A Case of Hyperammonemic Encephalopathy Secondary to a Combination of Valproic Acid and Topiramate

Purpose To report a case of hyperammonemic encephalopathy induced by a combination of valproic acid and topiramate. Case Summary A 30-year-old male was admitted to our institution after experiencing headaches, decreasing mental capacity and increasing somnolence over the previous 3 days. Past medical history was significant for generalized tonic-clonic seizure disorder and mild mental retardation for which he had been regularly taking valproic acid, topiramate, and lorazepam. The patient was seizure free for the past 9 months prior to his seizure 2 weeks prior to admission. Upon presentation, an electroencephalogram revealed excessive slowing in the left more than right, with a differential consistent with a metabolic encephalopathy, head injury, or postictal state. Laboratory workup revealed a valproic acid level that was slightly elevated, but still within normal limits, at 92.5 mcg/mL (normal = 50 to 100 mcg/mL). Furthermore, the patient's ammonia level was found to be elevated at 72 mcg/dL (normal = 14.7 to 55.3 mcg/dL). On hospital day 3, after discovering these findings, valproic acid was discontinued and lactulose 20 g three times daily was started. Five days after admission, the patient's mental status changes were resolved, and he was discharged with an ammonia level of 57 mcg/dL. Conclusion Hyperammonemic encephalopathy is rare, but a serious and sometimes fatal disorder can occur in patients receiving valproic acid therapy. The incidence of hyperammonemia may be increased in patients receiving concomitant valproic acid and topiramate therapy. In patients on valproic acid and topiramate who present with altered mental status, an ammonia level in addition to a serum valproate level should be ascertained to rule out this potentially serious adverse drug reaction.

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Valproic Acid and Topiramate Induced Hyperammonemic Encephalopathy in a Patient With Normal Serum Carnitine

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-18.2.128 ◽

2013 ◽

Vol 18 (2) ◽

pp. 128-136 ◽

Cited By ~ 1

Author(s):

Martha G. Blackford ◽

Stephanie T. Do ◽

Thomas C. Enlow ◽

Michael D. Reed

Keyword(s):

Valproic Acid ◽

Mental Status ◽

Pediatric Intensive Care ◽

Altered Mental Status ◽

Ammonia Concentration ◽

Normal Serum ◽

Urine Drug Screen ◽

Blood Ammonia ◽

Persistent Symptoms ◽

Hyperammonemic Encephalopathy

A 17-year-old female developed hyperammonemic encephalopathy 2 weeks after valproic acid (VPA), 500 mg twice a day, was added to her regimen of topiramate (TPM), 200 mg twice a day. She presented to the emergency department (ED) with altered mental status, hypotension, bradycardia, and lethargy. Laboratory analysis showed mild non-anion gap hyperchloremic acidosis, serum VPA concentration of 86 mg/L, and urine drug screen result that was positive for marijuana. She was admitted to the pediatric intensive care unit for persistent symptoms, prolonged QTc, and medical history. Blood ammonia concentrations were obtained because of her persistent altered mental status, initially 94 μmol/L and a peak of 252 μmol/L. A serum carnitine profile was obtained at the time of hyperammonemia and was found to be normal (results were available postdischarge). VPA and TPM were discontinued on day 1 and day 2, respectively, as the patient's blood ammonia concentration remained elevated. On day 3, her mental status had returned to baseline, and blood ammonia concentrations trended downward; by day 4 her blood ammonia concentration was 23 μmol/L. VPA has been associated with numerous side effects including hyperammonemia and encephalopathy. Recently, drug interactions with TPM and VPA have been reported; however, serum carnitine concentrations have not been available. We discuss the possible mechanisms that VPA and TPM may affect serum ammonia and carnitine concentrations and the use of levocarnitine for patients or treating toxicity.

