Renal Failure, 30:822–824, 2008 Copyright © Informa Healthcare USA, Inc.ISSN: 0886-022X print / 1525-6049 onlineDOI: 10.1080/08860220802272613

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LRNFCASE REPORT

Valproate-Induced Hyperammonemic Encephalopathy Treated by Hemodialysis

Valproate-Induced Hyperammonemic EncephalopathyMing-Feng Tsai and Chen-Yin ChenDepartment of Nephrology, Tian-Sheng Memorial Hospital, Ping-Tong, Taiwan, R.O.C.

Valproate-induced hyperammonemic encephalopathy is anunusual but serious complication that may occur in people withnormal liver-associated enzyme levels, despite normal therapeuticdoses and serum levels of valproate. Here, we describe an adolescentgirl who had absence seizure and complained about progressivedizziness and general malaise several days after restartingvalproate. Then, she presented vomiting and decreased con-sciousness three weeks after valproate use. Notably, her serumammonia level was five times the upper limit of normal(184 μmmol/L), with normal liver-associated enzyme and supra-therapeutic valproate level. EEG showed continuous generalizedslowing. The tandem mass analysis revealed carnitine deficiency.Consciousness improved after emergent hemodialysis. Ammonialevel and EEG also returned to normal. Possible mechanisms,risk factors and the treatments of valproate-induced hyperam-monemic encephalopathy are described. Physicians should con-sider this possibility when consciousness disturbance occurs inpatients treated with valproate.

Keywords hyperammonemia, encephalopathy, valproate

INTRODUCTION

Valproate is a branched-chain fatty acid that is widelyused in the therapy of epilepsy. Most of the side effects aremild and transient. However, several serious adverseeffects during valproate treatment can occur, such ashepatotoxicity, coagulation disorders, pancreatitis, bonemarrow suppression, and hyperammonemia. Valproateoccasionally induces stuporous or comatose states associ-ated with an increase in frequent seizures and EEGchanges. The encephalopathy frequently is accompaniedby hyperammonemia without signs of hepatic failure.[1]

Valproate-induced hyperammonemic encephalopathy(VHE) is a serious disease, but it can be reversed if aprecocious diagnosis is made.[2] The diagnosis of hyper-ammonemia is often overlooked due to an unspecific clini-cal presentation even with normal liver-associated enzymelevels.[3] Here, we describe an adolescent girl who devel-oped hyperammonemia encephalopathy while restartingvalproate monotherapy for absence seizure. Rapid clinicalsymptoms and hyperammonemia were improved afterdiscontinuing valproate and immediate hemodialysis.

CASE REPORT

A 14-year-old girl had an absence seizure via receivingregular valproate control for two years using the mainte-nance dose of 20–23 mg/kg/day (1000 mg/day). There wasno seizure attack, and the drug level was within the normallimit during this period. Developmental milestones andschool performance were normal. Four months beforeadmittance, however, she discontinued the drug by herself.Poor appetite presented after stopping valproate, withweight loss of about 8 kg within three months. Unfortu-nately, myoclonic jerks of both hands were also com-plained about intermittently from two months beforepresentation. Thus, valproate was prescribed again byanother doctor, using 25 mg/kg/day (1000 mg/day) threeweeks before admittance. She complained of dizziness,general malaise, and vomiting several days after restartingvalproate. She denied taking any other drugs in the mostrecent three months. Due to dizziness and general malaisedeteriorating progressively, she visited our emergencydepartment. On physical examination, body temperaturewas 35.7°C, pulse rate was 97 beats per minute, respira-tory rate was 20 breaths per minute; and blood pressurewas 103/72 mmHg. Her height was 152 cm (25–50th per-centile) and body weight was 42 kg (25th percentile). Thebody mass index was 18.1 (normal range: 17.6–22.7). Neuro-logic examination was normal, including clear conscious-ness. However, she became lethargic gradually in the

Address correspondence to Kuan-Chi Chiu, Department ofRadiology, Tainan Municipial Hospital, No 670, Chung-TeRoad, Tainan City, Taiwan, ROC; Tel.: 886-6-2606351; Fax:886-6-3350338; E-mail: cychen1234@gmail.com

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Valproate-Induced Hyperammonemic Encephalopathy 823

emergency room. Laboratory examination revealedammonia was 184 μmmol/L (normal range < 33 μmmol/L), and valproate level was 182 μg/mL (therapeutic range50–100 μg/mL). The other metabolic panel was as fol-lows: aspartate aminotransferase 12 IU/L, alanine ami-notransferase 5 IU/L. Blood sugar, blood urea nitrogen,creatinine, and electrolyte were normal. Blood gas analy-sis showed pH 7.455, PCO2 30.3 mm Hg, PO2 44.6 mmHg, and HCO3− 21.2 mEq/L. EEG showed continuousgeneralized slowing. Brain CT revealed no significantanomalies. Three hours later, she became irritable, withincoherent and dysarthric speech, delusion, and asterixis.The Glasgow Coma Scale was 14/15. Under the impressionof VHE, we discontinued valproate therapy. Then emergenthemodialysis was performed once for three hours. Her con-sciousness recovered rapidly to normal 12 hours afterhemodialysis. EEG also returned to a normal rhythm thenext day (see Figure 1B). There was also a rapid correctionof hyperammonemia when ammonia decreased to 1 μmmol/L on the next day and no further episode. The valproatelevel was 24 μg/mL detected two days after hemodialysis.The tandem mass spectrometry studies revealed carnitinedeficiency (carnitine/acylcarnitine: C0 = 0.58, C2 = 0.52;normal range: C0: 3.18–1.35, C2: 5.56–1.5) before hemodi-alysis. After three months of follow-up, the patient had nocognitive impairment or neurologic sequelae. The serumcarnitine was normal: free carnitine in serum was 5.67 mg/L(normal range: 4.3–8.5 mg/L), and total carnitine in serumwas 11.09 mg/L (normal range: 6.3–11.6 mg/L). The anti-epileptic drug was changed to lamotrigine due to theabsence of epilepsy recurring two months after discharge.

