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Effect of levetiracetam and valproate on late-onset post-traumatic seizures

Effect of levetiracetam and valproate on late-onset post-traumatic seizures Background To compare the preventive effects of levetiracetam and valproate on late-onset post-traumatic seizures in patients with traumatic brain injury ( TBI). Methods A total of 95 patients with TBI were recruited from 2017 to 2020. They were randomized into three groups: levetiracetam (LEV ) group (n = 30) receiving LEV treatment (500 mg, bid, po); valproate group (n = 32) receiving sodium valproate (500 mg/d, once daily, po); and control group (n = 33) receiving no anti-seizure medication. LEV and valproate were given to corresponding groups within seven days after TBI, and the administration lasted for one month. The incidence of epilepsy and adverse events were evaluated at 7 days and 12 months post-TBI. Results The cumulative incidences of late post-traumatic seizures at the 12-month follow-up in the LEV, valproate, and control groups were 3.33%, 12.50% and 15.63%, respectively. The cumulative incidence of late post-traumatic seizures in the LEV group was significantly lower than those in the valproate and control groups (P < 0.05). The cumu- lative incidence of late post-traumatic seizure in the valproate group was not significantly different from that in the control group (P > 0.05). Conclusions LEV can reduce the cumulative incidence of late post-traumatic seizures, whereas valproate can not. Keywords Levetiracetam, Valproate, Post-traumatic seizure seizures (LPTS). EPTS occur within one week post-TBI, Background whereas LPTS usually occur over one week after TBI [4]. With increased incidence of traffic accidents, traumatic Focal epilepsy and generalized epilepsy are more com- brain injury (TBI) has become a common and frequently mon after cerebral  trauma, while mixed epilepsy, psy- occurring condition, and one of the most common etiol- chomotor epilepsy or non-convulsive epilepsy are less ogies leading to secondary epilepsy [1, 2]. The incidence common. of post-traumatic seizures (PTS) after severe TBI ranges LPTS is one of the most medication-resistant epilep- 10–20% [3]. Two types of PTS have been identified: early sies and has serious impacts on the physical and men- post-traumatic seizures (EPTS) and late post-traumatic tal health of patients with TBI [5]. Risk factors for PTS include old age, penetrating injury, and a higher degree *Correspondence: of injury (eg, an intracranial hemorrhage, a midline dis- James X. Tao jtao@neurology.bsd.uchicago.edu placement greater than 5  mm, and a longer duration Meizhen Sun of coma). Several clinical trials have established that sunmeizhen213@126.com traditional anti-seizure medications (ASMs) can pre- Department of Rehabilitation, Shanxi Traditional Chinese Medical Hospital, Taiyuan 030012, China vent EPTS but not LPTS [6-8]. Valproate acid (VPA) is Department of Neurology, The First Hospital of Shanxi Medical a commonly used medication for epileptic seizures, but University, Taiyuan 030012, China its administration is associated with neurotoxic effects. Department of Neurology, University of Chicago, Chicago, IL 60601, USA In contrast, no such adverse effects have been reported © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Wang et al. Acta Epileptologica (2023) 5:10 Page 2 of 4 for levetiracetam (LEV) treatment. In addition, clini- severe (GCS 3–7), 33 moderate (GCS 8–12), and 46 mild cal studies have demonstrated favorable side effects and cases (GCS 13–15). pharmacokinetic data, as well as high efficacy of LEV. LEV is a broad-spectrum ASM that is widely used for Pharmacological treatment with ASMs the treatment of partial and generalized epilepsy. How- The 95 patients were randomized into three groups by a ever, whether LEV can prevent or reduce LPTS remains random number table: (1) the LEV group, in which they unclear [9-12]. VPA and phenytoin are commonly used were treated with 500  mg LEV twice daily after brain to prevent PTS in neurosurgery departments in China. injury, for one month; (2) the VPA group, in which they In an earlier investigation, the rates of LPTS did not dif- were treated with 500  mg VPA once daily after brain fer significantly between the VPA and phenytoin treat - injury, for one month; and (3) the control group, in which ment groups (P > 0.05) [13]. In this study, we aimed to they received no ASM treatment. In the VPA group, evaluate LEV prevention of LPTS in comparison