Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Original article
Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase Riyo Ueda a, Yoshiaki Saito a, Koyo Ohno a, Kanako Maruta b, Kunihiro Matsunami b, Yusuke Saiki a, Tatsuyuki Sokota a, Susumu Sugihara a, Yoko Nishimura a, Akiko Tamasaki a, Aya Narita a, Atsushi Imamura b, Yoshihiro Maegaki a,⇑ a
Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori Univesity, Yonago, Japan b Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan Received 16 June 2014; received in revised form 5 August 2014; accepted 7 August 2014
Abstract Aim: To clarify the effect of levetiracetam (LEV) for acute and chronic seizure control in acute encephalitis with refractory, repetitive partial seizures (AERRPS). Methods: We retrospectively reviewed the clinical course of six AERRPS cases treated with LEV, and explored the acute phase termination by withdrawal from barbiturate-induced coma under artificial ventilation, and the reduction in seizure frequency during the chronic phase. LEV was administrated orally or via nasogastric tubes as an add-on agent during acute (n = 3; age 8–10 years) and chronic (n = 3; age 19–30 years) AERRPS. Results: In the acute phase, administration of LEV (50–60 mg/kg/d) in combination with phenobarbital (n = 3; peak 57.9– 76.1 lg/ml) and potassium bromide (n = 2; 30–36 mg/kg/d)) resulted in successful reduction of intravenous barbiturate dosage and withdrawal from artificial ventilation. In the chronic phase, seizure frequency reduced by >75% for 5–18 months with LEV 750–1500 mg/d. Conclusion: LEV may affect seizure control in AERRPS, particularly during the chronic phase, through its unique action of inhibition of excitatory neurotransmitter release. The regimen of oral barbiturate, potassium bromide and LEV would be worth for trial during the acute phase of AERRPS. Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Status epilepticus; Levetiracetam; Febrile infection-related epilepsy syndrome; Barbiturate coma
1. Introduction Acute encephalitis with refractory repetitive partial seizures (AERRPS), or febrile infection-related epi⇑ Corresponding author. Address: Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori Univesity, 36-1 Nishi-cho, Yonago 683-8504, Japan. Tel.: +81 859 38 6777; fax: +81 859 38 6779. E-mail address: [email protected] (Y. Maegaki).
lepsy syndrome (FIRES), is a devastating seizure disorder of unclear etiology [1,2]. Typically, a schoolaged child manifests encephalitis-like symptoms that include a fever, followed by convulsive seizures and unconsciousness. Moreover, seizure control is subsequently more difficult than is normally the case with encephalitis, and frequently requires intensive suppressive therapy with high-dose barbiturate under artificial ventilation and vasopressor support. This acute, stormy phase lasts from 1 to several months, and
http://dx.doi.org/10.1016/j.braindev.2014.08.003 0387-7604/Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
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R. Ueda et al. / Brain & Development xxx (2014) xxx–xxx
the duration correlates with the degree of residual intellectual impairment [2]. Certain antiepileptic medications, including oral barbiturates, potassium bromide (KBr), and high-dose topiramate, as well as a ketogenic diet, appear helpful for withdrawal from the intensive therapy in individual cases [1,3–5]. However, further treatment options are needed to improve the outcomes in patients with AERRPS. In addition, intractable epilepsy often persists after the acute symptoms have resolved, and no optimal antiepileptic has been established. Levetiracetam (LEV) is a new antiepileptic drug with a novel pharmacological action involving presynaptic inhibition of excitatory neurotransmitter release. Furthermore, LEV has a broad therapeutic remit, and is reportedly effective for the treatment of refractory status epilepticus that is not controlled by benzodiazepines, phenytoin, or barbiturates [6]. Because LEV has been commercially available in Japan since 2010, experience has been accumulating on its use in children with epilepsy. In this study, we aimed to clarify the effect of LEV on acute and chronic seizure control in patients with AERRPS. 2. Subjects and methods We enrolled six children who suffered from AERRPS at the age of 7–10 years (4 males and 2 females, aged 8–30 years at the last follow-up) (Table 1). Clinical data were reviewed from the medical charts, including: encephalopathic symptoms such as the frequency and semiology of seizures; the results of laboratory, electroencephalography (EEG), and neuroimaging examinations; and the antiepileptic treatment regimen, together with any recorded blood concentrations or adverse effects. Specifically, we explored both the acute-phase termination, by withdrawal from barbiturate-induced burst suppression coma under artificial ventilation, and the reduction of seizure frequency during the chronic phase. Some of the clinical information concerning Patients 5 and 6 had previously been reported [3]. The study protocol was approved by our institutional review board. Clinical course of each child met the mandatory diagnostic criteria of AERRPS, except for one patient who had a preceding history of febrile seizures (Patient 2), and another who had two afebrile seizures (Patient 1). Psychomotor development was normal before the onset of disease, but moderate to severe intellectual disabilities were observed during the chronic phase in all participants. LEV was administrated during the acute phase in three patients and during chronic phase in the other three patients.
