Effect of Topiramate, in Combination with Lidocaine, and Phenobarbital, in Acute Encephalitis with Refractory Repetitive Partial

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Brain & Development 31 (2009) 605–611 www.elsevier.com/locate/braindev Original article Eﬀect of topiramate, in combination with lidocaine, and phenobarbital, in acute encephalitis with refractory repetitive partial seizures

Jainn-Jim Lin a,b, Kuang-Lin Lin a,*, Huei-Shyong Wang a, Shao-Hsuan Hsia b, Chang-Teng Wu b

a Division of Pediatric Neurology, Chang Gung Children’s Hospital and Chang Gung Memorial Hospital, Chang Gung University College of Medicine, #5 Fu-Shin Street, Kwei-Shan, Taoyuan 333, Taiwan b Divisions of Pediatric Critical Care and Emergency Medicine, Chang Gung Children’s Hospital and Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

Received 6 February 2008; received in revised form 11 September 2008; accepted 15 September 2008

Abstract

Objective: Acute encephalitis with refractory repetitive partial seizure (AERRPS) is a peculiar type of post-encephalitic/enceph- alopathic epilepsy. Here we report an analysis of AERRPS in a series of children and propose an effective treatment option for seizure control in these children. Methods: We retrospectively reviewed cases of AERRPS treated in a pediatric intensive care unit, between February 2002 and June 2006. Clinical characteristics were systemically assessed. Burst suppression coma was induced by high-dose suppressive therapy; 24-h electroencephalogram (EEG) monitoring was performed on each patient. The goal of treatment was to achieve complete clinical seizure control or burst-suppression pattern on EEG, aiming for an interburst interval of >5 s. Brain imaging was done for each patient. Results: There were nine patients (seven boys), aged 5–15 years. Clinical symptoms included fever (100%), upper respiratory symptoms (66.7%) and altered consciousness (66.7%). All patients received multiple high-dose suppressive drugs and were intubated with/without inotropic agents. Seizures in three patients were stopped after high-dose lidocaine infusion (6–8 mg/kg/h) in the acute stage and three patients were stopped after high dose phenobarbital (serum level 60–80 ug/mL) combined with high-dose oral topiramate (15–20 mg/kg/day). Follow-up for this study was 16–61 months. Two subjects died while seven developed epilepsy and/or neurologic deficits; none returned to baseline. All survivors were discharged and continued multiple antiepileptic medications. Conclusions: Our data indicates that children with AERRPS have high mortality and morbidity rates. High-dose topiramate combined with high-dose lidocaine infusion or high-dose phenobarbital in the acute stage might be an effective treatment option for children with AERRPS. Ó 2008 Elsevier B.V. All rights reserved.

Keywords: Acute encephalitis with refractory; Repetitive partial seizures

1. Introduction 1986 as a peculiar type of post-encephalitic epilepsy [1]. It is a rare condition wherein acute encephalitis is accom- Acute encephalitis with refractory, repetitive, partial panied by prolonged and refractory status epilepticus seizures (AERRPS) was ﬁrst reported by Awaya in from the onset of the disease, and intractable partial seizures persist even after recovery from the acute illness.

* Corresponding author. Tel.: +886 3 328 1200x8200; fax: +886 3 The incidence of AERRPS is unknown. Approximately 328 8957. 40 similar Japanese cases have been reported. Sakuma E-mail address: [email protected] (K.-L. Lin). et al. proposed the term AERRPS to describe this epilep-

