Acute Hepatic Injury in Four Children with Dravet Syndrome: Valproic Acid, Topiramate Or Acetaminophen?

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provided by Elsevier - Publisher Connector Seizure (2008) 17, 92—97

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CASE REPORT Acute hepatic injury in four children with Dravet syndrome: Valproic acid, topiramate or acetaminophen?

Joost Nicolai a,*, Boudewijn Gunning c, Piet L. Leroy b, Berten Ceulemans d, Johan S.H. Vles a

a Department of Neurology, University Hospital Maastricht, Maastricht, The Netherlands b Department of Paediatrics, University Hospital Maastricht, Maastricht, The Netherlands c Department of Neurology, Epilepsy Centre Kempenhaeghe, Heeze, The Netherlands d Epilepsy Centre for Children and Youth, Pulderbos, Belgium

Received 27 February 2007; received in revised form 19 June 2007; accepted 10 July 2007

KEYWORDS Summary We describe four children with Dravet syndrome treated with the Dravet syndrome; combination of valproic acid (VPA) and topiramate (TPM) who developed transient Acetaminophen; liver toxicity. The time-interval between fever, administration of acetaminophen, Stiripentol; epileptic status and liver enzyme disturbances in our four cases suggests that Topiramate; accumulation of toxic acetaminophen-metabolites is possibly responsible for liver Valproate; toxicity. If acetaminophen and its metabolites cause those liver problems in children Liver toxicity treated with the combination of VPA and TPM, the advice to use acetaminophen for treating fever in children using this combination, should be changed. Only future clinical observations and research can solve this clinical dilemma. # 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Introduction ﬁrst year of life. Later, myoclonic seizures, atypical absences and developmental delay occur. Seizures Dravet syndrome (severe myoclonic epilepsy in are often therapy-resistant to antiepileptic drugs. infancy) is characterized by febrile and afebrile, Antiepileptic treatment with valproic acid (VPA), generalised and partial seizures that start in the clobazam and stiripentol or the combination of VPA and topiramate (TPM) is often advised. Acute hepatic injury is a possible complication of Abbreviations: ALAT, alanine aminotransferase; APTT, acti- vated partial thromboplastin time; ASAT, aspartate aminotrans- many drugs. Acute VPA-induced liver toxicity is fatal 1 ferase; CBZ, carbamazepine; INR, International normalised ratio; in the majority of patients. Especially in very young IV, intravenous; PT, prothrombin time; TPM, topiramate; VPA, children the risk is high; the risk of fatal liver failure valproic acid (valproate) in children under 2 years of age receiving VPA as * Corresponding author at: Department of Neurology, University polytherapy is 1:600. In children between 3 and 10 Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Neth- 2 erlands. Tel.: +31 43 3875058; fax: +31 43 3877055. years using VPA polytherapy the risk is 1:8.300. The E-mail address: [email protected] (J. Nicolai). relation between TPM and hepatotoxicity has been