3. Results The onset of repetitive seizures with unconsciousness was preceded by 2–5 days of febrile illness in all participants. Transient resolution of pyrexia for >12 h on the day before the onset of encephalopathy was recorded for three subjects, suggesting a biphasic clinical course. In each case, seizures with generalization were predominant at the onset, but soon evolved to focal seizures with facial twitching, ocular deviation, apnea/salivation, and versive neck motion (Table 1). In each patient, EEG revealed asynchronous high-voltage slow activity with a frequent, often semirhythmic, and continuous emergence of spikes and/or sharp waves with multiple foci. Mild pleocytosis (14–40/ll) was noted in the cerebrospinal fluid at this stage in all cases. In five of the patients, treatment of the frequent seizures and persistent fever (lasting 1–3 months) was via burst-suppression coma therapy with a high-dose barbiturate and artificial ventilation for 23–45 days. The remaining patient was treated by continuous midazolam infusion and repeated bolus injection of pentobarbital in the acute phase (Patient 4). LEV was administrated during the acute phase in three patients (Figs. 1–3). In Patient 1, LEV was initiated with a gradually increasing dose toward day 26 of admission, resulting in a successful reduction of the thiamylal dosage (Fig. 1). This enabled the patient to be withdrawn from the burst-suppression coma and artificial ventilation. After thiamylal termination, the seizures recurred during treatment with LEV and valproate, and were suppressed after the addition of phenobarbital (PB) and increasing LEV doses (200 mg PB and 1500 mg LEV). Thereafter, the patient gradually recovered, and he was able to utter meaningful words, sit unsupported, and feed himself by day 70 of admission. In Patient 2, thiamylal was successfully replaced by high-dose enteral PB at a dose of 560 mg (73.3 lg/ml), with residual daily seizures. LEV was used to facilitate further dosage reduction, and ultimately, termination of PB. However, this resulted in a recurrence of seizures, which were controlled with 180 mg of PB (38.2 lg/ml), 1500 mg LEV, and 1000 mg KBr (Fig. 2). Seizures recurred after termination of KBr, which was necessary because of the emergence of bromoderma, but disappeared with an increase in LEV to 2250 mg. In Patient 3, LEV was initially started at a dose of 1000 mg but was terminated because of the emergence of a skin eruption within a few days. Unfortunately, a subsequent trial to reduce the patient’s thiamylal infusion resulted in seizure recurrence. LEV was then reintroduced in combination with KBr, with a gradually
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
Patient Age (years) Sex Current IQ Onset age of AERRPS (years) Duration of artificial ventilation during acute phase (days) Duration of hospital stay at initial admission (days) Seizure semiology
1 10 M NE 10
2 10 M NE 10
3 8 F 58 8
4 30 M 53 8
5 19 M 40 10
6 19 F Below 20 7
45
28
25
0
31
23
150
179
85
113
110
1135
Facial twitch and smacking with/without secondary generalization Spikes at central areas with Cz predominance
Facial twitch with/ without secondary generalization
Upward gaze, smacking, hemitonic with/without generalization
Interictal EEG at last follow-up Partially effective antiepileptics for seizure control Acute phase TA/PB, LEV Chronic phase NA Ineffective antiepileptics/termination due to adverse effects Acute phase DZP, MDL, fPHT, mPSL, VPA Chronic phase
Final dosage of LEV (mg; mg/kg) Seizure frequency before initiation of LEV (per months) Seizure frequency after LEV administration (per month) MRI findings
No epileptiform discharges
Hemifacial twitch/ hemi-clonic with/ without generalization Occipital predominant rhythmic delta No epileptiform activity with notches discharges
TA/PB, LEV (KBr) NA
TA/PB, KBr (LEV) NA
fPHT, MDL, CBZ, DEX DZP, MDL, PHT, IVIG, mPSL
Ocular deviation, motion Ocular deviation, facial twitch, arrest, apnea, facial twitch versive, with/without with/without generalization generalization Bilateral frontal sharp waves Spikes at bilateral frontal, central, and left occipital areas
TP/PB, VPA, CBZ PB, KBr, CZP CZP ZNS, PHT, GBP
PB CBZ, ZNS
KBr: bromodermaLTG: agitation, insomniaCZP, CBZ: somnolence 750; 13.3
MDL, IVIG, PHT, lidocaine, propofol VPA, PHT, NZP, AZA, CZP, CLB, VB7, mPSL, ketogenic diet KBr, LTG: somnolence 1500; 41.3
1500; 50
2250; 56.2
1500; 60
lidocaine, PB, PHT, CBZ AZA, NZP, PHT, ZNS: seizure aggravation 750; 9.7
MDL, DZP, IVIG, mPSL
NA
NA
NA
7–8
7–8
50–200
NA
NA
NA
0–2
0–5
Temporally reduced to 0–50 for several months
Mild cortical atrophy
Mild cortical atrophy with frontal predominance, hippocampal atrophy
Transient splenic high signal, diffuse Mild cortical cortical atrophy, high signal dots in the atrophy frontal subcortical white matter
Claustrum high signal, diffuse cortical atrophy
Diffuse cortical atrophy, transiently enhanced lesions at temporo-parietal cortex
R. Ueda et al. / Brain & Development xxx (2014) xxx–xxx
AZA, acetazolamide; CBZ, carbamazepine; CLB, clobazam; CSF, crebrospinal fluid; CZP, clonazepam; DZP, diazepam; DEX, dexamethazone; EEG, electroencephalography; fPHT, fosphenytoin; GBP, gabapentin; GluR, glutamate receptor; IVIG, intravenous immune globulin; IQ, intelligence quotient; KBr, potassium bromide; MRI, magnetic resonance imaging; LEV, levetiracetam; LTG, lamotrigine; MDL, midazolam; mPSL, methylpredonine pulse therapy; NA, not applicable; NE, not examined; NZP, nitrazepam; PB, phenobarbital; PHT, phenytoin; TA, thiamylal; TP, thiopental; VB6, vitamin B6; VPA, valproate; ZNS, zonisamide. 3
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
Table 1 Characteristics of patients with acute encephalitis with refractory, repetitive partial seizures (AERRPS) administrated with levetiracetam.