to the although the minimum dose of sodium valproate was effect of VPA. recommended to be 600  mg/day, it was administered at 500 mg/day for convenience as the sodium valproate sus- Methods tained-release tablets were 500  mg each. If the patients Subjects could not take drugs orally, the medication was given This study was approved by the Institutional Review through a nasogastric tube. The medication was started Board at the First Hospital of Shanxi Medical University, at an average of 4.5 days after brain injury. and informed consent was obtained from all patients. The seizure frequency of LPTS was recorded for Ninety-five patients with TBI who were admitted in the 12 months after brain injury. Neurosurgery and Emergency Departments of the First Hospital of Shanxi Medical University were included in Statistical analysis this study (32 females, 63 males; mean age 44.6 ± 2.17 Data of age, GCS, and the number of diagnoses were years, range 20–65 years). The inclusion criteria were: analyzed with One-way ANOVA test. Pearson χ test (1) age of 18–70 years; (2) seizures within 30 min after was applied to compare the EPTS, brain injuries, and TBI with at least one of the following conditions detected the cumulative incidence of LPTS among groups at by CT: brain contusion, subdural hematoma, epidural 12  months. All analyses were made using the SPSS hematoma, and intracranial hematoma. The exclusion 17.0 software. P < 0.05 was considered as statistically criteria were as follows: (1) a family history of epilepsy; significant. (2) patients with epilepsy before TBI; (3) pregnancy and lactation; (4) patients who did not receive ASM treat- Results ment within seven days after TBI; (5) patients with any Patient follow‑up of the following medical conditions: hypertension, diabe- All patients in the LEV and VPA groups completed tes, stroke, renal and hepatic dysfunctions, and malignant the12-month follow-up. One patient in the control group tumor. was lost to follow-up due to the wrong telephone number Of the 95 patients, 25 had simple brain contusion provided. Both LEV and VPA were well tolerated by the (SBC), 27 had SBC and subdural hematoma, 18 had SBC patients. One patient experienced brief dizziness during and epidural hematoma, and 25 had SBC and multiple the LEV treatment, but it was improved a few days later. intracranial hematomas. Glasgow coma score (GCS) [14] One patient experienced mild insomnia during the VPA was assessed within 4 h post-TBI (Table 1). There were 16 treatment, which diminished three days later. Another Table 1 Demographics and clinical data of the patients with acute brain injury n Sex (M/F) Age (mean ± SD) GCS score EPTS Brain injury (mean ± SD) n SBC SBH EPH MIH LEV group 30 20/10 40.9 ± 2.03 12.1 ± 2.10 3 10 9 5 6 VPA group 32 23/9 45.2 ± 1.81 11.9 ± 1.91 2 7 8 9 8 Control group 33 20/13 44.2 ± 3.22 10.4 ± 1.75 3 8 10 4 11 P 0.56 0.87 > 0.05 > 0.05 Abbreviations: EPTS early post-traumatic seizures, GCS score The Glass Coma Scale score, SBC simple brain contusion, SBH Subdural hematoma, EPH epidural hematoma, MIH multiple intracranial hematomas W ang et al. Acta Epileptologica (2023) 5:10 Page 3 of 4 patient in the VPA group had mild gastrointestinal dis- total adults developed epilepsy two years post-brain injury. comfort that improved one day later. More specifically, 10.9% (5/46) of the treated adults and 20% (8/40) of the untreated adults developed epilepsy two Cumulative incidence of seizures years post-brain injury (relative risk, 0.47; P = 0.18). How- The incidence of LPTS was significantly higher in the LEV ever, although LEV tended to prevent LPTS, this effect was group than in the VPA group (3.33% vs 12.50%, χ = 4.41, not statistically significant [9 ]. P = 0.031) and control group (3.33% vs 15.63%, χ = 6.07, In the trial by Klein et  al., LEV treatment was termi- P = 0.017). There was no statistically significant difference nated in 3% of the patients in the LEV group due to som- in the incidence of LPTS between VPA and control groups nolence. The most common adverse events were fatigue, (χ = 1.15, P = 0.36). headache, and somnolence. The mood scores and num - These findings indicated that LEV had a significant pre - ber of infections did not differ between the LEV group ventive effect against LPTS, whereas VPA did not (Table 2 ). and the control group [9]. In another study, LEV treat- ment at 2000 mg/day caused somnolence, manifested as Discussion reduced awake time during the Maintenance of Wakeful- In this study, we found that