1059-1311/$ — see front matter # 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2007.07.003 Acute hepatic injury in four children with Dravet syndrome 93 suggested before in two case-reports.3,4 However, in Three months later, he was admitted again to the both publications the adult patients used multiple paediatric intensive care unit because of an epilep- antiepileptic drugs including TPM. No reports on tic status triggered by fever (39.5 8C) of unknown hepatotoxicity in children or adults receiving TPM origin. Also this time, his parents had given him monotherapy have been published till now. There is acetaminophen. The rise of liver enzymes and coa- evidence that ingestion of acetaminophen in ther- gulation disturbance was even more severe now apeutic dosages can cause an evident rise in alanine (ASAT 7326 U/l; ALAT 5203 U/l; APTT 24.4 s; PT aminotransferase (ALAT) in 31—44% of healthy, adult 32 s; INR 2.6). VPA concentration was 45 mg/L (nor- volunteers.5 mal range 40—100 mg/L). Transaminases gradually We describe four children with Dravet syndrome normalised despite the continuation of VPA, TPM, who developed a serious rise of liver enzymes. All and L-carnitine. Also this time, screening for viral were treated with the combination of VPA, TPM and hepatitis was negative. acetaminophen. The medical histories of Case No. 1 and the other three children are summarised in Table 1. Antiepi- leptic drug concentrations were only measured in Case report case 1 (second episode), 3 and 4. All parents used acetaminophen according to the manufacturers Case No. 1, a 5-month-old boy from non-related instructions. The dose used at home was not docu- parents visited our outpatient clinic because of mented at admission in the other children. It is generalised tonic—clonic seizures and partial sei- important to note that case Nos. 1 and 3 developed zures with rhythmic twitches of the tongue and a rise in liver enzymes while receiving adequate L- facial musculature. EEG registration showed multi- carnitine prophylaxis (advised dose: 100 mg/kg/ focal spikes and for this reason carbamazepine (CBZ) day6,7). In case No. 2, carnitine concentration was was started. Metabolic screening revealed no ami- measured on the day of admission. At that moment noaciduria, no organic aciduria and normal serum she showed a serious rise in transaminases. Total, total, free, and acyl-carnitine concentrations. Cer- free, and acyl-carnitine concentrations in plasma ebrospinal fluid analysis and MRI scan showed no were normal. In case Nos. 3 and 4 the rise of abnormalities. Because of the fact that his seizure transaminases was less impressive, however a sig- frequency worsened and myoclonic seizures were nificant elevation of ammonia was noted. Because noted, CBZ was withdrawn and VPA was initiated at of the serious rise in ammonia, a partial ornithine the age of 8 months. Several episodes of epileptic transcarbamylase deficiency was ruled out in both status occurred, triggered by febrile episodes. children. He was admitted to Kempenhaeghe epilepsy centre for further analysis and treatment. At the age of 12 months, TPM was added to his medication and Discussion gradually increased, because of ongoing seizures. The diagnosis of Dravet syndrome was confirmed In Dravet syndrome (severe myoclonic epilepsy in when a c.2684T > G (p.Leu895Arg) mutation was infancy), seizures are often therapy-resistant. In a found in exon 15 of the SCN1A gene. randomized add-on study, the addition of stiripentol At the age of 15-month, he suffered from an to VPA and clobazam has been shown effective in epileptic status triggered by influenza B infection. Dravet syndrome.8 The efficacy of TPM in Dravet The day before, he was given acetaminophen syndrome has been proven in an open label study9 240 mg q.i.d. (73 mg/kg/day) by his parents in order and in a retrospective analysis, adding TPM to the to suppress his fever. A rise in liver enzymes was combination of VPA, clobazam, and stiripentol 10 noted, and L-carnitine 100 mg/kg/day was started seemed helpful. In recent literature discussing on the day of admission. His antiepileptic medica- the treatment of Dravet syndrome, the combination tion was continued in dosages equal to those before of VPA and TPM is advised, together with strict acute admission and acetaminophen was stopped. ASAT seizure treatment and prevention of hyperthermia.11 (2229 U/l) and ALAT (2022 U/l) levels peaked at day The molecular basis of Dravet syndrome is a 1. Coagulation times