Valproate-induced Hyperammonemic Encephalopathy Research Articles

VALPROATE INDUCED CEREBELLAR SYNDROME

Valproate-induced hyperammonemic encephalopathy is a rare event clinically characterized by altered sensorium, vomiting, headache, irritability and focal neurological decits. The pathogenesis of this dreadful complication is not well understood, although hyperammonemia has been implicated in causation of encephalopathy. In this case report, we bring to light a case of valproate-induced encephalopathy who presented mainly with difculty in walking and speech, body tremelousness. High index of suspicion of valproate-induced hyperammonemic encephalopathy is required if diffuse ataxia is present as it is a potentially reversible clinical disorder.

CARBAMAZEPINE-ASSOCIATED HYPERAMMONEMIC ENCEPHALOPATHY (HE)

CARBAMAZEPINE-ASSOCIATED HYPERAMMONEMIC ENCEPHALOPATHY (HE)

Valproate-induced hyperammonemic encephalopathy. A case report

IntroductionHyperammonemic encephalopathy is an unusual side-effect of the treatment with valproic acid. According to several sources, this side effect could be underdiagnosed and underreported.ObjectivesWe present the case of a 54-year-old patient institutionalized in a psychiatric hospital who was referred to a general hospital after an episode of delirium of unknown etiology. The patient had been diagnosed with Schizoaffective disorder 26 years prior to his admittance and had started treatment with valproic acid the previous month.MethodsA case report is presented alongside a review of the relevant literature regarding valproate-induced hyperammonemic encephalopathy, its differential diagnosis and treatment.ResultsDuring his hospital stay, the patient underwent a complete panel of tests including CT Scan, EEG, toxic panel and complete blood tests. In them the only altered parameter was hyperammonemia, therefore valproic acid was removed and was treated with lactulose and rifaximin to reduce ammonium levels.ConclusionsHyperammonemic encephalopathy in the context of the treatment with valproic acid is a side-effect which is more prevalent than what was thought in the past. Valproate could reduce ammonium elimination therefore increasing the levels of the molecule. It should be administered carefully in cases where the patient may be presenting with other causes of increased ammonium metabolism or decreased elimination. It is important to bear in mind this possible side-effect to increase patient’s safety.DisclosureNo significant relationships.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Hyperammonemia in Patients With Status Epilepticus Treated With or Without Valproic Acid.

Hyperammonemia is a common side effect of valproic acid (VPA) and can occur after generalized seizures, but the clinical significance is unclear. The aim of this study was to better understand the clinical practice and utility of ammonia testing in status epilepticus (SE) treated with or without VPA. Charts of adult patients with SE from St. Mary's Hospital Intensive Care Units (ICUs) (Mayo Clinic, Rochester, MN) from 2011 to 2016 were reviewed. Clinical factors were compared between patients who had ammonia checked versus those who did not, and those with normal ammonia versus hyperammonemia (>50 µg/dL). Charts were reviewed to determine if hyperammonemia changed clinical management and if it was felt to be symptomatic. There were 304 patients identified: 94 received VPA, 142 had ammonia checked and receiving VPA was associated with ammonia testing (P<0.001). Hyperammonemia was identified in 32 and associated with younger age, being in a non-neurological intensive care unit, and liver disease, but was not statistically associated with VPA. Only one patient had valproate-induced hyperammonemic encephalopathy; however, many patients received treatment for hyperammonemia such as lactulose, levocarnitine, or VPA dose reductions. This study demonstrated variability in ammonia testing and management changes in SE but does not support the routine monitoring of ammonia levels and showed that hyperammonemic encephalopathy was rare in this clinical setting.

Acute Hypoxic Respiratory Failure /Hyperammonemic encephalopathy in the setting of concurrent use of valproic acid and topiramate

Valproic acid (VPA) is widely used for the treatment of epilepsy, migraine, and a variety of psychiatric symptoms, including bipolar disorder, borderline personality disorder, and alcohol withdrawal. Valproate is associated with severe idiosyncratic adverse effects, the most notable being valproate-induced hyperammonemic encephalopathy (VHE). Topiramate is also a broad-spectrum anticonvulsant that is also extensively used for migraine prophylaxis, as a mood stabilizer, and for alcohol dependency. There is increased occurrence of VHE when valproate is used with other medications like phenytoin, phenobarbital, and topiramate. We report a young patient who was on valproic acid and topiramate and developed metabolic encephalopathy with hypoxic respiratory failure with review of the causes and management of the hyperammonemic encephalopathy. We believe that clinicians should be aware of possible hyperammonemic encephalopathy in any patient who is taking valproic acid and presenting with impaired consciousness and cognitive decline. We also underline the importance of early recognition and high index of suspicion of encephalopathy related to hyperammonemia.

