A systematic review of epileptic seizures in adults with subdural haematomas

Open ArchivePublished:November 25, 2016DOI:https://doi.org/10.1016/j.seizure.2016.11.017

      Highlights

      • Overall incidence of ePTS (lPTS) is 28% (43) in aSDH and 10% (5.3) in cSDH in 2–3 years.
      • Recurrence rate of seizures is higher in patients with late PTS compared to early PTS.
      • There are different risk factors for seizures in a- and cSDH.
      • aSDH: 24 h postoperative GCS < 9, craniotomy, preoperative GCS < 8.
      • cSDH: alcohol abuses, mental change, previous stroke and density of haematoma in CT.

      Abstract

      Background

      Posttraumatic epileptic seizures (PTS) are a serious complication in patients with subdural haematoma (SDH). However, to date, several studies have shown discordances about SDH-associated seizures in terms of incidence, risk factors and prophylactic antiepileptic treatment.

      Objective

      The aim of this study was to analyse the incidence, risk factors of PTS and the role of prophylactic antiepileptic treatment in patients with SDH.

      Data sources

      A systematic literature review examining PTS in patients with SDH was performed using PubMed gateway, Cochrane Central Register of Controlled Trials, and Excerpta Medica dataBASE between September 1961 and February 2016. Search terms included subdural haematoma, seizure, epilepsy, prophylactic antiepileptic drugs, anticonvulsive medication, and risk factors.

      Data selection

      Human-based clinical studies focusing on epileptic seizures in patients with SDH.

      Data extraction and synthesis

      PRISMA statements were used for assessing data quality. Two independent reviewers extracted data from included studies and disagreement was solved by consensus. Twenty-four studies were identified for inclusion into the study.

      Results

      Overall incidence of early PTS (ePTS) and late PTS (lPTS)/2 years was 28% and 43% in acute SDH (aSDH) whereas the incidence of e- and lPTS was lower in chronic SDH (cSDH; 5.3% vs. 10%). Overall risk factors for PTS in patients with aSDH were: 24 h postoperative Glasgow Coma Score (GCS) score below 9 (OR 10.5), craniotomy (OR 3.9), preoperative GCS below 8 (OR 3.1). In patients with cSDH the risk factors were alcohol abuse (OR 14.3), change of mental status (OR 7.2), previous stroke (OR 5.3) and density of haematoma in computer tomography (OR 3.8). Age, sex, haematoma size/side and midline shifts were not significant risk factors for PTS in both types of SDH. In prevention of PTS phenytoin and levetiracetam showed similar efficacy (OR 1.3), whereas levetiracetam was associated with significantly lower adverse effects (OR 0.1).

      Limitations

      Most of the studies were of retrospective nature with a small sample size. Due to the inclusion criteria, some studies had to be excluded and that might lead to selection bias.

      Conclusions

      PTS are a serious complication in patients with SDH, particularly in aSDH. The “prophylactic use” of antiepileptic drugs might be beneficial in patients with cumulative risk factors.