the cumulative incidence ness Test and increased nap duration and episodes [15]. of LPTS in the LEV group was significantly lower than However, a daily dose of 1000 mg caused no changes in those in the VPA and control groups. The incidence of the daytime sleepiness in the Multiple Sleep Latency Test LPTS in the VPA group was not significantly different [16]. Therefore, LEV dosage of 1000 mg/day was used in from that in the control group. These findings indicated our trial for the prevention of LPTS without somnolence. that LEV could prevent LPTS in patients suffering from In studies of Pearl et al. [10] and Klein et al. [9], LEV was TBI, whereas VPA could not. administered at the dose of 55 mg/kg per day, and both Our results were consistent with those of Pearl et al. pub- studies reported common adverse events of headache, lished in 2013 [10]. In their study, LEV (55 mg/kg per day fatigue, and drowsiness, indicating that the dose of LEV bid for 30 days, starting within 8 hours post-brain injury) for prevention of LPTS needs to be reduced (< 55 mg/kg more effectively prevented LPTS in 20 TBI children aged per day) in clinical settings [9, 10]. 6–17 years with high risk factors of developing posttrau- Our results were also consistent with the study con- matic epilepsy. They found that only 1 of the 20 patients ducted by Chaudhry et al. [17], which reported that LEV developed LPTS during the two-year follow-up period. caused less adverse effects and had a better tolerability. With respect to adverse events, brief dizziness occurred Although the pathogenesis of LPTS is not fully clear, this in the LEV group, which disappeared a few days later. Pearl condition can be prevented during its incubation period et  al. found that the most common severe adverse events after TBI [13]. were headache, fatigue, drowsiness and irritability, and Laure Peter-Derex et  al. conducted a phase 3 PEACH there was a higher incidence of infection, mood change, trial in France, in which patients who had a non-trau- or behavior problems among the treatment patients com- matic intracerebral hemorrhage received LEV treatment, pared to the observation patients. This may be because starting within 24  h after hemorrhage. They found that that the dose of LEV (adult, 1000 mg/day) was better toler- LEV effectively prevented acute seizures in intracerebral ated in the adult patients in our trial than in the pediatric hemorrhage [18]. patients (55 mg/kg per day) in the Pearl’ trial. There are several limitations in this study. First, the Our result was also consistent with the the study of Klein blood concentration of LEV and VPA were not measured et al. in 2012 [9]. In their study, treatment with LEV at 55 in the patients. Second, the study was not blinded, which mg/kg per day lasted for 30 days, starting within 8 hours might have caused a bias in analysis. Third, the sample post-brain injury. They found that 15.1% (13/86) of the size was relatively small. Fourth, the duration of follow- up was relatively short. Multicenter, randomized, pla- cebo-controlled trials are needed in the future to explore Table 2 Comparison of the cumulative incidences of LPTS in the preventive effects of LEV against LPTS. different groups Group n Lost to n of patients with Cumulative Conclusions follow up (n) seizure attacks incidence In this study, we found that VPA could not prevent LPTS (%) and caused more adverse events. This is consistent with LEV 30 0 1 3.33 the findings of Temkin et al. and Paqnl et al. [13, 19]. Val- VPA 32 0 4 12.50* proate sodium can exert antiepileptogenic effects at high Control 33 1 5 15.63* doses that may be toxic for human use. However, LEV : Compared with the LEV group, *P < 0.05 Wang et al. Acta Epileptologica (2023) 5:10 Page 4 of 4 7. Englander J, Bushnik T, Duong TT, Cifu DX, Zafonte R, Wright J, et al. can effectively reduce the cumulative incidence of LPTS Analyzing risk factors for late posttraumatic seizures: a prospective, multi- in patients with TBI. center investigation. Arch Phys Med Rehabil. 2003;84(3):365–73. 8. Asikainen I, Kaste M, Sarna S. Early and late posttraumatic seizures in traumatic brain injury rehabilitation patients: brain injury factors causing Abbreviations late seizures and influence of seizures on long-term outcome. Epilepsia. ASM Anti-seizure medication 1999;40(5):584–9. EPTS Early posttraumatic seizure 9. Klein P, Herr D, Pearl PL, Natale J, Levine Z, Nogay C, et al. Results of phase GCS Glasgow coma scale 2 safety and feasibility study of treatment with levetiracetam for preven- LEV Levetiracetam tion of posttraumatic epilepsy. Arch Neurol. 