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Fig. 1. Clinical course of Patient 1 during the acute phase. Note that the dosage of thiamylal was successfully reduced after initiating levetiracetam. Seizures were aggravated by the termination of thiamylal, despite treatment with levetiracetam and valproate. The seizures were suppressed after addition of phenobarbital. DZP, diazepam; fPHT, fosphenytoin; MDL, midazolam; PB, phenobarbital; VPA, valproate sodium; LEV, levetiracetam.
Fig. 2. Clinical course of Patient 2 during the acute phase. High-dose thiamylal was replaced by enteral phenobarbital and resulted in residual daily seizures. Initiation of levetiracetam and potassium bromide lead to complete seizure control. However, seizures recurred after termination of potassium bromide because of the emergence of bromoderma but disappeared after increasing levetiracetam dose to 2250 mg. CBZ, carbamazepine; KBr, potassium bromide; LEV, levetiracetam.
increasing dose; subsequently, the electrical seizures with repetitive epileptiform discharges on EEG disappeared, and continuous thiamylal infusion was successfully terminated (Fig. 3). Tapering KBr resulted in seizure recurrence, which was suppressed under a regimen of 180 mg PB, 1500 mg LEV, and 1100 mg KBr.
In the three patients assessed during the chronic phase (Patients 4–6), intractable seizures persisted for 9–21 years despite treatment with multiple antiepileptic agents (Table 1, Fig. 4). The seizures tended to emerge in clusters, necessitating several admissions per patient during the follow-up period. Patients 5 and 6 were
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
R. Ueda et al. / Brain & Development xxx (2014) xxx–xxx
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Fig. 3. Clinical course of Patient 3 during the acute phase. Administration of levetiracetam and potassium bromide, particularly during the period of levetiracetam dosage increases, resulted in the disappearance of electrical seizures with repetitive epileptiform discharges, and the successful termination of their continuous thiamylal infusion. Their seizures recurred after the potassium bromide was terminated but were suppressed by increasing the doses of potassium bromide and levetiracetam. ACV, acyclovir; BT, body temperature; EEG, electroencephalography; IVIG, intravenous immunoglobulin; mPSL, methylpredonine pulse therapy; VB6, vitamin B6; KBr, potassium bromide; LEV, levetiracetam.
maintained on PB with a serum concentration above 30 lg/ml, and any decrease of which resulted in deterioration in seizure control. Epileptiform discharges on interictal EEGs persisted in the same areas as observed during the acute phase; however, in Patient 4, epileptic discharges disappeared during adolescence. In the chronic phase group, all three patients showed moderate to severe intellectual disabilities during adolescence. Notably, Patient 5 demonstrated marked behavioral problems, including agitation, injuring his parents, and attempted suicide. LEV was initiated after 8–22 years of antiepileptic treatment in these patients. In Patient 4, LEV rapidly improved seizure control, leading to a disappearance of seizures for 5 months after increasing the dose to 750 mg (Fig. 4A). In Patient 5, a 500-mg dose of LEV resulted in an immediate and marked reduction in seizure frequency. However, we observed an aggravation of his behavioral problems 2– 3 months after LEV initiation. These were gradually ameliorated by risperidone treatment, and LEV was continued (Fig. 4B). Patient 6 had a prolonged acute phase (Patient 2 in an earlier report [3]) and suffered from the most severe AERRPS in this sample, with intractable seizures occurring 50–200 times per month over a 10-year chronic phase. The addition of LEV to the regimen initially showed no effect, but increasing the dosage to 250–500 mg resulted in a reduction of seizure frequency to below 50 episodes per month for
5 months, before returning to previous levels (Fig. 4C). Particularly, complete suppression of seizures longer than one month had never been achieved in this patient. We noted agitation in this patient when LEV dosage was increased beyond 500 mg. In summary, in the acute phases of AERRPS, administration of LEV (50–60 mg/kg/d) in combination with phenobarbital and/or potassium bromide resulted in a successful reduction of barbiturate dosage and withdrawal from artificial ventilation. During the chronic phase in other three patients, seizure frequency reduced by more than 75% for 5–18 months after treatment with LEV at doses of 750–1500 mg/d. 4. Discussion Since the recognition of AERRPS in the 1980s as “a peculiar type of postencephalitic/encephalopathic epilepsy” [7,8], the extreme severity and intractability of seizures during the acute phase has been the critical concern in its management. Moreover, because of hypotension and susceptibility to sepsis that accompanies prolonged high-dose barbiturate therapy, some individuals had poor outcomes such as persistent vegetative states or death [2,4]. A multicenter study confirmed that the acute phase duration correlated with lower cognitive levels at follow-up, and proposed that the dependence on relatively high dose oral PB during the chronic phase
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
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Fig. 4. Clinical course of Patients during the chronic phase (A: Patient 4, B: Patient 5, C: Patient 6) before and after administration of levetiracetam.