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Case Report of A Rare Idiosyncratic Hepatotoxicity Induced by Valproic Acid

10.47363/jghr/2021(2)111 ◽

2021 ◽

Vol 2 (2) ◽

pp. 1-6

Author(s):

Malek Michael Bouhairie ◽

◽

Sabrina Nasreddine ◽

Keyword(s):

Valproic Acid ◽

Drug Level ◽

Altered Mental Status ◽

Ammonia Level ◽

Normal Serum ◽

Accurate Information ◽

Hepatocellular Injury ◽

Idiosyncratic Reaction ◽

Acid Therapy ◽

New Biomarkers

Valproate induced hepatotoxicity is a well-known side effect, which frequently required periodic monitoring of serum drug level. Hepatotoxicity caused by valproate typically occurs at supratherapeutic drug levels. Once in a while, an idiosyncratic reaction is elicited, liver injury might occur despite normal serum valproate level mainly in chronic users. We hereby identify an unusual case of acute idiosyncratic valproate induced hepatotoxicity. We report a case of a 65 years old male with dyslipidemia and history of seizure, on valproic acid therapy, presented with altered mental status and drowsiness. The patient’s home medications include only zenil 10 mg daily and valproate which was started one month ago. At presentation, He was awake, oriented, but lethargic. Laboratory testing reveals hepatocellular injury with elevated transaminase levels, direct hyperbilirubinemia and coagulopathy. The ammonia level was normal and valproate level was within the therapeutic range. Abdomen computed tomography with IV contrast and MRCP results were irrelevant. Idiosyncratic valproate toxicity was diagnosed after exclusion of all other possible etiologies and after a rapid clinical and laboratory improvement once the drug was discontinued. Based on the patient’s clinical context the diagnosis of valproate induced hepatotoxicity was confirmed. This case emphasizes the importance of identifying, diagnosing, and managing valproate toxicity when no alternative clarification for their symptoms. We need further attempts and more researches to improve the detection of adverse hepatic reactions and to obtain reliable information about the discovery of new biomarkers or tools for early prediction of DILI, as well as to obtain accurate information on epidemiology, drug safety, and pathogenesis in order to improve management for better survival.

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Plasma Cell Myeloma Causing Hyperammonemia Associated with High Inpatient Mortality

Blood ◽

10.1182/blood.v120.21.5002.5002 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5002-5002

Author(s):

Anthony Pham ◽

John L. Reagan ◽

Jorge J Castillo

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Mental Status ◽

Altered Mental Status ◽

Ammonia Level ◽

Stage Iii ◽

Inpatient Mortality ◽

Medline Search ◽

Hyperammonemic Encephalopathy ◽

The Mean

Abstract Abstract 5002 INTRODUCTION: Hyperammonemia is commonly associated with severe liver cirrhosis. However, reports have described plasma cell myeloma (PCM)-induced hyperammonic encephalopathy. We present a retrospective case series of patients with PCM who present with altered mental status and hyperammonemia without signs of hepatic dysfunction over a twelve-year period. Additionally, we performed a systematic review of the literature looking for additional cases. METHODS: A retrospective chart review was performed of patients >18 years diagnosed with PCM between January 2000 and January 2012. A diagnosis of PCM-induced hyperammonemia was made in PCM patients with altered mental status, elevated serum ammonia levels (>50 umol/L) and no other cause of altered mental status including hepatic dysfunction, electrolyte and metabolic abnormalities or intracranial processes. The primary outcome was to examine factors predisposing these patients to hyperammonemia. Additionally, we performed a systematic MEDLINE search using multiple myeloma, ammonia and hyperammonemia looking for case reports and series on patients with PCM-induced hyperammonic encephalopathy meeting the above criteria. Available clinical characteristics were gathered from these reports. Characteristics are presented descriptively. RESULTS: Our retrospective study included 27 individual patients diagnosed with PCM with elevated ammonia levels in the context of presenting with altered mental status. Six out of the 27 patients had hyperammonemic encephalopathy without other known etiology. The mean age was 76 years with a 5:1 male-to-female ratio. All had stage III based on the International Staging Scale (ISS). Bone marrow biopsies demonstrated 54–98% (mean 69%) plasma cell infiltration. IgA subtype was seen in 50% (n=3), IgG in 33% (n=2) and biclonal IgG/IgA in 17% (n=1). The mean ammonia level was 113 umol/L (range: 50–171 umol/L). Each of these patients had stable hemoglobin, normal electrolytes, liver and kidney function tests, and INR. No intracranial processes were detected on imaging. Three patients had improvement in mental status and decreased ammonia levels after chemotherapy; the other three patients declined further interventions. Inpatient mortality was over 66%. Our MEDLINE search revealed 20 articles originating from the United States and Japan detailing a total of 32 patients who were diagnosed with PCM-induced hyperammonemic encephalopathy. The mean age was 52 years (range 23–89 years) with an equal distribution between men and women. The average ammonia level amongst these patients was 121 umol/L (range: 50–299 umol/L). All of these patients had stage III disease by the ISS or the Durie-Salmon system. IgG was the most common subtype at 44% (n=12), followed by IgA with 37% (n=10), light chain multiple myeloma with 11% (n=3), and IgD with 7% (n=2). Of the 25 patients that received chemotherapy, 15 (60%) survived until discharge. The inpatient mortality was 40% (n=10). Those patients who did not receive chemotherapy had a lower rate of survival at 25%. CONCLUSION: Multiple myeloma hyperammonemic encephalopathy is a rare disease process that typically occurs in patients with stage III disease. Hospitalization mortality is high for these patients despite chemotherapy and even higher without chemotherapy administration. Disclosures: No relevant conflicts of interest to declare.

