotics (98%), the use of high-speed drills for bone opening (88%), nonresorbable material for bone flap closure (85%), head fixation (90%), use of the surgical microscope (100%), and of free bone flaps. Other questions, such as the use of drains, electrocorticography (ECoG) and preoperative withdrawal of valproate, led to mixed, inconclusive results. Complications were noted in 3.8% of the patients submitted to cortical resection, 9.9% hemispheric surgery, 5% callosotomy, 1.8% depth electrode implantation, 5.9% subdural grids implantation, 11.9% hypothalamic hamartoma resection, 0.9% vagus nerve stimulation (VNS), and 0.5% deep brain stimulation. There were no major differences across regions or countries in any of the subitems above. The present data offer the first overview of the technical aspects of pediatric epilepsy surgery worldwide. Surprisingly, there seem to be more similarities than differences. That aside many of the evaluated issues should be examined by adequately designed multicenter randomized controlled trials (RCTs). Further knowledge on these technical issues might lead to increased standardization and lower costs in the future, as well as definitive practice guidelines.

Hand tremor possibly induced by interaction of risperidone and lithium in a case of bipolar disorder with schizophrenia: a case report

Drug-induced movement disorders possess a varied presentation and pose a challenging task for the physicians to diagnose such cases. A middle-aged woman with bipolar disorder comorbid with schizophrenia was under treatment with lithium carbonate, risperidone, sodium valproate, trihexiphenidyl tablets on a daily basis for two years. She experienced bilateral tremors of the hands which were present at rest and exacerbated by mental activity, when under observation and during voluntarily initiated activity. There were no associated extrapyramidal or cerebellar signs. The tremors persisted after withdrawal of sodium valproate and trihexiphenidyl, but disappeared completely after risperidone was stopped but lithium carbonate intake continued in an uninterrupted manner. Investigations did not reveal any positive finding. Hence, drug interaction may possibly be the offender for tremors in this case.

Valproate-induced hyperammonaemic encephalopathy in a neonate: Treatment with carglumic acid

Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual and serious complication of valproate (VA) treatment. When an early diagnosis is made, it can be reversed with VA withdrawal and early treatment for hyperammonemia. We describe the case of a 20 days old male, who developed a serious VHE after receiving VA for refractory neonatal seizures. The VHE was resolved with VA withdrawal in association with carglumic acid and other measures for hyperammonemia treatment.

Safe use of sodium valproate

Valproate is an anticonvulsant drug which is approved for use in epilepsy and bipolar disorder. Gastrointestinal adverse effects are common, particularly at the start of therapy. Important adverse effects include pancreatitis, hepatitis, weight gain and sedation. There is an increased risk of fetal abnormalities if valproate is taken in pregnancy. Measuring concentrations of serum valproate is often unnecessary. They do not correlate closely with its therapeutic effects. If withdrawal of valproate is required, this should be done slowly if possible. Rapid cessation may provoke seizures in patients with epilepsy.

Levetiracetam as alternative treatment in Jeavons syndrome

We report on a 25year old female patient who had a diagnosis of Jeavons syndrome since her childhood. Although valproate led to seizure freedom, she developed persistent reproductive endocrine disorders attributed to this drug. The withdrawal of valproate in parallel with an initiation of levetiracetam monotherapy resulted in a maintenance of clinical remission and a resolution of these abnormalities. This case together with relevant literature data supports the view that the use of levetiracetam might be of benefit for female patients with Jeavons syndrome.

Epilepsy with myoclonic absences in siblings

Epilepsy with myoclonic absences (EMAs) is a distinct form of childhood epilepsy characterized by a peculiar seizure type that identifies this condition. To describe the clinical, electroencephalographic features, treatment strategies and outcome in this first case series of two siblings with normal intelligence presenting with EMAs. Both siblings underwent video-polygraphic investigations (simultaneous recording of electroencephalogram [EEG] and electromyogram [EMG] from deltoids), high-resolution magnetic resonance imaging (MRI), karyotyping, neuropsychological evaluation and language assessment. Both the children had a mean age of onset of prototype seizures by 3.5 years. Myoclonic absences (MAs) were characterized by rhythmic, bilateral, synchronous, symmetric 3-Hz spike-wave discharges, associated with EMG myoclonic bursts at 3 Hz, superimposed on a progressively increasing tonic muscle contraction. The interictal EEG showed a normal background activity with bursts of generalized spike and waves (SWs) as well as rare focal SWs independently over bilateral temporal and frontal regions. Increase in the seizure frequency from 5 to 100/day was observed due to use of carbamazepine and phenobarbitone which decreased with its withdrawal and introduction of valproate. Though lamotrigine was given as an add on to valproate, it did not benefit them and was therefore replaced by topiramate at 3.5 mg/kg/day which has maintained them on remission at one year follow up. Recognition of this ictal pattern allows identification and differentiation of EMAs from other seizure types. Idiopathic and symptomatic EMAs need to be differentiated from childhood absence epilepsy with myoclonia. MAs are worsened by drugs like carbamazepine while valproate either alone or in combination with topiramate (preferred to lamotrigine) gives excellent outcome.

Encefalopatía hiperamoniémica inducida por ácido valproico en un neonato. Tratamiento con ácido carglúmico

Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual and serious complication of valproate (VA) treatment. When an early diagnosis is made, it can be reversed with VA withdrawal and early treatment for hyperammonemia. We describe the case of a 20 days old male, who developed a serious VHE after receiving VA for refractory neonatal seizures. The VHE was resolved with VA withdrawal in association with carglumic acid and other measures for hyperammonemia treatment.