in some patients may be partly responsible [2]. Similar patterns were observed in our series, and this study aimed to identify additional and/or optimal treatments to improve these problems. Specifically, we considered LEV therapy and reviewed of our past AERRPS cases that had been treated with this agent. LEV has been discussed as a strong candidate for second-line treatment of status epilepticus [6]. Its effect has
been reported in children with acute seizures or status epilepticus refractory to benzodiazepines, phenobarbital and/or phenytoin, which occur in the context of background infectious, destructive, or dysplastic etiologies [9,10]. In the literature, LEV has been used in the acute phase of AERRPS, and was reported as “most effective” in two out of five patients [11]; in contrast, it showed a “negative response” in all 12 patients in another series [12]. However, detailed information is lacking in these reports, particularly regarding LEV dosage, condition of the patients at LEV initiation, and the concurrent antiepileptics. In our experience in the present study, LEV was effective for withdrawal from high-dose barbiturate-induced comas with artificial ventilation in Patient 1, and for seizure control after dosage reduction of PB and KBr in Patient 2. In addition, EEG improvements were observed in Patient 3 after initiating LEV, although concurrent administration of KBr may have been effective in this case. Given the possibility that the acute phase may be self-limiting in several cases with AERRPS, it remains unclear whether LEV reduced the length of this phase. A beneficial effect of LEV was evident during the chronic phase in the three patients in this study, which has not yet been reported. This also included Patient 6 who experienced a transient disappearance of seizures for the first time in their 12-year treatment for refractory epilepsy. Although we did not obtain evidence to suggest that LEV could facilitate a dosage reduction in PB for persistent, refractory epilepsy, LEV may be helpful for the chronic-phase treatment of other patients with AERRPS. In two of the three patients receiving chronic phase therapy, aggression and impulsivity deteriorated, possibly representing an adverse effect of LEV, which prevented dosage increases above 500–750 mg. Although these psychological problems are common to the chronic phase of AERRPS, regardless of LEV administration [13], they may be augmented by LEV therapy. Therefore, LEV may need to be cautiously introduced in this population. Finally, histories of febrile and afebrile seizures were recorded in two patients. Although the absence of prior unprovoked seizures is suggested in the diagnosis of AERRPS [1], these patients showed otherwise typical clinical courses, EEG findings, and neuroimaging [1–3] (Table 1). We tentatively included these borderline patients for the delineation of LEV trials. Reassessment of whether the absence of preceding seizures is mandatory for the diagnosis of AERRPS may be needed. In conclusion, LEV was helpful for terminating the acute stormy phase of AERRPS when used in combination with PB and KBr. It also appeared to be effective for seizure control in the chronic phase. This antiepileptic may be a helpful option for the treatment of this severe seizure disorder.
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
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Acknowledgment This study was financially supported by the Research Grant for Nervous and Mental Disorders 24-7 from the Ministry of Health, Labor, and Welfare, Japan.
[6]
[7]
References [1] Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y, et al. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand 2010;121:251–6. [2] Kramer U, Chi CS, Lin KL, Specchio N, Sahin M, Olson H, et al. Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia 2011;52:1956–65. [3] Saito Y, Maegaki Y, Okamoto R, Ogura K, Togawa M, Nanba Y, et al. Acute encephalitis with refractory, repetitive partial seizures: case reports of this unusual post-encephalitic epilepsy. Brain Dev 2007;29:147–56. [4] Lin JJ, Lin KL, Wang HS, Hsia SH, Wu CT. Effect of topiramate, in combination with lidocaine, and phenobarbital, in acute encephalitis with refractory repetitive partial seizures. Brain Dev 2009;31:605–11. [5] Nabbout R, Mazzuca M, Hubert P, Peudennier S, Allaire C, Flurin V, et al. Efficacy of ketogenic diet in severe refractory
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status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010;51:2033–7. Deshpande LS, Delorenzo RJ. Mechanisms of levetiracetam in the control of status epilepticus and epilepsy. Front Neurol 2014;5:11. Awaya Y, Fukuyama Y. Epilepsy sequelae of acute encephalitis or encephalopathy (3rd report). Jpn J Psychiatr Neurol 1986;40:385–7. Shiomi M, Yamamoto K, Ko E, Maeyama M, Yabiku M, Ogawa H, et al. No To Hattatsu 1988;20(Suppl.):S195 [in Japanese]. Gallentine WB, Hunnicutt AS, Husain AM. Levetiracetam in children with refractory status epilepticus. Epilepsy Behav 2009;14:215–8. Goraya JS, Khurana DS, Valencia I, Melvin JJ, Cruz M, Legido A, et al. Intravenous levetiracetam in children with epilepsy. Pediatr Neurol 2008;38:177–80. van Baalen A, Ha¨usler M, Boor R, Rohr A, Sperner J, Kurlemann G, et al. Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood. Epilepsia 2010;51:1323–8. Caraballo RH, Reyes G, Avaria MF, Buompadre MC, Gonzalez M, Fortini S, et al. Febrile infection-related epilepsy syndrome: a study of 12 patients. Seizure 2013;22:553–9. Howell KB, Katanyuwong K, Mackay MT, Bailey CA, Scheffer IE, Freeman JL, et al. Long-term follow-up of febrile infectionrelated epilepsy syndrome. Epilepsia 2012;53:101–10.