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Case Report of A Rare Idiosyncratic Hepatotoxicity Induced by Valproic Acid

10.47363/jghr/2020(1)111 ◽

2021 ◽

pp. 1-6

Author(s):

Malek Michael Bouhairie ◽

Keyword(s):

Valproic Acid ◽

Drug Level ◽

Altered Mental Status ◽

Ammonia Level ◽

Normal Serum ◽

Accurate Information ◽

Hepatocellular Injury ◽

Idiosyncratic Reaction ◽

Acid Therapy ◽

New Biomarkers

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Delirium Secondary to Lamotrigine Toxicity

Current Drug Safety ◽

10.2174/1574886315666200225111057 ◽

2020 ◽

Vol 15 (2) ◽

pp. 156-159 ◽

Cited By ~ 1

Author(s):

Deborah L. Sanchez ◽

Adam J. Fusick ◽

Steven R. Gunther ◽

Michael J. Hernandez ◽

Gregory A. Sullivan ◽

...

Keyword(s):

Bipolar Disorder ◽

Valproic Acid ◽

Mental Status ◽

The United States ◽

Clinical Correlation ◽

Medication Regimen ◽

Medication Effects ◽

United States Food ◽

States Food ◽

Rule Out

Background: Lamotrigine is a phenyltriazine medication that has been approved by the United States Food and Drug Administration as monotherapy and as an adjunctive agent for the treatment of seizure disorder. It was later approved by the FDA for the treatment of bipolar disorder. Lamotrigine is generally well tolerated by patients, but some serious symptoms can occur during treatment. These severe side effects include rashes and multi-organ failure. Lamotrigine has also been associated with the development of mental status changes, frequently when used concurrently with other medications that may impact the metabolism of lamotrigine. Objective: To present the case of a 65-year-old man being treated with lamotrigine and valproic acid who developed mental status changes after the addition of sertraline to his medication regimen, and to compare this case to existing cases reported in the literature. Discussion: Our case adds to the existing literature by demonstrating that patients may experience adverse medication effects despite lamotrigine levels that are normally considered to be in the therapeutic range, highlighting the importance of clinical correlation when obtaining medication levels. Conclusion: Clinicians should use caution interpreting lamotrigine levels when working up delirium, as normal levels may not rule out the development of lamotrigine toxicity.

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Recurrent noncirrhotic hyperammonemia causing acute metabolic encephalopathy in a patient with a continent ileocecal pouch: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-021-02842-1 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

T. M. Skipina ◽

S. Macbeth ◽

E. L. Cummer ◽

O. L. Wells ◽

S. Kalathoor

Keyword(s):