2012;69(10):1290–5. LPTS Lat e posttraumatic seizure 10. Pearl PL, McCarter R, McGavin CL, Yu Y, Sandoval F, Trzcinski S, et al. Results PTS Post-traumatic seizures of phase II levetiracetam trial following acute head injury in children at SBC Simple brain contusion risk for posttraumatic epilepsy. Epilepsia. 2013;54(9):e135–7. TBI Traumatic brain injury 11. Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, VPA Valproic acid single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care. 2010;12(2):165–72. Acknowledgements 12. Younus SM, Basar S, Gauri SA, Khan AA, Imran M, Abubakar S, et al. Com- No acknowledgement. parison of Phenytoin versus Levetiracetam in Early Seizure Prophylaxis after Traumatic Brain Injury, at a Tertiary Care Hospital in Karachi. Pakistan Authors’ contributions Asian J Neurosurg. 2018;13(4):1096–100. Yanli Wang participated in data collection and manuscript writing. Yiqi Wang 13. Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A participated in data collection. Huifang Wang and Xiaoping Du analyzed the randomized, double-blind study of phenytoin for the prevention of post- results. Jie Miao participated in data collection and analyzed the results. James traumatic seizures. N Engl J Med. 1990;323(8):497–502. X. Tao was involved in the revision of the clinical trial protocol, and Meizhen 14. Barlow Philip. A Practial review of the glasgow coma scale and score. Sun designed and supervised this study. All authors approved the final version Surgeon. 2012;10:114–9. of the manuscript. 15. Yilmaz H. Comparison of motor activity and sleep in patients with com- plex partial seizures on levetiracetam treatment and a group of healthy Authors’ information subjects. Behav Neurol. 2007;18:165–70. Yanli Wang came from Shanxi Traditional Chinese Medical Hospital, James X. 16. Zhou JY, Tang XD, Huang LL, Zhong ZQ, Lei F, Zhou D. The acute effects of Tao came from the University of Chicago, and the other authors came from levetiracetam on nocturnal sleep and daytime sleepiness in patients with The First Hospital of Shanxi Medical University. partial epilepsy. J Clin Neurosci. 2012;19(7):956–60. 17. Chaudhry SA, Jong G, Koren G. The fetal safety of Levetiracetam: a sys- Funding tematic review. Reprod Toxicol. 2014;46:40–5. This study was funded by the Scientific Research Fund of China Association 18. Peter-Derex L, Philippeau F, Garnier P, et al. Safety and efficacy of pro - Against Epilepsy (No 2012002). phylactic levetiracetam for prevention of epileptic seizures in the acute phase of intracerebral haemorrhage (PEACH): a randomised, double- Availability of data and materials blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2022;21:781–91. Not applicable. 19. Pagni CA, Zenga F. Prevention and treatment of post-traumatic epilepsy. Expert Rev Neurother. 2006;6(8):1223–33. Declarations Ethics approval and informed consent The study was approved by the the First Hospital of Shanxi Medical University (No. KYLL-2023–030). All participants had given informed consent. Consent for publication Not applicable. Competing interests The authors declare no conflict of interest. Received: 1 November 2022 Accepted: 28 March 2023 Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : References fast, convenient online submission 1. Lowenstein DH. Epilepsy after head injury: an overview. Epilepsia. 2009;50(Suppl 2):4–9. thorough peer review by experienced researchers in your field 2. Salinsky M, Storzbach D, Goy E, Evrard C. Traumatic brain injury and psy- rapid publication on acceptance chogenic seizures in veterans. J Head Trauma Rehabil. 2015;30(1):E65-70. support for research data, including large and complex data types 3. D’Ambrosio R, Perucca E. Epilepsy after head injury. Curr Opin Neurol. 2004;17(6):731–5. • gold Open Access which fosters wider collaboration and increased citations 4. Temkin NR. Risk factors for posttraumatic seizures in adults. Epilepsia. maximum visibility for your research: over 100M website views per year 2003;44(s10):18–20. 5. Herman ST. Epilepsy after brain insult: targeting epileptogenesis. Neurol- At BMC, research is always in progress. ogy. 2002;59(9 Suppl 5):S21–6. 6. Benardo LS. Prevention of epilepsy after head trauma: do we need new Learn more biomedcentral.com/submissions drugs or a new approach? Epilepsia. 2003;44(s10):27–33. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Epileptologica Springer Journals