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
Original article
Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase Riyo Ueda a, Yoshiaki Saito a, Koyo Ohno a, Kanako Maruta b, Kunihiro Matsunami b, Yusuke Saiki a, Tatsuyuki Sokota a, Susumu Sugihara a, Yoko Nishimura a, Akiko Tamasaki a, Aya Narita a, Atsushi Imamura b, Yoshihiro Maegaki a,⇑ a
Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori Univesity, Yonago, Japan b Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan Received 16 June 2014; received in revised form 5 August 2014; accepted 7 August 2014
Abstract Aim: To clarify the effect of levetiracetam (LEV) for acute and chronic seizure control in acute encephalitis with refractory, repetitive partial seizures (AERRPS). Methods: We retrospectively reviewed the clinical course of six AERRPS cases treated with LEV, and explored the acute phase termination by withdrawal from barbiturate-induced coma under artificial ventilation, and the reduction in seizure frequency during the chronic phase. LEV was administrated orally or via nasogastric tubes as an add-on agent during acute (n = 3; age 8–10 years) and chronic (n = 3; age 19–30 years) AERRPS. Results: In the acute phase, administration of LEV (50–60 mg/kg/d) in combination with phenobarbital (n = 3; peak 57.9– 76.1 lg/ml) and potassium bromide (n = 2; 30–36 mg/kg/d)) resulted in successful reduction of intravenous barbiturate dosage and withdrawal from artificial ventilation. In the chronic phase, seizure frequency reduced by >75% for 5–18 months with LEV 750–1500 mg/d. Conclusion: LEV may affect seizure control in AERRPS, particularly during the chronic phase, through its unique action of inhibition of excitatory neurotransmitter release. The regimen of oral barbiturate, potassium bromide and LEV would be worth for trial during the acute phase of AERRPS. Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Status epilepticus; Levetiracetam; Febrile infection-related epilepsy syndrome; Barbiturate coma
1. Introduction Acute encephalitis with refractory repetitive partial seizures (AERRPS), or febrile infection-related epi⇑ Corresponding author. Address: Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori Univesity, 36-1 Nishi-cho, Yonago 683-8504, Japan. Tel.: +81 859 38 6777; fax: +81 859 38 6779. E-mail address: [email protected] (Y. Maegaki).
lepsy syndrome (FIRES), is a devastating seizure disorder of unclear etiology [1,2]. Typically, a schoolaged child manifests encephalitis-like symptoms that include a fever, followed by convulsive seizures and unconsciousness. Moreover, seizure control is subsequently more difficult than is normally the case with encephalitis, and frequently requires intensive suppressive therapy with high-dose barbiturate under artificial ventilation and vasopressor support. This acute, stormy phase lasts from 1 to several months, and
http://dx.doi.org/10.1016/j.braindev.2014.08.003 0387-7604/Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
2
R. Ueda et al. / Brain & Development xxx (2014) xxx–xxx
the duration correlates with the degree of residual intellectual impairment [2]. Certain antiepileptic medications, including oral barbiturates, potassium bromide (KBr), and high-dose topiramate, as well as a ketogenic diet, appear helpful for withdrawal from the intensive therapy in individual cases [1,3–5]. However, further treatment options are needed to improve the outcomes in patients with AERRPS. In addition, intractable epilepsy often persists after the acute symptoms have resolved, and no optimal antiepileptic has been established. Levetiracetam (LEV) is a new antiepileptic drug with a novel pharmacological action involving presynaptic inhibition of excitatory neurotransmitter release. Furthermore, LEV has a broad therapeutic remit, and is reportedly effective for the treatment of refractory status epilepticus that is not controlled by benzodiazepines, phenytoin, or barbiturates [6]. Because LEV has been commercially available in Japan since 2010, experience has been accumulating on its use in children with epilepsy. In this study, we aimed to clarify the effect of LEV on acute and chronic seizure control in patients with AERRPS. 2. Subjects and methods We enrolled six children who suffered from AERRPS at the age of 7–10 years (4 males and 2 females, aged 8–30 years at the last follow-up) (Table 1). Clinical data were reviewed from the medical charts, including: encephalopathic symptoms such as the frequency and semiology of seizures; the results of laboratory, electroencephalography (EEG), and neuroimaging examinations; and the antiepileptic treatment regimen, together with any recorded blood concentrations or adverse effects. Specifically, we explored both the acute-phase termination, by withdrawal from barbiturate-induced burst suppression coma under artificial ventilation, and the reduction of seizure frequency during the chronic phase. Some of the clinical information concerning Patients 5 and 6 had previously been reported [3]. The study protocol was approved by our institutional review board. Clinical course of each child met the mandatory diagnostic criteria of AERRPS, except for one patient who had a preceding history of febrile seizures (Patient 2), and another who had two afebrile seizures (Patient 1). Psychomotor development was normal before the onset of disease, but moderate to severe intellectual disabilities were observed during the chronic phase in all participants. LEV was administrated during the acute phase in three patients and during chronic phase in the other three patients.