Emergency Department ◽

Metabolic Acidosis ◽

Mental Status ◽

Rare Case ◽

Liver Function Tests ◽

Altered Mental Status ◽

Potassium Citrate ◽

Metabolic Encephalopathy ◽

History Of ◽

Normal Urine

Abstract Introduction Acute encephalopathy, while a common presentation in the emergency department, is typically caused by a variety of metabolic, vascular, infectious, structural, or psychiatric etiologies. Among metabolic causes, hyperammonemia is relatively common and typically occurs in the setting of cirrhosis or liver dysfunction. However, noncirrhotic hyperammonemia is a rare occurrence and poses unique challenges for clinicians. Case presentation Here we report a rare case of a 50-year-old Caucasian female with history of bladder cancer status post chemotherapy, radical cystectomy, and ileocecal diversion who presented to the emergency department with severe altered mental status, combativeness, and a 3-day history of decreased urine output. Her laboratory tests were notable for hyperammonemia up to 289 μmol/L, hypokalemia, and hyperchloremic nonanion gap metabolic acidosis; her liver function tests were normal. Urine cultures were positive for Enterococcus faecium. Computed tomography imaging showed an intact ileoceal urinary diversion with chronic ileolithiasis. Upon administration of appropriate antibiotics, lactulose, and potassium citrate, she experienced rapid resolution of her encephalopathy and a significant reduction in hyperammonemia. Her hyperchloremic metabolic acidosis persisted, but her hypokalemia had resolved. Conclusion This case is an example of one of the unique consequences of urinary diversions. Urothelial tissue is typically impermeable to urinary solutes. However, when bowel segments are used, abnormal absorption of solutes occurs, including exchange of urinary chloride for serum bicarbonate, leading to a persistent hyperchloremic nonanion gap metabolic acidosis. In addition, overproduction of ammonia from urea-producing organisms can lead to abnormal absorption into the blood and subsequent oversaturation of hepatic metabolic capacity with consequent hyperammonemic encephalopathy. Although this is a rare case, prompt identification and treatment of these metabolic abnormalities is critical to prevent severe central nervous system complications such as altered mental status, coma, and even death in patients with urinary diversions.

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Unusual Presentation of Myxedema Coma in Type 1 Diabetes Mellitus With Hyperglycemia and Polysubstance Abuse

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1985 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A971-A972

Author(s):

Yumna Hamid ◽

Steven Douedi ◽

Johnathan Nold ◽

Raquel Kristin Ong ◽

Jennifer Cheng ◽

...

Keyword(s):

Type 1 Diabetes ◽

Mortality Rate ◽

Mental Status ◽

White Male ◽

Altered Mental Status ◽

Close Monitoring ◽

Urine Drug Screen ◽

Metabolic Encephalopathy ◽

Myxedema Coma

Abstract Background: Myxedema coma is a severe manifestation of hypothyroidism that typicallypresents with altered mental status and requires close monitoring in the intensive care unit dueto 30-60% mortality rate. Clinical Case: A 56 year old white male with type 1 diabetes with recurrent DKA, polysubstanceabuse, Bipolar disorder on lithium and post surgical hypothyroidism presented due to change inmental status after being brought in by sister. Patient was found to be lethargic with confusionthat worsened over the last week. The patient was admitted several times in the past monthsecondary to pneumonia, sepsis, and recurrent DKA. On physical examination, he found to have lethargy, macroglossia, hyporeflexia, and periorbitaledema. Patient had acute respiratory failure with metabolic encephalopathy, bradycardia,tachypnea, severe hyperglycemia, hypotension of 77/51, tachypnea of 31 breaths per minuteand hyponatremia. Laboratory findings showed T4 levels 2.87(n=5.28-9.87ug/dL) withundetectable FT4 and elevated TSH (>50, n=0.300-4.500uIU/mL). Electrolyte panel showedhyponatremia (133, n=136-145mmol/L), hyperglycemia up to 532mg/dL and lithium levels werewithin normal limits (n=0.5-1.5 mmol/L). Urine drug screen was positive for cocaine. A CT scanof the head was negative. His myxedema score was diagnostic (>60). The patient wasdiagnosed with myxedema coma and admitted to the ICU. Patient was treated with IV LT4 400mcg, LT3 10mcg and hydrocortisone 100mg and started onIV LT4 100mcg daily, LT3 2.5mcg daily and hydrocortisone 100mg Q8 hours. There was wideglycemic variation from 46-532 mg/dL on POCT. The patient improved clinically, with resolutionof lethargy, confusion, fatigue, improved appetite, and improved lab work of FT3 2.30 (n=2.28-3.96pg/mL), FT4 at 0.76 (n=0.50-1.26ng/dL) and was downgraded from the ICU. On hospitalday four, he was transitioned to oral levothyroxine and discharged home. Conclusion: It is important to diagnose early and promptly manage decompensatedhypothyroidism in the setting of other comorbidities such as hyperglycemia in diabetes andpolysubstance abuse. The cocaine in the system may cause tachypnea and tachycardia. Manyconditions may have altered mental status, but with a history of hypothyroidism, Myxedemacoma should be on the differential due to its high mortality rate.