      Keywords

      1. Introduction

      Post-traumatic epileptic seizures (PTSs) are a serious complication after traumatic brain injury (TBI), particularly in patients with subdural haematomas (SDHs). The prevalence of PTSs in SDHs is reported to be 24% in acute SDHs (aSDHs) and 11% in chronic SDHs (cSDHs) [
      • Hamasaki T.
      • Yamada K.
      • Kuratsu J.
      Seizures as a presenting symptom in neurosurgical patients: a retrospective single-institution analysis.
      ,
      • Huang K.T.
      • Bi W.L.
      • Abd-El-Barr M.
      • et al.
      The neurocritical and neurosurgical care of subdural hematomas.
      ,
      • Temkin N.R.
      Risk factors for posttraumatic seizures in adults.
      ]. Despite the high prevalence of PTSs in SDHs, which patients are at risk of developing PTSs and could eventually profit from a prophylactic antiepileptic medication remains a matter of speculation. In fact, some retrospective studies showed that older age, chronic alcoholism and the severity of trauma were associated with PTSs [
      • Annegers J.F.
      • Hauser W.A.
      • Coan S.P.
      • et al.
      A population-based study of seizures after traumatic brain injuries.
      ,
      • Servadei F.
      Prognostic factors in severely head injured adult patients with acute subdural haematomas.
      ,
      • Wiedemayer H.
      • Triesch K.
      • Schafer H.
      • et al.
      Early seizures following non-penetrating traumatic brain injury in adults: risk factors and clinical significance.
      ,
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      ,
      • Englander J.
      • Bushnik T.
      • Duong T.T.
      • et al.
      Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation.
      ]; however, classifying PTSs is more complex than it seems at first sight. In the literature, PTSs are classified by arbitrary time limits into three groups: immediate seizures occur within 24 h after insult; early acute symptomatic seizures within 7 days after insult; and late unprovoked seizures 7 days after insult. It seems important to differentiate between those groups due to the different underlying pathophysiology, which might be associated with different seizure recurrence rates. Unfortunately, the time limits are not used consistently: some authors delineate between early and late seizures at 14 days. Compared to early PTSs (ePTSs), late PTSs (lPTSs) have a much higher risk of recurrence of seizures (<20% compared to >60%). Although the risk of PTS is highest within 24 h after TBI as an acute symptom, lPTSs can occur up to 20 years after TBI, thereby suggesting clinical alertness. In particular, injuries involving SDHs are likely to increase both ePTSs and lPTSs in children and adults compared to other TBIs [
      • Temkin N.R.
      Risk factors for posttraumatic seizures in adults.
      ]. The prognosis after an SDH depends on multiple factors such as age, Glasgow coma scale (GCS), size of haemorrhage and time from the SDH until treatment, but the occurrence of a PTS is an independent marker of poor functional and social outcome [
      • Seifi A.
      • Asadi-Pooya A.A.
      • Carr K.
      • et al.
      The epidemiology, risk factors, and impact on hospital mortality of status epilepticus after subdural hematoma in the United States.
      ,
      • Phuenpathom N.
      • Choomuang M.
      • Ratanalert S.
      Outcome and outcome prediction in acute subdural hematoma.
      ,
      • Howard 3rd, M.A.
      • Gross A.S.
      • Dacey Jr., R.G.
      • et al.
      Acute subdural hematomas: an age dependent clinical entity.
      ,
      • Servadei F.
      Prognostic factors in severely head injured adult patients with acute subdural haematomas.
      ,
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      ,
      • Asikainen I.
      • Kaste M.
      • Sarna S.
      Early and late posttraumatic seizures in traumatic brain injury rehabilitation patients: brain injury factors causing late seizures and influence of seizures on long-term outcome.
      ].
      Antiepileptic drugs (AEDs) are standard treatment for lPTSs, but their use in ePTSs remains controversial. There have been some prospective studies verifying the positive effect of prophylactic AEDs like phenytoin, which was largely used in the past as the gold standard in reducing ePTSs [
      • Temkin N.R.
      • Dikmen S.S.
      • Wilensky A.J.
      • et al.
      A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures.
      ]. Recently, more tolerable AEDs like levetiracetam, which have a similar efficacy, were introduced into the market to replace the standard AEDs [
      • Ertl J.
      • Hapfelmeier J.
      • Peckmann T.
      • et al.
      Guideline conform initial monotherapy increases in patients with focal epilepsy: a population-based study on German health insurance data.
      ]. However, to date, there have been no prospective controlled studies describing the value of prophylactic AEDs exclusively focusing on SDHs. One retrospective study showed a significant reduction of epileptic seizures by administering prophylactic AEDs [
      • Huang K.T.
      • Bi W.L.
      • Abd-El-Barr M.
      • et al.
      The neurocritical and neurosurgical care of subdural hematomas.
      ,
      • Sabo R.A.
      • Hanigan W.C.
      • Aldag J.C.
      Chronic subdural hematomas and seizures: the role of prophylactic anticonvulsive medication.
      ], but other retrospective studies were not able to show any advantage of prophylactic AEDs [
      • Rubin G.
      • Rappaport Z.H.
      Epilepsy in chronic subdural haematoma.
      ,
      • Grobelny B.T.
      • Ducruet A.F.
      • Zacharia B.E.
      • et al.
      Preoperative antiepileptic drug administration and the incidence of postoperative seizures following burr hole-treated chronic subdural hematoma.
      ,
      • Ohno K.
      • Maehara T.
      • Ichimura K.
      • et al.
      Low incidence of seizures in patients with chronic subdural haematoma.
      ]. Therefore, further studies are needed to clarify the ongoing debate about the benefit of using prophylactic AEDs in patients with SDHs.
      During the last few years, several studies have reported a correlation between SDHs and epileptic seizures, but many studies disagree about SDH-associated seizures. In the present study, we performed the first systematic review on epileptic seizures in SDHs. The objective of this study was to identify and summarize the incidence and risk factors of SDH-associated seizures and the current state of prophylactic use of AEDs.

      2. Methods

      A systematic review was performed following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was approved by the Clinical Ethics Committee of the University of Frankfurt (Nr.509/15) [
      • Moher D.
      • Liberti A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ,
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      ].