3. Results The onset of repetitive seizures with unconsciousness was preceded by 2–5 days of febrile illness in all participants. Transient resolution of pyrexia for >12 h on the day before the onset of encephalopathy was recorded for three subjects, suggesting a biphasic clinical course. In each case, seizures with generalization were predominant at the onset, but soon evolved to focal seizures with facial twitching, ocular deviation, apnea/salivation, and versive neck motion (Table 1). In each patient, EEG revealed asynchronous high-voltage slow activity with a frequent, often semirhythmic, and continuous emergence of spikes and/or sharp waves with multiple foci. Mild pleocytosis (14–40/ll) was noted in the cerebrospinal fluid at this stage in all cases. In five of the patients, treatment of the frequent seizures and persistent fever (lasting 1–3 months) was via burst-suppression coma therapy with a high-dose barbiturate and artificial ventilation for 23–45 days. The remaining patient was treated by continuous midazolam infusion and repeated bolus injection of pentobarbital in the acute phase (Patient 4). LEV was administrated during the acute phase in three patients (Figs. 1–3). In Patient 1, LEV was initiated with a gradually increasing dose toward day 26 of admission, resulting in a successful reduction of the thiamylal dosage (Fig. 1). This enabled the patient to be withdrawn from the burst-suppression coma and artificial ventilation. After thiamylal termination, the seizures recurred during treatment with LEV and valproate, and were suppressed after the addition of phenobarbital (PB) and increasing LEV doses (200 mg PB and 1500 mg LEV). Thereafter, the patient gradually recovered, and he was able to utter meaningful words, sit unsupported, and feed himself by day 70 of admission. In Patient 2, thiamylal was successfully replaced by high-dose enteral PB at a dose of 560 mg (73.3 lg/ml), with residual daily seizures. LEV was used to facilitate further dosage reduction, and ultimately, termination of PB. However, this resulted in a recurrence of seizures, which were controlled with 180 mg of PB (38.2 lg/ml), 1500 mg LEV, and 1000 mg KBr (Fig. 2). Seizures recurred after termination of KBr, which was necessary because of the emergence of bromoderma, but disappeared with an increase in LEV to 2250 mg. In Patient 3, LEV was initially started at a dose of 1000 mg but was terminated because of the emergence of a skin eruption within a few days. Unfortunately, a subsequent trial to reduce the patient’s thiamylal infusion resulted in seizure recurrence. LEV was then reintroduced in combination with KBr, with a gradually
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
Patient Age (years) Sex Current IQ Onset age of AERRPS (years) Duration of artificial ventilation during acute phase (days) Duration of hospital stay at initial admission (days) Seizure semiology
1 10 M NE 10
2 10 M NE 10
3 8 F 58 8
4 30 M 53 8
5 19 M 40 10
6 19 F Below 20 7
45
28
25
0
31
23
150
179
85
113
110
1135
Facial twitch and smacking with/without secondary generalization Spikes at central areas with Cz predominance
Facial twitch with/ without secondary generalization
Upward gaze, smacking, hemitonic with/without generalization
Interictal EEG at last follow-up Partially effective antiepileptics for seizure control Acute phase TA/PB, LEV Chronic phase NA Ineffective antiepileptics/termination due to adverse effects Acute phase DZP, MDL, fPHT, mPSL, VPA Chronic phase
Final dosage of LEV (mg; mg/kg) Seizure frequency before initiation of LEV (per months) Seizure frequency after LEV administration (per month) MRI findings
No epileptiform discharges
Hemifacial twitch/ hemi-clonic with/ without generalization Occipital predominant rhythmic delta No epileptiform activity with notches discharges
TA/PB, LEV (KBr) NA
TA/PB, KBr (LEV) NA
fPHT, MDL, CBZ, DEX DZP, MDL, PHT, IVIG, mPSL
Ocular deviation, motion Ocular deviation, facial twitch, arrest, apnea, facial twitch versive, with/without with/without generalization generalization Bilateral frontal sharp waves Spikes at bilateral frontal, central, and left occipital areas