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High Blood Ammonia Levels Associated with Long-term Valproic Acids Therapy in Epileptic Children

Molecular and Cellular Biomedical Sciences ◽

10.21705/mcbs.v4i2.105 ◽

2020 ◽

Vol 4 (2) ◽

pp. 83

Author(s):

I Gusti Lanang Sidiartha ◽

I Gusti Ngurah Made Suwarba ◽

Dyah Kanya Wati ◽

Ida Bagus Subanada

Keyword(s):

Valproic Acid ◽

Combination Therapy ◽

Ammonia Level ◽

Blood Ammonia ◽

Cross Sectional ◽

Acid Therapy ◽

Blood Ammonia Level ◽

Significant Difference ◽

Epileptic Children

Background: Valproic acid is an effective drug for controlling seizure in children with epilepsy and it is usually used for treatment as long as two years or more. Blood ammonia level often increased in epileptic children who were treated with long-term valproic acid. The study was conducted to determine the relationship between blood ammonia level with valproic acid therapy in epileptic children.Materials and Methods: This is an observational study with cross-sectional approach. The subjects were 64 children with epilepsy, average age of 6.2 years old. Subjects were 33 boys and 31 girls. Blood ammonia level was examined using enzymatic glutamate dehydrogenase. Subjects were divided into 2 therapeutic groups based on the duration, doses and combination therapy of valproic acid. Subjects were recruited from Pediatric Neurology Clinic, Sanglah General Hospital, Bali, Indonesia, from May to December 2017. Comparison of blood ammonia level between groups were analyzed using an Independent t-test with significances if the p<0.05. Results: A significant difference of blood ammonia level was found between subjects who were treated with valproic acid less than 2 years and more than 2 years (45.7±16.4 mmol/L vs. 70.9±43.6 mmol/L; p=0.032). However, significant difference was not found between the groups according to the doses and combination therapy (p=0.450 and p=0.647, respectively).Conclusion: Blood ammonia level was significantly higher in epileptic children who used long-term valproic acid, hence it was recommended to check the blood ammonia level routinely.Keywords: ammonia, epilepsy, valproic, children

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

Medical Research Archives ◽

10.18103/mra.v9i4.2383 ◽

2021 ◽

Vol 9 (4) ◽

Author(s):

Fuad Zeid ◽

Yonas Raru

Keyword(s):

Valproic Acid ◽

Respiratory Failure ◽

Psychiatric Symptoms ◽

Early Recognition ◽

Mood Stabilizer ◽

Metabolic Encephalopathy ◽

Hyperammonemic Encephalopathy ◽

Concurrent Use ◽

Hypoxic Respiratory Failure ◽

High Index Of Suspicion

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.

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Two Siblings With Valproate-Related Hyperammonemia and Novel Mutations in Glutamine Synthetase (GLUL) Treated With Carglumic Acid

Child Neurology Open ◽

10.1177/2329048x20967880 ◽

2020 ◽

Vol 7 ◽

pp. 2329048X2096788 ◽

Cited By ~ 1

Author(s):

Jennifer Bennett ◽

Christy Gilkes ◽

Karin Klassen ◽

Marina Kerr ◽

Aneal Khan

Keyword(s):

Valproic Acid ◽

Case Report ◽

Glutamine Synthetase ◽

Negative Correlation ◽

Seizure Control ◽

Novel Mutations ◽

Strong Negative Correlation ◽

Acid Therapy ◽

Plasma Ammonia ◽

Hyperammonemic Encephalopathy

This case report describes 2 siblings with myoclonic epilepsy who had novel mutations in the glutamine synthetase ( GLUL) gene: c.316C>T, p.(Arg106*) and c.42G>C, p.(Lys14Asn). Valproic acid improved seizure control, but was associated with hyperammonemic encephalopathy. Addition of carglumic acid reduced ammonia levels but drug coverage was declined. We therefore designed a protocol to measure the reduction in plasma ammonia in response to carglumic acid therapy. After the first dose of carglumic acid, Patient 1 showed a reduction in plasma ammonia levels within 3 hours, from 114 umol/L to 68 umol/L (reference 12-47 umol/L), and Patient 2 from 108 umol/L to 80 umol/L, which was sustained over a 2 week period. Overall, there was a strong negative correlation between plasma ammonia levels and carglumic acid levels (r = −0.86, p = 0.0013), and recurrence of hyperammonemic encephalopathy was not observed while the patients were taking carglumic acid.

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