VALPROATE-INDUCED HYPERAMMONEMIC ENCEPHALOPATHY IN A CHILD WITHOUT HEPATIC FAILURE: A CASE REPORT

Sodium valproate or valproic acid (VPA) is an effective antiepileptic drug that is commonly used for epilepsy in children because of its broad-spectrum activity. The use of VPA frequently results in elevated plasma levels of ammonia with or without raised transaminases. This condition usually happens when VPA with polypharmacy or underlying metabolic disorders like urea cycle defects. We are reporting a case of valproate-induced hyperammonemic encephalopathy in a child which is rare in children. Health professionals should be aware of this potential complication, and it is highly recommended to check ammonia levels in patients taking VPA who present with a change in mental status. If identified early, it can treat with appropriate measures and it can reversible.

Valproate-induced hyperammonemic encephalopathy: a case report

BackgroundHyperammonemic encephalopathy is a rare and serious adverse reaction to valproate. Although there is documentation of this reaction in previous reports, very little is still known about the exact mechanism of action. In addition, there are no established guidelines of the next steps needed when a patient does develop this reaction. Therefore, this case report highlights what is known as well as the areas of research still needed.Case presentationOur patient was a 57-year-old Caucasian woman with a medical history of bipolar I disorder, opioid use disorder, benzodiazepine use disorder, and Crohn’s disease who was admitted to our behavioral health unit for suicidal ideation. She had been experiencing multiple panic attacks for 2.5 weeks along with poor sleep, increased energy, excessive spending, and feelings of helplessness. The patient was diagnosed with bipolar I disorder, manic episode without psychotic features, and benzodiazepine use disorder. She was started on valproic acid, citalopram, propranolol, and quetiapine. By day 6 of her hospitalization, the patient had altered mental status, varying levels of consciousness, confusion, and ataxic gait. Her ammonia levels were found to be elevated. All of her medications were discontinued, and lactulose was initiated. She returned to her baseline mentation within 48 hours and was discharged with lithium and quetiapine. The treatment team concluded that this patient had valproate-induced hyperammonemic encephalopathy, a rare but reversible reaction to valproate.ConclusionFortunately, rapid identification of this rare condition led to a favorable outcome in our patient. This case report illustrates the course of treatment in a patient who experienced this reaction and reviews current knowledge as well as areas of needed research in regard to valproate-induced hyperammonemic encephalopathy.

104 Valproate-Induced Hyperammonemic Encephalopathy: Case Studies

AbstractBACKGROUNDHyperammonemia and carnitine deficiency with concomitant encephalopathy have been reported to result from valproic acid administration (Coulter DL, J Child Neurol 1991Jan; 6(1); 7-14 and Mock, CM, et al, Am J Health Syst Pharm, 2012 Jan; 69(1):35-9). Although there have been numerous publications regarding this adverse event in the neurology literature, there have been very few reports published in the psychiatric literature. The reported incidence of hyperammonemia in children treated with valproate is 19%. It is important that prescribers be aware of the risk of valproic acid induced hyperammonemic encephalopathy, as well as its diagnosis and management.OBJECTIVEThe current study explores the feasibility of reversing Valproate Induced Hyperammonemic Encephalopathy (VHE) by discontinuing valproic acid and normalizing the carnitine level via L-carnitine supplementation.METHODSThree males (ages 10-16 years), are reported with 12 - 24 month histories of cognitive decline during treatment for “Bipolar Disorder of Childhood” with valproate. All were referred with multi-year histories of explosive/impulsive aggression and multiple unsuccessful psychopharmacological regimes. The one consistent medication throughout treatment was sodium valproate. The subjects received serial neuropsychological testing, complex EEG, MRI, valproic acid, carnitine, and ammonia blood levels. Oxcarbazepine titrated to 30-50 mg/kg/day was substituted for valproate after initial testing was completed. Normative reference laboratory levels were as follows: (1) ammonia (reference interval 15-45 mcg/dl), (2) total carnitine (reference interval 34-77 nmol/ml), and (3) valproic acid (reference interval 50-125 mcg/ml).RESULTSCase Study 1: Male, 10 years old, ammonia 78 mcg/dl; carnitine 17 nmol/ml; valproic acid 92 mcg/ml. IQ 79 (compared to 105 one year earlier); MRI cerebral atrophy; EEG - left temporal aberrancies.Case Study 2: Male, 12 years old, ammonia 76 mcg/dL; carnitine 14 nmol/ml; valproic acid 104 mcg/ml. IQ 89 (compared to 109); MRI normal; EEG - left temporal aberrancies.Case Study 3: Male, 16 years old, ammonia 72 mcg/dl; carnitine 24 nmol/ml; valproic acid 125 mcg/ml. IQ 45 (compared to 65); MRI normal; EEG - left temporal aberrancies.In all three subjects, after valproate was removed (oxcarbazepine substituted) and supplemental L-carnitine added, ammonia and total carnitine levels normalized. At one year follow up, IQ’s returned to previous baselines, and MRI atrophy (Case 1) normalized. EEG aberrancies were unchanged. Patients were mood and behaviorally stable on oxcarbazepine.CONCLUSIONEvidence of cognitive decline while on valproate warrants ammonia and carnitine level testing. If these levels are abnormal, VHE should be diagnosed and valproate should be removed as rapidly as feasible; L-carnitine supplementation (the lesser of 100 mg/kg/day or 2 grams/day) should be implemented to normalize the carnitine level.Funding AcknowledgementsNo funding.