were increased (APTT 20.9 s; mutation of the SCN1A gene expressing a sodium INR 2.1). Screening for Hepatitis virus A, B and C, channel alpha subunit. This sodium channel is only Epstein-Barr virus and Cytomegalovirus was nega- expressed in neuronal tissue, so a relation between tive. A spontaneous decrease of transaminases and liver failure and the SCN1A gene mutation does not coagulation parameters to almost normal values was seem obvious. noticed in the week after admission. On discharge, VPA-induced hepatic failure has been related to L-carnitine was added to his regular medication. carnitine deficiency. Chronic use of VPA leads to a 94 J. Nicolai et al. Discharged on day 18 ASAT 63 U/l; ALAT 89 U/l day 15 ASAT 42 U/l; ALAT 150 U/l day 8 ASAT 66 U/l; ALAT 40 U/l day 16 of admission VPA reintroduced after several months without problems without problems -carnitine L -carnitine VPA restarted after 1 month L -carnitine -carnitine Change in medication Follow-up TPM and clobazam Continuation of VPA, TPM, clobazam and kg/day 100 mg/kg/day L L Start lactulose mol/l mol/l Continuation of mol/l Start mol/l Continuation of VPA, mol/l Carnitine 100 mg/ m m m m m ALAT/ASAT Ammonia 7326/5203 U/ l35 42 49 -carnitine L -carnitine 60 mg/kg/day TPM 10 mg/kg/day (1.8 mg/L) 134 Medication (plasma concentration) VPA 26 mg/kg/day (45 mg/L) TPM 3.9 mg/kg/day Clobazam 1.2 mg/kg/day 70 mg/kg/day Acetaminophen L Acetaminophen TPM 6 mg/kg/day Clobazam 1.4 mg/kg/day Acetaminophen Lamotrigine 1.0 mg/kg/day (8.2 mg/L) Clonazepam 0.1 mg/kg/day TPM 5.7 mg/kg/day Ethosuximide 29 mg/kg/day Clonazepam 0.14 mg/kg/day Acetaminophen Clobazam 0.3 mg/kg/dayAcetaminophen Start lactulose pneumonia Reason admission 1 year and 6Epileptic months status Fever, unknown origin Influenza B infection Adenovirus infection SCN1A+ Post-influenza SCN1A+ RS virus bronchiolitis TPM 8.4 mg/kg/day 212 SCN1A + Epileptic status; SCN1A+ Epileptic status Patient overview 1/M M. Dravet 1 year and 3 months VPA 31 mg/kg/day 2229/2022 U/l Day 0: start Table 1 Patient Diagnosis Age at admission 3/F M. Dravet 1 year and 7 months VPA 51 mg/kg/day (78 mg/L) 280/340 U/l VPA stop Normalisation of liver enzymes 4/F M. Dravet 3 years and 1 month VPA 27 mg/kg/day (123 mg/L) 480/340 U/l VPA stop Normalisation of liver enzymes 2/F M. Dravet 1 year and 3 months VPA 41 mg/kg/day 5898/3186 U/l VPA stop Normal plasma carnitine on day Acute hepatic injury in four children with Dravet syndrome 95 secondary carnitine deficiency and carnitine con- TPM is frequently used in children. In a recent centrations are even lower in children receiving large open-label study, no rise in liver enzymes was polytherapy including VPA. Children and adolescents observed in any of the 277 children (age: 12 months treated with TPM monotherapy show normal con- and 16 years) treated with add-on TPM.15 No reports centrations of carnitine.12 on hepatotoxicity after the introduction of TPM VPA-induced liver toxicity in caused by several monotherapy have been published till now. co-occurring mechanisms. L-carnitine supplementa- A causal relation between TPM and hepatotoxicity tion is often recommended in young children who has been mentioned in two case-reports.3,4 However, are receiving VPA, especially those younger than 2 both adults used polypharmacy (Table 2). Longin years with a complex neurological disorder who are et al.16 reported a child and Bumb et al.17 reported receiving multiple antiepileptic drugs.6,13 The effi- an adult, both treated with VPA/TPM polytherapy cacy of L-carnitine supplementation has never been who developed an elevation of liver enzymes determined, but only one child developing VPA- (Table 2). Both patients were on stable VPA dosage induced liver failure while receiving adequate L- while TPM was gradually increased. Those reports carnitine supplementation has been reported.14 provide anecdotal evidence that TPM increases the In a retrospective analysis, it has been shown that risk of liver toxicity when added to VPA. the survival in patients with severe VPA-induced Liver enzymes normalised in case No. 1 in both hepatotoxicity is significantly higher after treatment episodes although both VPA and TPM were contin- with L-carnitine (48% versus 10% without L-carnitine ued. In case Nos. 3 and 4 TPM was continued and VPA suppletion).1 IV treatment is associated with signifi- initially stopped but reintroduced in an equal dose cant better survival than enteral treatment.1 without problems. This probably implicates that