Effect of levetiracetam and valproate on late-onset post-traumatic seizures

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Abstract

Background To compare the preventive effects of levetiracetam and valproate on late-onset post-traumatic seizures in patients with traumatic brain injury ( TBI). Methods A total of 95 patients with TBI were recruited from 2017 to 2020. They were randomized into three groups: levetiracetam (LEV ) group (n = 30) receiving LEV treatment (500 mg, bid, po); valproate group (n = 32) receiving sodium valproate (500 mg/d, once daily, po); and control group (n = 33) receiving no anti-seizure medication. LEV and valproate were given to corresponding groups within seven days after TBI, and the administration lasted for one month. The incidence of epilepsy and adverse events were evaluated at 7 days and 12 months post-TBI. Results The cumulative incidences of late post-traumatic seizures at the 12-month follow-up in the LEV, valproate, and control groups were 3.33%, 12.50% and 15.63%, respectively. The cumulative incidence of late post-traumatic seizures in the LEV group was significantly lower than those in the valproate and control groups (P < 0.05). The cumu- lative incidence of late post-traumatic seizure in the valproate group was not significantly different from that in the control group (P > 0.05). Conclusions LEV can reduce the cumulative incidence of late post-traumatic seizures, whereas valproate can not. Keywords Levetiracetam, Valproate, Post-traumatic seizure seizures (LPTS). EPTS occur within one week post-TBI, Background whereas LPTS usually occur over one week after TBI [4]. With increased incidence of traffic accidents, traumatic Focal epilepsy and generalized epilepsy are more com- brain injury (TBI) has become a common and frequently mon after cerebral  trauma, while mixed epilepsy, psy- occurring condition, and one of the most common etiol- chomotor epilepsy or non-convulsive epilepsy are less ogies leading to secondary epilepsy [1, 2]. The incidence common. of post-traumatic seizures (PTS) after severe TBI ranges LPTS is one of the most medication-resistant epilep- 10–20% [3]. Two types of PTS have been identified: early sies and has serious impacts on the physical and men- post-traumatic seizures (EPTS) and late post-traumatic tal health of patients with TBI [5]. Risk factors for PTS include old age, penetrating injury, and a higher degree *Correspondence: of injury (eg, an intracranial hemorrhage, a midline dis- James X. Tao jtao@neurology.bsd.uchicago.edu placement greater than 5  mm, and a longer duration Meizhen Sun of coma). Several clinical trials have established that sunmeizhen213@126.com traditional anti-seizure medications (ASMs) can pre- Department of Rehabilitation, Shanxi Traditional Chinese Medical Hospital, Taiyuan 030012, China vent EPTS but not LPTS [6-8]. Valproate acid (VPA) is Department of Neurology, The First Hospital of Shanxi Medical a commonly used medication for epileptic seizures, but University, Taiyuan 030012, China its administration is associated with neurotoxic effects. Department of Neurology, University of Chicago, Chicago, IL 60601, USA In contrast, no such adverse effects have been reported © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Wang et al. Acta Epileptologica (2023) 5:10 Page 2 of 4 for levetiracetam (LEV) treatment. In addition, clini- severe (GCS 3–7), 33 moderate (GCS 8–12), and 46 mild cal studies have demonstrated favorable side effects and cases (GCS 13–15). pharmacokinetic data, as well as high efficacy of LEV. LEV is a broad-spectrum ASM that is widely used for Pharmacological treatment with ASMs the treatment of partial and generalized epilepsy. How- The 95 patients were randomized into three groups by a ever, whether LEV can prevent or reduce LPTS remains random number table: (1) the LEV group, in which they unclear [9-12]. VPA and phenytoin are commonly used were treated with 500  mg LEV twice daily after brain to prevent PTS in neurosurgery departments in China. injury, for one month; (2) the VPA group, in which they In an earlier investigation, the rates of LPTS did not dif- were treated with 500  mg VPA once daily after brain fer significantly between the VPA and phenytoin treat - injury, for one month; and (3) the control group, in which ment groups (P > 0.05) [13]. In this study, we aimed to they received no ASM treatment. In the VPA group, evaluate LEV prevention of LPTS in comparison to the although the minimum dose of sodium valproate was effect of VPA. recommended