TP/PB, VPA, CBZ PB, KBr, CZP CZP ZNS, PHT, GBP
PB CBZ, ZNS
KBr: bromodermaLTG: agitation, insomniaCZP, CBZ: somnolence 750; 13.3
MDL, IVIG, PHT, lidocaine, propofol VPA, PHT, NZP, AZA, CZP, CLB, VB7, mPSL, ketogenic diet KBr, LTG: somnolence 1500; 41.3
1500; 50
2250; 56.2
1500; 60
lidocaine, PB, PHT, CBZ AZA, NZP, PHT, ZNS: seizure aggravation 750; 9.7
MDL, DZP, IVIG, mPSL
NA
NA
NA
7–8
7–8
50–200
NA
NA
NA
0–2
0–5
Temporally reduced to 0–50 for several months
Mild cortical atrophy
Mild cortical atrophy with frontal predominance, hippocampal atrophy
Transient splenic high signal, diffuse Mild cortical cortical atrophy, high signal dots in the atrophy frontal subcortical white matter
Claustrum high signal, diffuse cortical atrophy
Diffuse cortical atrophy, transiently enhanced lesions at temporo-parietal cortex
R. Ueda et al. / Brain & Development xxx (2014) xxx–xxx
AZA, acetazolamide; CBZ, carbamazepine; CLB, clobazam; CSF, crebrospinal fluid; CZP, clonazepam; DZP, diazepam; DEX, dexamethazone; EEG, electroencephalography; fPHT, fosphenytoin; GBP, gabapentin; GluR, glutamate receptor; IVIG, intravenous immune globulin; IQ, intelligence quotient; KBr, potassium bromide; MRI, magnetic resonance imaging; LEV, levetiracetam; LTG, lamotrigine; MDL, midazolam; mPSL, methylpredonine pulse therapy; NA, not applicable; NE, not examined; NZP, nitrazepam; PB, phenobarbital; PHT, phenytoin; TA, thiamylal; TP, thiopental; VB6, vitamin B6; VPA, valproate; ZNS, zonisamide. 3
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
Table 1 Characteristics of patients with acute encephalitis with refractory, repetitive partial seizures (AERRPS) administrated with levetiracetam.
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Fig. 1. Clinical course of Patient 1 during the acute phase. Note that the dosage of thiamylal was successfully reduced after initiating levetiracetam. Seizures were aggravated by the termination of thiamylal, despite treatment with levetiracetam and valproate. The seizures were suppressed after addition of phenobarbital. DZP, diazepam; fPHT, fosphenytoin; MDL, midazolam; PB, phenobarbital; VPA, valproate sodium; LEV, levetiracetam.
Fig. 2. Clinical course of Patient 2 during the acute phase. High-dose thiamylal was replaced by enteral phenobarbital and resulted in residual daily seizures. Initiation of levetiracetam and potassium bromide lead to complete seizure control. However, seizures recurred after termination of potassium bromide because of the emergence of bromoderma but disappeared after increasing levetiracetam dose to 2250 mg. CBZ, carbamazepine; KBr, potassium bromide; LEV, levetiracetam.
increasing dose; subsequently, the electrical seizures with repetitive epileptiform discharges on EEG disappeared, and continuous thiamylal infusion was successfully terminated (Fig. 3). Tapering KBr resulted in seizure recurrence, which was suppressed under a regimen of 180 mg PB, 1500 mg LEV, and 1100 mg KBr.
In the three patients assessed during the chronic phase (Patients 4–6), intractable seizures persisted for 9–21 years despite treatment with multiple antiepileptic agents (Table 1, Fig. 4). The seizures tended to emerge in clusters, necessitating several admissions per patient during the follow-up period. Patients 5 and 6 were
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
R. Ueda et al. / Brain & Development xxx (2014) xxx–xxx
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Fig. 3. Clinical course of Patient 3 during the acute phase. Administration of levetiracetam and potassium bromide, particularly during the period of levetiracetam dosage increases, resulted in the disappearance of electrical seizures with repetitive epileptiform discharges, and the successful termination of their continuous thiamylal infusion. Their seizures recurred after the potassium bromide was terminated but were suppressed by increasing the doses of potassium bromide and levetiracetam. ACV, acyclovir; BT, body temperature; EEG, electroencephalography; IVIG, intravenous immunoglobulin; mPSL, methylpredonine pulse therapy; VB6, vitamin B6; KBr, potassium bromide; LEV, levetiracetam.