Table 2 Review of literature on hepatotoxicity due to topiramate and valproic acid (or carbamazepine) combination therapy Patient Age/sex Diagnosis Medication ASAT/ALAT Change in Follow-up Ammonia medication Bjoro et al. 3 39 years/F Complex Carbamazepine a/10.000 U/l b Liver partial 800 mg/day transplantation seizures TPM 300 mg/ de day; c Doan and 21 years/F Bipolar VPA 1000 mg/ 1909/1044 U/l All medication Liver enzymes Clendenning 4 disorder day stopped peaked at day 8 and obesity TPM 200 mg/ 42 mmol/l e Reintroduction day VPA & quetiapine without elevation of liver enzymes Longin et al. 16 1 year and Lennox- VPA 50 mg/ >400/>150 U/l VPA & TPM Complete 5 months/M Gastaut kg/day stopped recovery of syndrome liver enzymes TPM 7 mg/ 61 mmol/l d Carnitine 100 kg/day mg/kg/day Bumb et al. 17 51 years/F Symptomatic VPA 3600 262/464 U/l VPA stopped; e Somnolence epilepsy after mg/day improved in clipping of a few days aneurysm TPM 250 mg/ 52 mmol/l d TPM continued Normal ASAT day & ALAT f Start gabapentin a ASAT level is not mentioned in the manuscript. b Information which medication was immediately stopped is not given in this letter. c The woman described by Doan and Clendenning was on a regimen of VPA, benztropine, risperidone, clonazepam and an oral contraceptive. Simultaneous with the introduction of TPM, clonazepam was stopped and flurazepam was added to the medication. d Ammonia concentration not mentioned by Bjoro et al. In the articles by Longin et al. and Bumb et al., ammonia concentration is expressed in mg/dL (1 mg/dL = 0.588 mmol/L). e Both the articles by Bjoro et al., Doan and Clendenning and Bumb et al. do not mention L-carnitine supplementation. f The woman described by Bumb et al. also used citalopram, omeprazole, enoxaparin and lorazepam. 96 J. Nicolai et al. there have to be other mechanisms beside the venous ammonia concentrations. This is a result of exposure to VPA and TPM. A potential mechanism inhibition of the glutamine synthetase enzyme by for liver damage especially in this group is the TPM. Glutamine synthetase is essential in the break- rigorous treatment of fever with acetaminophen. down of ammonia and glutamate inside neurons, so Searching Medline and PUBMED, we have not been inhibition leads to an increase of intracellular able to find any interaction between VPA and acet- ammonia concentrations. In several patients aminophen or TPM and acetaminophen. However, reported, consciousness improved significantly after the time-interval between fever, ingestion of acet- withdrawal of TPM, although venous ammonia levels aminophen, seizures and discovery of liver enzyme did not change.21,22 disturbances in our four cases and normal carnitine concentrations at admission in case No. 3, suggest that accumulation of metabolites of acetamino- Conclusion phen, due to inhibition of cytochrome P450 enzymes by VPA and TPM, is possibly responsible for hepato- We report four young children diagnosed with Dra- toxicity. Another mechanism could be reduced glur- vet syndrome that developed a rise in liver enzymes uronide conjugation of acetaminophen due to the (and a rise of ammonia in two children) after admis- fact that this pathway is already used in VPA elim- sion because of an epileptic status. All were treated ination. A very interesting study found that stiripen- with VPA and TPM and with acetaminophen because tol is able to prevent hepatic necrosis after of fever the days before admission. It is important to 18 acetaminophen overdose in rats. Stiripentol inhi- note that liver toxicity occurred in two children bits the synthesis of N-acetyl-p-benzoquinone- while they had adequate L-carnitine supplementa- 18 imine, a highly reactive metabolite. In clinical tion. The clinical course of those four children practice, the combination of stiripentol, VPA, and supposes that there may be other mechanisms TPM seems safe; in a retrospective series of 24 beside the exposure to TPM and VPA. 10 children no liver problems were reported. The time-interval between fever,acetaminophen, Case No 1. received 73 mg/kg/day acetamino- epileptic status and liver enzyme disturbances in our phen. It is advised that the daily dose should not four cases suggests that accumulation of toxic acet- 19 exceed 75 mg/kg. However, also the use of acetaminophen-metabolites is possibly responsible for aminophen in normal dose can lead to an elevation the liver toxicity. Only future research and clinical of transaminases. 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