Valproate-Induced Hyperammonemic Encephalopathy in General Hospital Patients With One or More Psychiatric Disorders

Divalproex sodium/valproic acid (VPA) is an antiepileptic drug approved for use in epilepsy and bipolar disorder. Valproate-induced hyperammonemia occurs in up to 50% of VPA-treated patients, some of whom may become encephalopathic. Valproate-induced hyperammonemic encephalopathy (VHE) is thought to be rare, and for a variety of reasons, the diagnosis requires a high index of suspicion. The study's goals are to determine how common VHE is, and the quality of treatment provided when diagnosed. Retrospective, cross-sectional survey of general hospital patients. The hospital's laboratory and pharmacy databases were combined to identify a cohort of all VPA-treated patients who developed hyperammonemia during a 5-year period. Hospital records of the subset of patients with a psychiatric disorder were selected and reviewed for data collection. Twenty of 793 (2.52%) VPA-treated patients had signs and symptoms consistent with VHE. The majority were White males on multiple psychotropic agents. Valproate was appropriately discontinued in 8 (40%) patients. Lactulose was the only ammonia-lowering drug used, and it was administered to 6 patients and only one among them had VPA discontinued. Study results indicate that VHE may be more common in psychiatric patients than previously assumed but underrecognized and inadequately treated. The diagnosis of VHE requires a high index of suspicion. Outcome is favorable once it is recognized and treated appropriately.

Valproate-Induced Hyperammonemic Encephalopathy in a patient with Ischemic Stroke

ABSTRACTHyperammonemic encephalopathy is a rare, life threatening complication of valproate therapy. We describe an adult male with manic disorder and alcohol dependence who developed encephalopathy within two weeks of therapy with valproate. Risperidone and lorazepam were the concomitant medications. His serum ammonia was found to be elevated. There was complete resolution of symptoms after valproate was stopped. The patient's clinical picture was further complicated by imaging findings of ischemic changes and infarcts in the brain. Our report highlights the importance of considering hyperammonemic encephalopathy in any patients who develops acute changes in mental state while receiving valproate.

Commentary on clinical significance of CYP2C9‐status‐guided valproic acid therapy in children