0387-7604/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2008.09.010 606 J.-J. Lin et al. / Brain & Development 31 (2009) 605–611 tic syndrome, with the following diagnostic criteria: (1) The diagnosis of seizure patterns and seizure types in acute phase lasting for two or more weeks, (2) persistent the acute phase were based upon clinical impressions of partial seizures of a similar nature occurring from the the attending neurologists. Frequencies of emergence in acute phase through to the recovery phase, (3) frequent the acute stage were categorized as less than 10 min, seizures often evolving into recurrent status epilepticus, every 10–20 min and more than 20 min. The seizure pat- (4) marked intractability of the seizures, and (5) exclusion terns, seizure types and the maximum frequency of of a specific etiology such as viral encephalitis and meta- emergence in the chronic phase (defined as last visit) bolic disorders [2]. However, many children with ‘‘viral were described by family. EEGs were categorized as encephalitis” stemming from undetected viral agents having either a high voltage slow wave, or a focal, mul- tend to have similar clinical courses with refractory repet- tifocal or generalized epileptiform discharge. Metabolic itive seizures. AERRPS may be a heretogeneous entity, survey included analysis of blood samples by tandem where infective or autoimmune factors may be involved mass, urine organic acid, serum total and free carnitine in the pathogenesis. This condition is diagnosed by the concentrations. Patient outcomes, including mortality, listed criteria, and we identified nine Taiwanese patients new neurological deficits and return to baseline, were presenting with clinical symptoms and courses which determined from the last clinical visit, which was a min- met the criteria for AERRPS. We also found that addi- imum of 6 months after the episode of status epilepticus. tional treatment options were effective for the manage- The follow-up for the study group was 16–61 months. ment of acute-phase seizures in these patients, apart from the barbiturate therapy that has been recommended 3. Results in preceding reports [3]. Ages at presentation for the nine children (two girls) 2. Subjects and methods ranged from 5–15 years. Prodromal symptoms included fever (9/9, 100%), upper respiratory symptoms (6/9, From February 2002 to August 2006, nine children 66.7%), altered consciousness (6/9, 66.7%), vomiting with AERRPS, treated in the pediatric intensive care (4/9, 44.4%) and headache (4/9, 44.4). Acute phase unit of Chang Gung Children’s Hospital, were enrolled. duration ranged from 20 to 52 days. The seizure patterns Approval for this study was obtained from the institu- of emergence, in the acute stage of hospitalization, were tional review board. Information was collected by retro- categorized as simple/complex partial (1/9, 11.1%), com- spective chart review regarding age, sex, clinical plex partial (4/9, 44.4%), primary complex partial and symptoms, initial seizure type, initial EEG patterns, secondary generalized (4/9, 44.4%). The most common neuroimaging, cerebrospinal fluid (CSF) analysis, meta- partial seizure types in the acute phase were eye devia- bolic survey, acute-stage suppressive drugs, hospital tion (9/9, 100%), hemifacial twitching (9/9, 100%) and days and outcomes. hemiclonic (6/9, 66.7%) and apneic seizures (9/9, AERRPS was diagnosed according to the diagnostic 100%). Frequencies of emergence in the acute phase criteria proposed by Sakuma. All children were previ- were divided into three groups: less than 10 min (3/9, ously healthy and none had prior seizures, including feb- 33.3%), every 10–20 min (4/9, 44.5%) and greater than rile seizures. Any children with a prior neurological 20 min (2/9, 22.2%). The initial EEG patterns of admis- insult, progressive neurological disorder, electrolytic sion revealed high voltage slow wave in 4 (44.4%), focal imbalance, hypoglycemia and a family history of epi- epileptiform discharge in 1 (11.1%), multifocal in 2 lepsy or febrile seizures were excluded. The acute phase (22.2%) and primary multifocal with secondary general- was defined as a period of appearance of diffuse, peri- ized in 2 (22.2%) subjects. EEG patterns during the odic bursts of high voltage spikes on EEG [2]. The goal acute stage revealed high-voltage slow-wave with multi- of treatment was to achieve complete clinical seizure focal epileptiform discharge in 4 (44.4%), and high-volt- control or burst-suppression pattern on electroencepha- age slow-wave with primary multifocal and secondary logram (EEG), aiming for an interburst interval of >5 s generalized in 5 (55.6%) subjects. Clinical characteris- [4]. Burst suppression coma was induced by high-dose tics, duration of acute phase and EEG patterns of all suppressive therapy consisting of midazolam, lidocaine, nine children are summarized in Table 1. Seizure types, propofol and thiopental. The duration of first-cycle patterns of emergence and frequencies in the acute and burst suppression was 2–4 days. Weaning of high-dose chronic phases are listed in Table 2. suppressive therapy was guided by EEG monitoring All patients underwent a thorough investigation dur- [5]. The weaning process was aborted if there was return ing their hospitalization, including serological tests for of status epilepticus or frequent clinical or electro- viruses, polymerase chain reaction (PCR) in CSF for graphic seizures. All children were cared for in the pedi- Herpes Simplex Virus (HSV) DNA (n = 5) and viral cul- atric intensive care unit. Round-the-clock EEG tures of throat (n = 8), CSF (n = 9), and rectal (n =8) monitoring was performed on each patient. All EEGs specimens. Most children underwent serological tests were interpreted by pediatric neurologists. for influenza A and B (n = 9), HSV (n = 8), Epstein- J.-J. Lin et al. / Brain & Development 31 (2009) 605–611 607