      2.1 Data sources and data searches

      A broad search for all studies describing epileptic seizures in patients with SDHs using the PubMed gateway of the MEDLINE database, the Cochrane Central Register of Controlled Trials (CENTRAL) and the Excerpta Medica dataBASE (EMBASE) was performed from 1961 to February 2016. Additionally, we researched the reference lists of those studies. The following keywords were used individually or in combination with “AND”: subdural haematoma; SDH (acute/chronic); seizure; epilepsy; prophylactic antiepileptic drugs; anticonvulsive medication; risk factors of seizure.

      2.2 Study selection

      Inclusion required human-based clinical studies that focused on epileptic seizures in patients with SDHs. Exclusion criteria included studies reporting only paediatric patients (<18 years old), language other than English, redundant data and deficient insufficient disaggregation to identify incidence or risk factors of PTSs. Case reports, presentations and conference abstracts were excluded as well. The study selection process is illustrated in Fig. 1.
      Fig. 1
      Fig. 1Flow chart summarizing the study selection process. Inclusion criteria required human-based clinical studies focusing on epileptic seizures in patients with subdural haematomas. Exclusion criteria required studies reporting on paediatric patients only (<18 years old), language other than English, redundant data or deficientinsufficient disaggregation to identify the incidence or risk factors of epileptic seizure in subdural haematomas. Overall, 24 studies met the inclusion and exclusion criteria.

      2.3 Data extraction and synthesis

      Two reviewers performed eligibility assessment independently in an unblinded standardized manner. Two independent review authors acquired the literature, selected the studies and extracted data from the included studies. Disagreement between reviewers was resolved by consensus [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      ]. In the case of no agreement, third third author was authorized to decide.
      In total, 982 studies were identified. After screening the titles and abstracts, 42 studies were identified as addressing subdural haematomas and epileptic seizures. Among those studies, 18 were excluded (not in English, redundant, not disaggregated, no manuscript available) and 24 were included. Among these studies, 17 investigated seizure incidence, 11 explored risk factors for seizures and 10 studies examined prophylactic antiepileptic treatment. For all parameters, we distinguished between aSDHs and cSDHs. The incidence that we describe in this review is a crude incidence estimate and not from population-based studies. Furthermore, we tried to analyse immediate, early and late PTSs separately; however, the majority of the studies considered immediate PTSs and ePTSs as one category. Due to the lack of granularity provided in the reviewed literature we were only able to distinguish between ePTSs and lPTSs.

      2.4 Statistical analysis

      GraphPad Prism (6.0, GraphPad Software Inc., USA) was used for statistical analysis. Parametric data were analysed between group differences using an unpaired t-test. For categorical variables, we used Fisher’s exact or the Chi-square test. For dichotomy risk factors, we counted odds ratios (ORs) with 95% confidence intervals (CI95). A p-value ≤ 0.05 was regarded as statistically significant.