to be 600  mg/day, it was administered at 500 mg/day for convenience as the sodium valproate sus- Methods tained-release tablets were 500  mg each. If the patients Subjects could not take drugs orally, the medication was given This study was approved by the Institutional Review through a nasogastric tube. The medication was started Board at the First Hospital of Shanxi Medical University, at an average of 4.5 days after brain injury. and informed consent was obtained from all patients. The seizure frequency of LPTS was recorded for Ninety-five patients with TBI who were admitted in the 12 months after brain injury. Neurosurgery and Emergency Departments of the First Hospital of Shanxi Medical University were included in Statistical analysis this study (32 females, 63 males; mean age 44.6 ± 2.17 Data of age, GCS, and the number of diagnoses were years, range 20–65 years). The inclusion criteria were: analyzed with One-way ANOVA test. Pearson χ test (1) age of 18–70 years; (2) seizures within 30 min after was applied to compare the EPTS, brain injuries, and TBI with at least one of the following conditions detected the cumulative incidence of LPTS among groups at by CT: brain contusion, subdural hematoma, epidural 12  months. All analyses were made using the SPSS hematoma, and intracranial hematoma. The exclusion 17.0 software. P < 0.05 was considered as statistically criteria were as follows: (1) a family history of epilepsy; significant. (2) patients with epilepsy before TBI; (3) pregnancy and lactation; (4) patients who did not receive ASM treat- Results ment within seven days after TBI; (5) patients with any Patient follow‑up of the following medical conditions: hypertension, diabe- All patients in the LEV and VPA groups completed tes, stroke, renal and hepatic dysfunctions, and malignant the12-month follow-up. One patient in the control group tumor. was lost to follow-up due to the wrong telephone number Of the 95 patients, 25 had simple brain contusion provided. Both LEV and VPA were well tolerated by the (SBC), 27 had SBC and subdural hematoma, 18 had SBC patients. One patient experienced brief dizziness during and epidural hematoma, and 25 had SBC and multiple the LEV treatment, but it was improved a few days later. intracranial hematomas. Glasgow coma score (GCS) [14] One patient experienced mild insomnia during the VPA was assessed within 4 h post-TBI (Table 1). There were 16 treatment, which diminished three days later. Another Table 1 Demographics and clinical data of the patients with acute brain injury n Sex (M/F) Age (mean ± SD) GCS score EPTS Brain injury (mean ± SD) n SBC SBH EPH MIH LEV group 30 20/10 40.9 ± 2.03 12.1 ± 2.10 3 10 9 5 6 VPA group 32 23/9 45.2 ± 1.81 11.9 ± 1.91 2 7 8 9 8 Control group 33 20/13 44.2 ± 3.22 10.4 ± 1.75 3 8 10 4 11 P 0.56 0.87 > 0.05 > 0.05 Abbreviations: EPTS early post-traumatic seizures, GCS score The Glass Coma Scale score, SBC simple brain contusion, SBH Subdural hematoma, EPH epidural hematoma, MIH multiple intracranial hematomas W ang et al. Acta Epileptologica (2023) 5:10 Page 3 of 4 patient in the VPA group had mild gastrointestinal dis- total adults developed epilepsy two years post-brain injury. comfort that improved one day later. More specifically, 10.9% (5/46) of the treated adults and 20% (8/40) of the untreated adults developed epilepsy two Cumulative incidence of seizures years post-brain injury (relative risk, 0.47; P = 0.18). How- The incidence of LPTS was significantly higher in the LEV ever, although LEV tended to prevent LPTS, this effect was group than in the VPA group (3.33% vs 12.50%, χ = 4.41, not statistically significant [9 ]. P = 0.031) and control group (3.33% vs 15.63%, χ = 6.07, In the trial by Klein et  al., LEV treatment was termi- P = 0.017). There was no statistically significant difference nated in 3% of the patients in the LEV group due to som- in the incidence of LPTS between VPA and control groups nolence. The most common adverse events were fatigue, (χ = 1.15, P = 0.36). headache, and somnolence. The mood scores and num - These findings indicated that LEV had a significant pre - ber of infections did not differ between the LEV group ventive effect against LPTS, whereas VPA did not (Table 2 ). and the control group [9]. In another study, LEV treat- ment at 2000 mg/day caused somnolence, manifested as Discussion reduced awake time during the Maintenance of Wakeful- In this study, we found that the cumulative incidence ness Test and increased nap duration and episodes [15]. of