Table 1 Characteristics, duration of acute phase and EEG patterns of nine AERRPS children Case Age Sex Clinical symptoms Duration of acute EEG patterns phase (days) Initial Acute phase Last EEG 1 9y9m M Fever, URI, vomiting 26 H H/MFE H/MFE 2 15y3m M Fever, headache, URI, sore throat 23 FE H/MFE/GE H/MFE 3 9y8m M Fever, headache, URI 20 MFE/GE H/MFE/GE H/MFE 4 14y5m F Fever, headache, vomiting, URI 52 MFE/GE H/MFE/GE H/FE 5 9y3m M Fever, headache, vomiting 26 MFE H/MFE H/FE 6 6y1m F Fever, URI 31 H H/MFE H/MFE 7 6y9m M Fever, conscious change 30 MFE H/MFE/GE FE 8 5y2m M Fever, conscious change 35 H H/MFE H/MFE 9 11y8m M Fever, URI 30 H H/MFE H/MFE M, Male; F, Female; EEG, Electroencephalogram, URI, Upper respiratory tract infections; EEG pattern: H, High-voltage slow-wave; FE, Focal epileptiform discharge; MFE, Multifocal epileptiform discharge; GE, Generalized epileptiform discharge.

Table 2 Types, patterns of emergence and frequency of seizures of nine AERRPS children in acute and chronic phases Case Acute phase Follow up (months) Chronic phase (Last visit) Seizure patterns Seizure types Frequency (maximum) Seizure patterns Seizure types Frequency (maximum) 1 C/GTC 1,2,4,5 <10 min 61 C/GTC 1,2,4,5 >10 times/day 2 C/GTC 1,2,3,4,5 10–20 min (Died) 3 C/GTC 1,2,3,4,5 <10 min (Died) 4 C/GTC 1,2,3,4,5 <10 min 30 C 1,2,4 3–4 times/day 5 C 1,2,4 >20 min 22 C 1,2,4 1–2 times/day 6 C 1,2,3,4 10–20 min 17 C 1,2,3,4 >10 times/day 7 C 1,2,3,4 10–20 min 28 C 1,2,4 3–4 times/day 8 S/C 1,2,3,4 10–20 min 23 C/GTC 1,2,3,4,5 5–8 times/day 9 C 1,2,4 >20 min 16 C 1,2,4 3–4 times/day Seizure patterns: S, Simple partial seizure; C, Complex partial seizure; GTC, Generalized tonic–clonic. Seizure types: (1) Eye deviation; (2) Hemifacial twitching; (3) Hemiclonic; (4) Apneic seizures; (5) Generalized tonic–clonic.

Barr virus (EBV) (n = 7), Mycoplasma pneumoniae encephalopathy; four had no specific findings. Follow- (n = 9), and Human herpes virus 6 (HHV-6) (n = 2). up phase cranial CT (n = 4) or MRI (n = 3) revealed In all cases, no organisms were identified by CSF bacte- brain atrophy in six patients and hippocampal atrophy rial and viral culture. Metabolic surveys were performed in one patient. Table 4 shows the brain imaging from in all patients and all were negative. the nine AERRPS children. Lumbar punctures were performed in nine patients. In terms of management, all patients received multi- White blood cell (WBC) count in the CSF studies ran- ple high-dose suppressive drugs and were intubated ged from 0 to 31 cells/uL; there was a predominance with/without inotropic agents. Eight patients received of monocytes (60–100%). CSF glucose levels ranged intravenous immunoglobulin (IVIG). The seizures of from 48 to 104 mg/dL and protein levels were 12.1– three patients (Patient #4–6) were stopped after high- 179.5 mg/dL. Table 3 summarizes serum and CSF dose lidocaine infusion (6–8 mg/kg/h) in the acute stage, data. followed by high-dose oral topiramate (15–20 mg/kg/ Neuroimaging studies [computed tomography (CT) day) combined with multiple anticonvulsants. In the or magnetic resonance imaging (MRI)] were divided three patients (Patient #7–9), burst suppression was into an initial phase (<1 week after disease onset), hos- achieved by midazolam infusion and the midazolam pitalization phase (1 week to 3 months after disease infusion could terminate the seizures temporally, but onset) and follow-up (>3 months after disease onset). the seizures were still present later. Finally, they were Cranial CT (n = 6) performed during the initial phase stopped after high-dose phenobarbital (serum level: was non-specific and included leptomeningeal enhance- 60–80 ug/mL) and combined with high-dose oral topira- ment or brain swelling with sulcal effacement, whereas mate (15–20 mg/kg/day) in the acute stage, and the high hospitalization-phase MRI (n = 9) revealed mild atro- dose phenobarbital and topiramate were effective to phy in one patient. Two patients had unilateral or bilat- taper off the midazolam infusion. A cluster of seizures eral hippocampal hyperintensities in T2, suggesting in Patient #1 was terminated after thiopental (10 mg/ focal edema. Two others had global hypoxic ischemic kg/h). Another (Patient #2) was stopped after thiopen- 608 J.-J. Lin et al. / Brain & Development 31 (2009) 605–611