      3. Results

      In total, 17 studies reporting incidence of seizures in patients with acute and chronic SDHs were analysed [
      • Temkin N.R.
      Risk factors for posttraumatic seizures in adults.
      ,
      • Seifi A.
      • Asadi-Pooya A.A.
      • Carr K.
      • et al.
      The epidemiology, risk factors, and impact on hospital mortality of status epilepticus after subdural hematoma in the United States.
      ,
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      ,
      • Englander J.
      • Bushnik T.
      • Duong T.T.
      • et al.
      Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation.
      ,
      • Haltiner A.M.
      • Temkin N.R.
      • Dikmen S.S.
      Risk of seizure recurrence after the first late posttraumatic seizure.
      ,
      • Sabo R.A.
      • Hanigan W.C.
      • Aldag J.C.
      Chronic subdural hematomas and seizures: the role of prophylactic anticonvulsive medication.
      ,
      • Grobelny B.T.
      • Ducruet A.F.
      • Zacharia B.E.
      • et al.
      Preoperative antiepileptic drug administration and the incidence of postoperative seizures following burr hole-treated chronic subdural hematoma.
      ,
      • Glotzner F.L.
      • Haubitz I.
      • Miltner F.
      • et al.
      Seizure prevention using carbamazepine following severe brain injuries.
      ,
      • Ohno K.
      • Maehara T.
      • Ichimura K.
      • et al.
      Low incidence of seizures in patients with chronic subdural haematoma.
      ,
      • Luxon L.M.
      • Harrison M.J.
      Chronic subdural haematoma.
      ,
      • Hirakawa K.
      • Hashizume K.
      • Fuchinoue T.
      • et al.
      Statistical analysis of chronic subdural hematoma in 309 adult cases.
      ,
      • Kotwica Z.
      • Brzeinski J.
      Epilepsy in chronic subdural haematoma.
      ,
      • Huang Y.H.
      • Yang T.M.
      • Lin Y.J.
      • et al.
      Risk factors and outcome of seizures after chronic subdural hematoma.
      ,
      • Rudzinski L.A.
      • Rabinstein A.A.
      • Chung S.Y.
      • et al.
      Electroencephalographic findings in acute subdural hematoma.
      ,
      • Robinson R.G.
      Chronic subdural hematoma: surgical management in 133 patients.
      ,
      • Chen C.W.
      • Kuo J.R.
      • Lin H.J.
      • et al.
      Early post-operative seizures after burr-hole drainage for chronic subdural hematoma: correlation with brain CT findings.
      ,
      • Jennett B.
      Epilepsy and acute traumatic intracranial haematoma.
      ,
      • Cole M.
      • Spatz E.
      Seizures in chronic subdural hematoma.
      ]. Two of the 17 studies (11.7%) reported PTSs in SDHs, without differentiating the type of SDH. Nine of the 17 studies (52.9%) distinguished between ePTSs and lPTSs, but none of them differentiated between immediate PTSs and ePTSs. Therefore immediate PTSs and ePTS were considered as one category. Other studies did not differentiate between these entities and referred to PTS as one entity, which we classified as unspecified PTS. Eleven of the 17 studies (64.7%) analysed additionally risk factors for PTSs in SDHs. Apart from two prospective studies [
      • Englander J.
      • Bushnik T.
      • Duong T.T.
      • et al.
      Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation.
      ,
      • Young B.
      • Rapp R.P.
      • Norton J.A.
      • et al.
      Failure ofprophylactically administered phenytoin to prevent late posttraumatic seizures.
      ], all other studies were retrospectively analysed with an evidence level of 3.

      3.1 Incidence of PTS in patients with acute subdural haematoma

      The results are illustrated in Table 1. In total, three studies were identified as describing the incidence of PTS in patients with aSDHs. About 40 years ago, Jennett [
      • Jennett B.
      Epilepsy and acute traumatic intracranial haematoma.
      ] reported that 58 out of 159 patients with aSDHs (36%) developed ePTSs, which was the highest incidence among all intracranial haematomas. Recently, similar results (24%, 25%) were reported by Temkin and Rabinstein et al. [
      • Temkin N.R.
      Risk factors for posttraumatic seizures in adults.
      ,
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      ]. The mean time to occurrence of ePTS was one day, indicating the highest incidence within 24 h after onset [
      • Seifi A.
      • Asadi-Pooya A.A.
      • Carr K.
      • et al.
      The epidemiology, risk factors, and impact on hospital mortality of status epilepticus after subdural hematoma in the United States.
      ]. Furthermore, two of those studies analysed cumulative lPTS incidence in aSDHs within a two-year period. In both studies, the incidence of lPTS was more than 40% [
      • Temkin N.R.
      Risk factors for posttraumatic seizures in adults.
      ,
      • Jennett B.
      Epilepsy and acute traumatic intracranial haematoma.
      ]. One prospective study observing lPTSs in mixed SDHs found that the incidence varied between 15% and 28%, depending on the treatment [
      • Englander J.
      • Bushnik T.
      • Duong T.T.
      • et al.
      Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation.
      ].
      Table 1Incidence of PTS in patients with subdural haematoma.
      SDH: subdural haematoma; PTS: post-traumatic seizure.