LPTS in the LEV group was significantly lower than However, a daily dose of 1000 mg caused no changes in those in the VPA and control groups. The incidence of the daytime sleepiness in the Multiple Sleep Latency Test LPTS in the VPA group was not significantly different [16]. Therefore, LEV dosage of 1000 mg/day was used in from that in the control group. These findings indicated our trial for the prevention of LPTS without somnolence. that LEV could prevent LPTS in patients suffering from In studies of Pearl et al. [10] and Klein et al. [9], LEV was TBI, whereas VPA could not. administered at the dose of 55 mg/kg per day, and both Our results were consistent with those of Pearl et al. pub- studies reported common adverse events of headache, lished in 2013 [10]. In their study, LEV (55 mg/kg per day fatigue, and drowsiness, indicating that the dose of LEV bid for 30 days, starting within 8 hours post-brain injury) for prevention of LPTS needs to be reduced (< 55 mg/kg more effectively prevented LPTS in 20 TBI children aged per day) in clinical settings [9, 10]. 6–17 years with high risk factors of developing posttrau- Our results were also consistent with the study con- matic epilepsy. They found that only 1 of the 20 patients ducted by Chaudhry et al. [17], which reported that LEV developed LPTS during the two-year follow-up period. caused less adverse effects and had a better tolerability. With respect to adverse events, brief dizziness occurred Although the pathogenesis of LPTS is not fully clear, this in the LEV group, which disappeared a few days later. Pearl condition can be prevented during its incubation period et  al. found that the most common severe adverse events after TBI [13]. were headache, fatigue, drowsiness and irritability, and Laure Peter-Derex et  al. conducted a phase 3 PEACH there was a higher incidence of infection, mood change, trial in France, in which patients who had a non-trau- or behavior problems among the treatment patients com- matic intracerebral hemorrhage received LEV treatment, pared to the observation patients. This may be because starting within 24  h after hemorrhage. They found that that the dose of LEV (adult, 1000 mg/day) was better toler- LEV effectively prevented acute seizures in intracerebral ated in the adult patients in our trial than in the pediatric hemorrhage [18]. patients (55 mg/kg per day) in the Pearl’ trial. There are several limitations in this study. First, the Our result was also consistent with the the study of Klein blood concentration of LEV and VPA were not measured et al. in 2012 [9]. In their study, treatment with LEV at 55 in the patients. Second, the study was not blinded, which mg/kg per day lasted for 30 days, starting within 8 hours might have caused a bias in analysis. Third, the sample post-brain injury. They found that 15.1% (13/86) of the size was relatively small. Fourth, the duration of follow- up was relatively short. Multicenter, randomized, pla- cebo-controlled trials are needed in the future to explore Table 2 Comparison of the cumulative incidences of LPTS in the preventive effects of LEV against LPTS. different groups Group n Lost to n of patients with Cumulative Conclusions follow up (n) seizure attacks incidence In this study, we found that VPA could not prevent LPTS (%) and caused more adverse events. This is consistent with LEV 30 0 1 3.33 the findings of Temkin et al. and Paqnl et al. [13, 19]. Val- VPA 32 0 4 12.50* proate sodium can exert antiepileptogenic effects at high Control 33 1 5 15.63* doses that may be toxic for human use. However, LEV : Compared with the LEV group, *P < 0.05 Wang et al. Acta Epileptologica (2023) 5:10 Page 4 of 4 7. Englander J, Bushnik T, Duong TT, Cifu DX, Zafonte R, Wright J, et al. can effectively reduce the cumulative incidence of LPTS Analyzing risk factors for late posttraumatic seizures: a prospective, multi- in patients with TBI. center investigation. Arch Phys Med Rehabil. 2003;84(3):365–73. 8. Asikainen I, Kaste M, Sarna S. Early and late posttraumatic seizures in traumatic brain injury rehabilitation patients: brain injury factors causing Abbreviations late seizures and influence of seizures on long-term outcome. Epilepsia. ASM Anti-seizure medication 1999;40(5):584–9. EPTS Early posttraumatic seizure 9. Klein P, Herr D, Pearl PL, Natale J, Levine Z, Nogay C, et al. Results of phase GCS Glasgow coma scale 2 safety and feasibility study of treatment with levetiracetam for preven- LEV Levetiracetam tion of posttraumatic epilepsy. Arch Neurol. 