Table 3 Laboratory data of nine children with AERRPS Serum CSF Metabolic screening WBC(/ul) S/L/B (%) CRP (mg/dl) WBC(/ul) RBC(/ul) TP(mg/dl) Sugar(mg/dl) Culture 1 7800 54/30/3 5.2 13 387 – – NN 2 9500 72/16/11 <2.0 31 9000 175.9 88 NN 3 13900 82.0/6/10 53.55 1 2 – – NN 4 11900 81.0/10/7 2.85 0 0 16.6 62 NN 5 5800 62/21/3 1.02 1 0 17.8 80 NN 6 7900 84.0/10/6 46.03 0 110 12.1 48 NN 7 2700 75/15/30 4.87 – – 142.4 104 NN 8 2200 54/39/3.7 0.89 6 2 26 82 NN 9 7200 41/54 3.76 0 1 54.4 81 NN CSF, Cerebrospinal ﬂuid; S/L/B, Segmental/lymphocyte/band; TP, Total proteins. Culture; Bacterial and viral culture; N, Negative. Metabolic screening: Tandem mass (blood organic acid); Urine organic acid; Free and total carnitine.

Table 4 Brain images of nine AERRPS children Initial phase Hospitalization phase Follow-up phase Brain CT Brain MRI 1 No specific finding Profound HIE Diffuse multicystic encephalomalacia (CT) 2 No specific finding No specific finding 3 ND Cortical laminar necrosis, global hypoxia Diffuse multicystic encephalomalacia (CT) 4 No specific finding Bilateral hippocampus sclerosis Hippocampus atrophy (MRI) 5 ND Increased leptomeningeal enhancement 6 No specific finding Brain atrophy Brain atrophy, hydrocephalus (CT) 7 No specific finding Left medial temporal lobe Diffuse brain atrophy (MRI) 8 No specific finding No specific finding Cortical atrophy (CT) 9 ND Increased leptomeningeal enhancement Diffuse brain atrophy (MRI) CT, Computed tomography; MRI, Magnetic resonance imaging; ND, Not done. Initial phase: <1 week after disease onset; Hospitalization phase: 1 week to 3 months after disease onset; Follow-up phase neuroimaging: >3 months after disease onset. tal (10 mg/kg/h). Patient #3 had persistent seizures after eyelid twitching and smacking, on day 6 of admission, a combination therapy of lidocaine (6 mg/kg/h) and the midazolam infusion rate was increased to 1.2 mg/ propofol (6 mg/kg/h). All of these latter three patients kg/h. When the midazolam infusion rate was increased had severe cardiopulmonary complications, including up to 0.7 mg/kg/h, inotropic agents were required for profound hypotension, despite inotropic agent use. hypotension management. Because of the emergence of Two of these three patients died. Patient #2 died from frequent clinical/subclinical seizures, we administered the adverse effects of thiopental-induced profound hypo- high-dose lidocaine (6 mg/kg/h) on day 9. Subsequent tension, despite inotropic agent use. Patient #3 died of EEG revealed a burst-suppression pattern (Fig. 1B). sepsis. Total duration of high-dose suppressive therapy The propagation of the focal epileptiform discharges ranged from 20 to 41 days. Total durations of high-dose decreased markedly. Clinical seizures terminated within suppressive therapy are listed in Table 5. 24 h of high-dose lidocaine infusion. Topiramate (1 mg/ As a representative example, patient #4, a 14-year- kg/day) was started via nasogastric tube on day 9. old female, experienced high fever, headache and fluctu- Localized rhythmic epileptiform discharges persisted, ations of consciousness on the second day of illness and generalization increased after the dose of lidocaine along with complex partial with/without secondary gen- was tapered (Fig. 1C). We then increased the dosage eralized tonic–clonic convulsions. On admission, she of topiramate (1 mg/kg/day) every 3 days, up to was comatosed and on artificial ventilation. CSF cell 15 mg/kg/day on day 51. After trials with various com- count and brain CT were normal. Phenytoin, phenobar- binations of anticonvulsants, the complex partial sei- bital, and valproic acid could not suppress the recurrent zures were controlled to less than 2–3 times/day by seizures, and midazolam infusion was initiated on day 2 treatment with clonazepam, high dose phenobarbital of admission. EEG on admission showed multifocal epi- (10 mg/kg/day), valproic acid, and high-dose topiramate leptiform discharges over the bilateral hemispheres (15 mg/kg/day). Lidocaine could be completely tapered (Fig. 1A). Due to repetitive generalized seizures, with off after 41 days of continuous infusion. A diffuse sharp J.-J. Lin et al. / Brain & Development 31 (2009) 605–611 609