The results of this retrospective study1 suggest a positive effect of cytochrome P450 (CYP)2C9–guided valproate (VPA) treatment when compared with non–CYP2C9-guided treatment, based on the significant lower rate of patients with hyperammonemia in the CYP2C9-guided cohort. Eight of 47 patients in the control group versus one of 51 patients in the CYP2C9-guided group showed hyperammonemia 1 month after the beginning of VPA treatment. We think that the study results should be interpreted with caution, however. In the intervention group, CYP2C9 status was determined, but the incidence of low expressers was higher than expected according to the literature.2 If the expression of the CYP2C9 gene was different in the control group, this could have led to a substantial bias. This potential bias could influence the (significant) higher ratio of patients with a serum VPA concentration outside the therapeutic range. The intervention and control groups also differed with respect to VPA dosing. The control group received a dosing of 20–40 mg/kg. Dosing for the normal expressers in the intervention group was 30–40 mg/kg. The authors did not explain why normal expressers did not receive VPA treatment based on standard clinical protocol, and the mean or average dose in either cohorts were not reported, as could influence outcome. The authors found a higher rate of hyperammonemia in the control group without hepatotoxicity. Literature reports between 100 and 260 clinical apparent cases of hepatotoxicity or hepatotoxicity with a fatal outcome in the period ranging from 1977 until 2013. However, the literature also notes that serious adverse reactions are rare, especially those leading to fatalities.3, 4 One patient with hyperammonemia was observed with secondary symptoms (nausea, vomiting, lack of appetite, fatigue, drowsiness, confusion, cognitive slowing, or loss of consciousness). It is not mentioned if this was in the control or intervention group. Also Segura-Bruna et al.5 have noted that no relationship has been found between the daily doses of VPA and the appearance and severity of valproate-induced hyperammonemic encephalopathy (VHE).6 They also noted no relationship between the development of VHE and serum VPA levels. Others described no correlation between clinical severity of VHE and higher blood ammonium levels when hyperammonemia was confirmed.6 So there does not seem to be a solid relationship between the development of clinically significant VHE and serum VPA levels.5 As is suggested by Monostory et al. In conclusion, in our opinion the authors note this research as a first attempt to establish the influence of CYP2C9 on VPA metabolism. However, based on presented data and given the low prevalence of hepatotoxicity, the study seems to be too small to make firm conclusions such as that CYP2C9-status-guided VPA treatment is preferable to non–CYP2C9-guided treatment and that CYP2C9-guided VPA treatment has demonstrated to improve the safety of VPA treatment. None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Case: Valproat-Induced Hyperammonemic Encephalopathy

Valproate induced hyperammonemic encephalopathy (VHE) is a severe adverse effect of medicine. An epileptic patient with an acute hyperammonemia after the addition of valproic acid to his treatment presented with acute mental status changes consistent with encephalopathy. Notably, plasma ammonia level was 2 times of the upper limit, despite normal liver function tests. Plasma valproic acid level was in the therapeutic range. His symptoms resolved with the discontinuation of valproic acid and L-carnitine administration. We discuss this case and review the possible mechanisms of valproic acid–associated encephalopathy and the efficacy of L-carnitine.

Valproate-induced hyperammonemic encephalopathy in an elderly patient with bipolar disorder

Hyperammonemia is a rare side effect of valproate, diagnosis of which requires a high level of clinical suspicion. We describe a case of 57-year-old man, suffering from bipolar affective disorder, who had multiple physical comorbidities (diabetes mellitus, benign prostatic hyperplasia, hydroureteronephrosis, and chronic kidney disease) and was on sodium valproate 1500 mg/day along with risperidone 6 mg/day, who developed delirium when the dose of sodium valproate was increased from 1500 mg/day to 2000 mg/day. In view of use of high doses of valproate, hyperammonemia was suspected, and on investigations, patient was found to have high ammonia levels (159 μmol/l). He was managed conservatively with stoppage of valproate and syrup lactulose. To conclude this case depicts that use of high doses of valproate can lead to hyperammonemia, especially among those with chronic medical illnesses.

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 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.

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.

Valproate induced hyperammonemic encephalopathy successfully treated with levocarnitine

Valproate-induced hyperammonemic encephalopathy is an unusual but serious adverse effect that is usually characterized by the acute onset of impaired consciousness, focal neurological symptoms and increased seizure frequency. It has been reported to occur at therapeutic valproate levels. We report a patient who developed valproate-induced hyperammonemic encephalopathy after a short treatment with valproate and was successfully treated with levocarnitine. We discuss this patient and review the literature regarding the use of levocarnitine in similar patients.

Valproate-induced hyperammonemic encephalopathy with triphasic waves: A case report

Introduction: Sodium valproate (VPA) is an effective antiepileptic drug used in neurology as well as in psychiatry. It is also associated with a hyperammonemic encephalopathy, when used in combination with other drugs.

Valproate-Induced Hyperammonemic Encephalopathy

Almost 50 years after its discovery, valproic acid remains a mainstay in the treatment of epilepsy, both alone and in combination with other anticonvulsants. It is also associated with a hyperammonemic encephalopathy, when used in combination with other drugs. We present a case of valproate-induced hyperammonemic encephalopathy in a patient on multiple anticonvulsant and psychotropic medications. The patient presented with altered mental status and became progressively more obtunded and finally began to experience seizures. Her symptoms resolved with the discontinuation of valproic acid and with supportive care.