2012;69(10):1290–5. LPTS Lat e posttraumatic seizure 10. Pearl PL, McCarter R, McGavin CL, Yu Y, Sandoval F, Trzcinski S, et al. Results PTS Post-traumatic seizures of phase II levetiracetam trial following acute head injury in children at SBC Simple brain contusion risk for posttraumatic epilepsy. Epilepsia. 2013;54(9):e135–7. TBI Traumatic brain injury 11. Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, VPA Valproic acid single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care. 2010;12(2):165–72. Acknowledgements 12. Younus SM, Basar S, Gauri SA, Khan AA, Imran M, Abubakar S, et al. Com- No acknowledgement. parison of Phenytoin versus Levetiracetam in Early Seizure Prophylaxis after Traumatic Brain Injury, at a Tertiary Care Hospital in Karachi. Pakistan Authors’ contributions Asian J Neurosurg. 2018;13(4):1096–100. Yanli Wang participated in data collection and manuscript writing. Yiqi Wang 13. Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A participated in data collection. Huifang Wang and Xiaoping Du analyzed the randomized, double-blind study of phenytoin for the prevention of post- results. Jie Miao participated in data collection and analyzed the results. James traumatic seizures. N Engl J Med. 1990;323(8):497–502. X. Tao was involved in the revision of the clinical trial protocol, and Meizhen 14. Barlow Philip. A Practial review of the glasgow coma scale and score. Sun designed and supervised this study. All authors approved the final version Surgeon. 2012;10:114–9. of the manuscript. 15. Yilmaz H. Comparison of motor activity and sleep in patients with com- plex partial seizures on levetiracetam treatment and a group of healthy Authors’ information subjects. Behav Neurol. 2007;18:165–70. Yanli Wang came from Shanxi Traditional Chinese Medical Hospital, James X. 16. Zhou JY, Tang XD, Huang LL, Zhong ZQ, Lei F, Zhou D. The acute effects of Tao came from the University of Chicago, and the other authors came from levetiracetam on nocturnal sleep and daytime sleepiness in patients with The First Hospital of Shanxi Medical University. partial epilepsy. J Clin Neurosci. 2012;19(7):956–60. 17. Chaudhry SA, Jong G, Koren G. The fetal safety of Levetiracetam: a sys- Funding tematic review. Reprod Toxicol. 2014;46:40–5. This study was funded by the Scientific Research Fund of China Association 18. Peter-Derex L, Philippeau F, Garnier P, et al. Safety and efficacy of pro - Against Epilepsy (No 2012002). phylactic levetiracetam for prevention of epileptic seizures in the acute phase of intracerebral haemorrhage (PEACH): a randomised, double- Availability of data and materials blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2022;21:781–91. Not applicable. 19. Pagni CA, Zenga F. Prevention and treatment of post-traumatic epilepsy. Expert Rev Neurother. 2006;6(8):1223–33. Declarations Ethics approval and informed consent The study was approved by the the First Hospital of Shanxi Medical University (No. KYLL-2023–030). All participants had given informed consent. Consent for publication Not applicable. Competing interests The authors declare no conflict of interest. Received: 1 November 2022 Accepted: 28 March 2023 Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : References fast, convenient online submission 1. Lowenstein DH. Epilepsy after head injury: an overview. Epilepsia. 2009;50(Suppl 2):4–9. thorough peer review by experienced researchers in your field 2. Salinsky M, Storzbach D, Goy E, Evrard C. Traumatic brain injury and psy- rapid publication on acceptance chogenic seizures in veterans. J Head Trauma Rehabil. 2015;30(1):E65-70. support for research data, including large and complex data types 3. D’Ambrosio R, Perucca E. Epilepsy after head injury. Curr Opin Neurol. 2004;17(6):731–5. • gold Open Access which fosters wider collaboration and increased citations 4. Temkin NR. Risk factors for posttraumatic seizures in adults. Epilepsia. maximum visibility for your research: over 100M website views per year 2003;44(s10):18–20. 5. Herman ST. Epilepsy after brain insult: targeting epileptogenesis. Neurol- At BMC, research is always in progress. ogy. 2002;59(9 Suppl 5):S21–6. 6. Benardo LS. Prevention of epilepsy after head trauma: do we need new Learn more biomedcentral.com/submissions drugs or a new approach? Epilepsia. 2003;44(s10):27–33.

Journal

Acta Epileptologica – Springer Journals

Published: Apr 23, 2023

Keywords: Levetiracetam; Valproate; Post-traumatic seizure

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