Table 5 Management and outcomes of nine children with AERRPS MV Inotropic IVIG AED in acute phase Duration Hospital Outcome AED during follow-up agent of HDST days Ineﬀective Eﬀective 1 Y D+E Y PHT,PB,VPA Thiopental (10 mg/kg/h) 26 83 Epilepsy VPA + TPM + LEV MDL(1.2 mg/kg/h), Vegetative + OXC + clonazepam Propofol (6 mg/kg/h) status 2 Y D+E Y PHT,PB,VPA Thiopental (10 mg/kg/h) 20 27 Expired – MDL(1.2 mg/kg/h) 3 Y D+E Y PHT,PB,VPA Lidocaine(6 mg/kg/h) 20 271 Expired – MDL(1.2 mg/kg/h) + Propofol(6 mg/kg/h) 4 Y D Y PHT,PB,VPA, Lidocaine(6 mg/kg/h) 41 102 Epilepsy HPB + TPM + LEV MDL(1.2 mg/kg/h) ? TPM(15 mg/kg/day) Moderate + acetazolamide PMR 5 Y D Y PHT,PB,VPA Lidocaine(6 mg/kg/h) 21 65 Epilepsy HPB + TPM + OXC + MDL(1.2 mg/kg/h) ? TPM(15 mg/kg/day) Mild PMR tiagabine 6 Y D Y PHT,PB,VPA, Lidocaine(8 mg/kg/h) 21 137 Epilepsy HPB + TPM + PHT MDL(1.2 mg/kg/h) ? TPM(20 mg/kg/day) Vegetative + LEV status 7 Y – Y PHT,PB,VPA HPB + TPM(15 mg/kg/day) 27 63 Epilepsy HPB + TPM + VPA MDL(1.2 mg/kg/h) Severe + clonazepam PMR 8 Y D Y PHT,PB,VPA HPB + TPM(15 mg/kg/day) 33 107 Epilepsy VPA + TPM + MDL(1.2 mg/kg/h) Severe PMR clonazepam 9 Y – – PHT,PB,VPA HPB + TPM(20 mg/kg/day) 20 63 Epilepsy HPB + VPA + MDL(1.2 mg/kg/h) Mild PMR carbamazepine + clonazepam MV, Mechanical ventilation; D, Dopamine, E, Epinephrine; AED, Anticonvulsant; HDST, High-dose suppressive therapy. PHT, Phenytoin, PB, Phenobarbital, HPB, High-dose phenobarbital, VPA, Valproic acid; MDL, Midazolam, TPM, Topiramate. LEV, Levetiracetam, OXC, Oxcarbazepine; PMR, Psychomotor retardation.