DISCUSSION

The reported incidence of asymptomatic hyperammone-mia in children with valproate monotherapy is 19%.[4] How-ever, the incidence of VHE is unknown. In contrast tohyperammonemia due to advanced liver disease, patients withVHE usually have normal liver-associated enzyme levels, sug-gesting a mechanism other than hepatic cell injury or death.[5]

The clinical manifestations of VHE include acute orsubacute decreasing levels of consciousness that go fromdrowsiness to lethargy and coma, vomiting, dizziness, andfocal neurological deficit. Low-grade fever and an increasedin the frequency of seizures can also be found. Laboratorytests usually show a normal liver function with hyperam-monemia.[2] VHE may occur in people with normal doseand serum levels of valproate.[6] The main findings of EEGare diffuse slowing with a predominance of rhythmical thetaand delta activity, as seen in the initial EEG in our patient.Occasionally, triphasic waves can be found.[2] Our patientwas compatible with all these diagnostic findings.

The pathogenesis of VHE is not completely under-stood. Valproate can lead to hyperammonemia because ofseveral mechanisms. The most important one appears tobe the inhibition of hepatic mitochondrial carbamoylphos-phate synthetase-I, the enzyme that begins the ureacycle.[2] Hyperammonemia has been postulated as themain cause of encephalopathy. Ammonia toxicity is medi-ated by the excessive activation of the N-methyl-D-asparticacid type of glutamate receptor, which can increase seizurefrequency. On the other hand, excessive ammonia is con-jugated in the brain with alpha-ketoglutarate to formglutamate and causes alpha-ketoglutarate depletion.Depletion of alpha-ketoglutarate in the brain produces ablock in Krebs cycle and causes cell damage and neuronaldeath.[7] Some data suggest that VHE may be promotedeither by a pre-existing carnitine deficiency or by defi-ciency induced by valproate per se.[8]

The risk factors of valproate-associated hyperam-monemia include underlying urea cycle enzyme deficien-cies, underlying liver disease, long-term valproate,concomitant anti-epileptic drug therapy, particular topira-mate, or strict vegetarianism. VHE usually developswithin days to weeks of initiation of treatment.[1] High ini-tial dose and catabolic state also increase the risk.[5,9]

These three risk factors (initiation of treatment, high initialdose, and catabolic state) might have been associated withVHE in our patient while she restarted valproate therapy.

It has been known that there is no relationshipbetween daily dosages and serum concentration of val-proate, hyperammonemia, and the severity of VHE. In onereport reviewing 15 VHE patients, the valproate drug levelexceeded the therapeutic level in 40% of patients and waswithin the therapeutic level in the other 60% of patients.[3]

Moreover, VHE may be evident even in patients who hadpreviously received valproate without any clinical and lab-oratory problems,[10] as seen in our patient.

The primary treatment for VHE is the withdrawal ofvalproate. Reviewing the articles, complete consciousnessrecovery generally occurs over a period of 2 days to 14days and has no mortality cases.[3,11] Hydration, sodiumphenyl acetate, and sodium benzoate may be of benefit.[12]

On the other hand, L-carnitine may be helpful in theprevention, as well as treatment, of hyperammonia due tovalproate.[5] Hemodialysis is a therapeutic option managinghyperammonemia. Most authors agree that ammonia lev-els greater than 680 μg/dL (400 μmol/L) under valproatetherapy or significant clinical symptoms secondary tohyperammonemia require aggressive intervention.[13]

Valproic acid is a small molecule (1440 da) with asmall volume of distribution (0.2 L/Kg). Ninety to ninety-five percent is protein bound at therapeutic concentrations.Metabolic acidosis, low albumin levels, and older age alsocorrelate with decreased protein binding. Hemodialysis

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824 M.-F. Tsai and C.-Y. Chen

may thus be beneficial in valproic acid overdose because ofthese characteristics. In a review of 32 patients with toxicvalproate levels, six patients received hemodialysis. Thehalf-life of valproate could decrease from 2.2–4.3 hoursduring hemodialysis. The authors recommended hemodial-ysis as a component of the management of patients withnecessitation for stability and deteriorating neurologic con-dition that necessitates intubation.[14] In our case, bothhyperammonemia and toxic valproate level were seen withrapid deterioration in the level of consciousness. Weregarded that it fit “significant clinical symptoms second-ary to hyperammonemia” and decided to perform immedi-ate hemodialysis. Hemodialys should be considered acomponent of the management in patients with hemody-namic instability and deteriorating neurological condition.

In conclusion, VHE is a potentially serious compli-cation of valproate treatment. Physicians should considerthis possibility while consciousness disturbance occursin patients being treated with valproate, and should mon-itor ammonia and be aware of risk factors. Early inter-vention of VHE or withdrawal of valproate could benecessary. In our patient, hemodialysis rapidly improvedthe consciousness and hyperammonemia with the toxicvalproate level.

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authorsalone are responsible for the content and writing of the paper.

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