maintained on PB with a serum concentration above 30 lg/ml, and any decrease of which resulted in deterioration in seizure control. Epileptiform discharges on interictal EEGs persisted in the same areas as observed during the acute phase; however, in Patient 4, epileptic discharges disappeared during adolescence. In the chronic phase group, all three patients showed moderate to severe intellectual disabilities during adolescence. Notably, Patient 5 demonstrated marked behavioral problems, including agitation, injuring his parents, and attempted suicide. LEV was initiated after 8–22 years of antiepileptic treatment in these patients. In Patient 4, LEV rapidly improved seizure control, leading to a disappearance of seizures for 5 months after increasing the dose to 750 mg (Fig. 4A). In Patient 5, a 500-mg dose of LEV resulted in an immediate and marked reduction in seizure frequency. However, we observed an aggravation of his behavioral problems 2– 3 months after LEV initiation. These were gradually ameliorated by risperidone treatment, and LEV was continued (Fig. 4B). Patient 6 had a prolonged acute phase (Patient 2 in an earlier report [3]) and suffered from the most severe AERRPS in this sample, with intractable seizures occurring 50–200 times per month over a 10-year chronic phase. The addition of LEV to the regimen initially showed no effect, but increasing the dosage to 250–500 mg resulted in a reduction of seizure frequency to below 50 episodes per month for
5 months, before returning to previous levels (Fig. 4C). Particularly, complete suppression of seizures longer than one month had never been achieved in this patient. We noted agitation in this patient when LEV dosage was increased beyond 500 mg. In summary, in the acute phases of AERRPS, administration of LEV (50–60 mg/kg/d) in combination with phenobarbital and/or potassium bromide resulted in a successful reduction of barbiturate dosage and withdrawal from artificial ventilation. During the chronic phase in other three patients, seizure frequency reduced by more than 75% for 5–18 months after treatment with LEV at doses of 750–1500 mg/d. 4. Discussion Since the recognition of AERRPS in the 1980s as “a peculiar type of postencephalitic/encephalopathic epilepsy” [7,8], the extreme severity and intractability of seizures during the acute phase has been the critical concern in its management. Moreover, because of hypotension and susceptibility to sepsis that accompanies prolonged high-dose barbiturate therapy, some individuals had poor outcomes such as persistent vegetative states or death [2,4]. A multicenter study confirmed that the acute phase duration correlated with lower cognitive levels at follow-up, and proposed that the dependence on relatively high dose oral PB during the chronic phase
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
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Fig. 4. Clinical course of Patients during the chronic phase (A: Patient 4, B: Patient 5, C: Patient 6) before and after administration of levetiracetam.
in some patients may be partly responsible [2]. Similar patterns were observed in our series, and this study aimed to identify additional and/or optimal treatments to improve these problems. Specifically, we considered LEV therapy and reviewed of our past AERRPS cases that had been treated with this agent. LEV has been discussed as a strong candidate for second-line treatment of status epilepticus [6]. Its effect has
been reported in children with acute seizures or status epilepticus refractory to benzodiazepines, phenobarbital and/or phenytoin, which occur in the context of background infectious, destructive, or dysplastic etiologies [9,10]. In the literature, LEV has been used in the acute phase of AERRPS, and was reported as “most effective” in two out of five patients [11]; in contrast, it showed a “negative response” in all 12 patients in another series [12]. However, detailed information is lacking in these reports, particularly regarding LEV dosage, condition of the patients at LEV initiation, and the concurrent antiepileptics. In our experience in the present study, LEV was effective for withdrawal from high-dose barbiturate-induced comas with artificial ventilation in Patient 1, and for seizure control after dosage reduction of PB and KBr in Patient 2. In addition, EEG improvements were observed in Patient 3 after initiating LEV, although concurrent administration of KBr may have been effective in this case. Given the possibility that the acute phase may be self-limiting in several cases with AERRPS, it remains unclear whether LEV reduced the length of this phase. A beneficial effect of LEV was evident during the chronic phase in the three patients in this study, which has not yet been reported. This also included Patient 6 who experienced a transient disappearance of seizures for the first time in their 12-year treatment for refractory epilepsy. Although we did not obtain evidence to suggest that LEV could facilitate a dosage reduction in PB for persistent, refractory epilepsy, LEV may be helpful for the chronic-phase treatment of other patients with AERRPS. In two of the three patients receiving chronic phase therapy, aggression and impulsivity deteriorated, possibly representing an adverse effect of LEV, which prevented dosage increases above 500–750 mg. Although these psychological problems are common to the chronic phase of AERRPS, regardless of LEV administration [13], they may be augmented by LEV therapy. Therefore, LEV may need to be cautiously introduced in this population. Finally, histories of febrile and afebrile seizures were recorded in two patients. Although the absence of prior unprovoked seizures is suggested in the diagnosis of AERRPS [1], these patients showed otherwise typical clinical courses, EEG findings, and neuroimaging [1–3] (Table 1). We tentatively included these borderline patients for the delineation of LEV trials. Reassessment of whether the absence of preceding seizures is mandatory for the diagnosis of AERRPS may be needed. In conclusion, LEV was helpful for terminating the acute stormy phase of AERRPS when used in combination with PB and KBr. It also appeared to be effective for seizure control in the chronic phase. This antiepileptic may be a helpful option for the treatment of this severe seizure disorder.
Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
R. Ueda et al. / Brain & Development xxx (2014) xxx–xxx
Acknowledgment This study was financially supported by the Research Grant for Nervous and Mental Disorders 24-7 from the Ministry of Health, Labor, and Welfare, Japan.
[6]
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Please cite this article in press as: Ueda R et al. Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.08.003