Fig. 1. Electroencephalographic findings in patient #4. (A) EEG, obtained on admission day 1, showing multiple focal epileptiform discharges over bilateral hemispheres. (B) Burst-suppression pattern can be seen on the EEG, who received high-dose lidocaine infusion (6 mg/kg/h) on day 9. (C) Localized rhythmic epileptiform discharges persisted and generalization increased after the dose of lidocaine was tapered to 5 mg/kg/h on day 14. (D) A diffuse sharp wave can be noted over bilateral hemispheres after the discontinuation of lidocaine on day 55. 610 J.-J. Lin et al. / Brain & Development 31 (2009) 605–611 wave was noted over the bilateral hemispheres after the Neuroimaging in AERRPS patients usually shows discontinuation of lidocaine (Fig. 1D). non-specific, mild atrophy of the cerebrum [6]. In our ser- With regards to the outcome of the nine children, ies, the brain CT in the acute phase showed no specific two died and seven survived. Hospital stays ranged findings, such as increased leptomeningeal enhancement from 63 to 137 days. All survivors were discharged or brain swelling, whereas the follow-up brain CT on antiepileptic medications. Seven children were fol- (n = 4) or MRI (n = 3) revealed brain atrophy in six lowed up with a minimum duration of 6 months. All patients and hippocampal atrophy in one patient. How- seven developed epilepsy and/or neurological deficits, ever, the presence of ‘‘hypoxic–ischemic encephalopathy” and none returned to baseline. Three showed mild to is quite unusual for AERRPS, and may be secondary. moderate psychomotor retardation, two patients In the acute stage, high-dose barbiturate anesthesia is remained severely psychomotor retarded and two the sole means to suppress such refractory, repetitive showed vegetative status. All survivors were dis- partial seizures. Sakuma et al. reviewed the efficacy of charged on multiple antiepileptic medications. Man- anticonvulsants in 21 AERRPS cases and found that agement and outcomes of the nine children with barbiturate infusion was effective in 15 out of 17 cases, AERRPS are summarized in Table 5. including five cases treated with pentobarbital sodium at a dose higher than 5 mg/kg/h [2]. Saito et al. studied 4. Discussion three AERRPS patients who required high-dose pentobarbital therapy under artificial ventilation in the acute Refractory epileptic seizures for AERRPS begin at stage and proposed high-dose barbiturate anesthesia as the onset of encephalitis as status epilepticus or clusters a tentative therapeutic strategy for the acute stage of this of seizures. All of our cases had a history of acute febrile catastrophic epileptic syndrome [3]. Since pentobarbital illness, and suddenly developed refractory status epilep- was not available in Taiwan, we tried different agents ticus. Based on these symptoms, along with mild pleocy- beyond the recommended dosage guildelines [7–15]. tosis or elevated CSF proteins, a diagnosis of We used high-dose lidocaine continuous infusion (6– encephalitis was made for these patients; however, no 8 mg/kg/h) in three patients, which resulted in seizure infective agents were identified. termination within 24–36 h. In addition, we used high- A hypothesis concerning AERRPS etiology, includ- dose phenobarbital (serum level: 60–80 ug/mL) com- ing unknown viral infection or immunological disorders, bined with high dose topiramate (15–20 mg/kg/day) in has been proposed in Japan. When Awaya et al. three other patients and successfully controlled seizures reported AERRPS, cases of influenza encephalopathy in the acute stage. Topiramate is an anticonvulsant with were not well recognized or detected as much as now. multiple mechanisms of action, including modification Some patients with influenza encephalopathy may also of Na+ and/or Ca++-dependent action potentials, have similar clinical presentations. Besides, children enhancement of GABA-mediated ClÀ fluxes into neu- with genetic disorders such as with SCN1A mutation rons, and inhibition of kainate-mediated conductance may have similar clinical presentations. In our cases, at glutamate receptors of the AMPA/kainate type. In serology for influenza A and B were done on all nine addition, topiramate has been shown to reduce neuronal children and all were negative. However, we did not injury after prolonged status epilepticus and may check for the SCN1A mutation. Further study is neces- prevent delayed neuronal death [15]. Because of these sary to establish the etiology. multiple mechanisms of action and potential neuropro- The characteristic of epilepsy in AERRPS is that an tective effects, topiramate was evaluated as an agent to identical seizure pattern, consisting of complex partial treat refractory status epilepticus. In previous reports seizures with or without secondary generalization. Apart in children, topiramate administered via a nasogastric from the secondary generalization during the early tube has been reported to be effective in terminating phase, (1) eye deviation, (2) hemifacial twitching, (3) refractory status epilepticus. Two pediatric series have hemiclonic or (4) apneic seizures are the predominating used low initial doses of topiramate (1–5 mg/kg/day), seizure types in both acute and chronic phases in indi- with titration to doses ranging from 5 to 25 mg/kg/d vidual patients [3]. This suggests that the essential over several days [12–13]. Another pediatric study used pathology underlying the long-term refractory seizures 10 mg/kg/d, for two consecutive days, followed by is initiated during the acute phase of illness, in contrast maintenance doses of 5 mg/kg/day [14]. In each case, to the usual post-encephalitic epilepsy with a latent per- status epilepticus was aborted within 24–72 h after iod. In our cases, the seizure type in the acute stage of reaching the maximum dose. In our study, we used a hospitalization was categorized as simple/complex par- lower initial dose of topiramate (1 mg/kg/day) and tial (1/9, 11.1%), complex partial (4/9, 44.4%), primary titrated to doses ranging about 15–20 mg/kg/day over complex partial and secondary generalized (4/9, several days. Seizures were aborted within 24–72 h after 44.4%). The clinical features and seizure pattern of our reaching the maximum dose. Topiramate was not patients all met the criteria of AERRPS. enough to control the seizures alone; however, as above, J.-J. Lin et al. / Brain & Development 31 (2009) 605–611 611 there appears to have been some beneficial effect of topi- seizures: case reports of this unusual post-encephalitic epilepsy. ramate regarding mortality, as two out of three patients Brain Dev 2007;29:147–56. that did not receive topiramate died, while six out of [4] Sahin M, Riviello Jr JJ. Prolonged treatment of refractory status epilepticus in a child. J Child Neurol 2001;16:147–50. seven who received topiramate survived. Therefore, we [5] Lin JJ, Lin KL, Wang HS, Hsia SH, Wu CT. Analysis of status propose that high-dose lidocaine or high dose phenobar- epilepticus related presumed encephalitis in children. Eur J bital combined with high dose topiramate might play an Paediatr Neurol 2008;12:32–7. important role for seizure control in the acute stage of [6] Fukuyama Y, Awaya Y, Hayashi K, Miyamoto A. On a peculiar AERRPS. type of post-encephalitis/encephalopathy epilepsy (in Japanese). In: Seino S, editor. Research on the prevention and management of intractable epilepsy. Tokyo: Report of Research Grant for 5. Conclusion Neurological Disorders from the Ministry of Health and Welfare; 1989. p. 131–6. [7] Basu H, Callaghan FO’. Status epilepticus: beyond guidelines. Because of the small number of patients, there are Curr Paediatr 2005;15:324–32. limitations to interpretation of the results; further stud- [8] Pascual J, Sedano MJ, Polo JM, Berciano J. Intravenous ies may be needed to confirm such findings in a larger lidocaine for status epilepticus. Epilepsia 1988;29:584–9. number of children with AERRPS. Nevertheless, in this [9] De Giorgio CM, Altman K, Hamilton-Byrd E, Rabinowicz AL. report, we demonstrate a tentative therapeutically effec- Lidocaine in refractory status epilepticus: confirmation of efficacy with continuous EEG monitoring. Epilepsia 1992;33:913–6. tive regimen for seizure control. High-dose topiramate [10] Aggarwal P, Wali JP. Lidocaine in refractory status epilepticus: a combined with high-dose lidocaine infusion or high- forgotten drug in the emergency department. Am J Emerg Med dose phenobarbital in the acute stage might be an 1993;11:243–4. effective treatment option in children with AERRPS. [11] Walker IA, Slovis CM. Lidocaine in the treatment of status epilepticus. Acad Emerg Med 1997;4:918–22. [12] Kahriman M, Minecan D, Kutluay E, Selwa L, Beydoun A. References Efficacy of topiramate in children with refractory status epilepticus. Epilepsia 2003;44:1353–6. [1] Awaya Y, Fukuyama Y. Epilepsy sequelae of acute encephalitis [13] Blumkin L, Lerman-Sagie T, Houri T, Gilad E, Nissenkorn or encephalopathy (third report). Jpn J Psychiatry Neurol A, Ginsberg M, et al. Pediatric refractory partial status 1986;40:385–7. epilepticus responsive to topiramate. J Child Neurol [2] Sakuma H, Fukumizu M, Kohyama J. Efficacy of anticonvulsants 2005;20:239–41. on acute encephalitis with refractory, repetitive partial seizures [14] Perry MS, Holt PJ, Sladky JT. Topiramate loading for refractory (AERRPS) (in Japanese). No To Hattatsu 2001;33:385–90. status epilepticus in children. Epilepsia 2006;47:1070–1. [3] Saito Y, Maegaki Y, Okamoto R, Ogura K, Togawa M, Nanba [15] Niebauer M, Gruenthal M. Topiramate reduces neuronal injury Y, et al. Acute encephalitis with refractory, repetitive partial after experimental status epilepticus. Brain Res 1999;837:263–9.