      3.2 Incidence of PTS in patients with chronic subdural haematoma

      We identified 12 studies focusing on PTSs in patients with cSDHs. Five of the 12 studies (41.7%) distinguished between ePTSs and lPTSs whereas other studies distinguished between pre- and post-operative seizures. The overall incidence of PTS in patients with cSDHs is in general lower than with aSDHs; it varies between 2% and 42% [
      • Sabo R.A.
      • Hanigan W.C.
      • Aldag J.C.
      Chronic subdural hematomas and seizures: the role of prophylactic anticonvulsive medication.
      ,
      • Rubin G.
      • Rappaport Z.H.
      Epilepsy in chronic subdural haematoma.
      ,
      • Grobelny B.T.
      • Ducruet A.F.
      • Zacharia B.E.
      • et al.
      Preoperative antiepileptic drug administration and the incidence of postoperative seizures following burr hole-treated chronic subdural hematoma.
      ,
      • Ohno K.
      • Maehara T.
      • Ichimura K.
      • et al.
      Low incidence of seizures in patients with chronic subdural haematoma.
      ,
      • Ratilal B.O.
      • Pappamikail L.
      • Costa J.
      • et al.
      Anticonvulsants for preventing seizures in patients with chronic subdural haematoma.
      ,
      • Luxon L.M.
      • Harrison M.J.
      Chronic subdural haematoma.
      ,
      • Hirakawa K.
      • Hashizume K.
      • Fuchinoue T.
      • et al.
      Statistical analysis of chronic subdural hematoma in 309 adult cases.
      ,
      • Kotwica Z.
      • Brzeinski J.
      Epilepsy in chronic subdural haematoma.
      ,
      • Huang Y.H.
      • Yang T.M.
      • Lin Y.J.
      • et al.
      Risk factors and outcome of seizures after chronic subdural hematoma.
      ,
      • Robinson R.G.
      Chronic subdural hematoma: surgical management in 133 patients.
      ,
      • Chen C.W.
      • Kuo J.R.
      • Lin H.J.
      • et al.
      Early post-operative seizures after burr-hole drainage for chronic subdural hematoma: correlation with brain CT findings.
      ,
      • Cole M.
      • Spatz E.
      Seizures in chronic subdural hematoma.
      ,
      • Dudek H.
      • Michno T.
      • Michalski J.
      • et al.
      Late posttraumatic epilepsy in patients with an alcoholic problem treated surgically for posttraumatic chronic subdural hematomas.
      ], and the incidence of post-operative seizures is reported as between 1% and 23% [
      • Ohno K.
      • Maehara T.
      • Ichimura K.
      • et al.
      Low incidence of seizures in patients with chronic subdural haematoma.
      ,
      • Ratilal B.O.
      • Pappamikail L.
      • Costa J.
      • et al.
      Anticonvulsants for preventing seizures in patients with chronic subdural haematoma.
      ,
      • Luxon L.M.
      • Harrison M.J.
      Chronic subdural haematoma.
      ,
      • Hirakawa K.
      • Hashizume K.
      • Fuchinoue T.
      • et al.
      Statistical analysis of chronic subdural hematoma in 309 adult cases.
      ,
      • Kotwica Z.
      • Brzeinski J.
      Epilepsy in chronic subdural haematoma.
      ,
      • Huang Y.H.
      • Yang T.M.
      • Lin Y.J.
      • et al.
      Risk factors and outcome of seizures after chronic subdural hematoma.
      ]. The incidence of ePTS ranged between 3.6% and 42% whereas the incidence of lPTS ranged between 5% and 20.6% within a three-year period [
      • Ohno K.
      • Maehara T.
      • Ichimura K.
      • et al.
      Low incidence of seizures in patients with chronic subdural haematoma.
      ,
      • Huang Y.H.
      • Yang T.M.
      • Lin Y.J.
      • et al.
      Risk factors and outcome of seizures after chronic subdural hematoma.
      ,
      • Chen C.W.
      • Kuo J.R.
      • Lin H.J.
      • et al.
      Early post-operative seizures after burr-hole drainage for chronic subdural hematoma: correlation with brain CT findings.
      ,
      • Cole M.
      • Spatz E.
      Seizures in chronic subdural hematoma.
      ,
      • Dudek H.
      • Michno T.
      • Michalski J.
      • et al.
      Late posttraumatic epilepsy in patients with an alcoholic problem treated surgically for posttraumatic chronic subdural hematomas.
      ]. Presumably, the wide range of PTS incidence between studies may be due to the different surgical treatments, the status of patients and the severity of the head injury. Hirakawa et al. [
      • Hirakawa K.
      • Hashizume K.
      • Fuchinoue T.
      • et al.
      Statistical analysis of chronic subdural hematoma in 309 adult cases.
      ] compared 309 patients with cSDHs after different surgical treatments and found that patients undergoing burr hole treatment had a decreased incidence of epileptic seizures compared to patients with craniotomy and haematoma-membrane resection (capsulotomy) [
      • Ohno K.
      • Maehara T.
      • Ichimura K.
      • et al.
      Low incidence of seizures in patients with chronic subdural haematoma.
      ,
      • Hirakawa K.
      • Hashizume K.
      • Fuchinoue T.
      • et al.
      Statistical analysis of chronic subdural hematoma in 309 adult cases.
      ]. Moreover, patients with a history of alcohol abuse or severe head trauma had a higher PTS incidence (42%) in combination with cSDH [
      • Annegers J.F.
      • Hauser W.A.
      • Coan S.P.
      • et al.
      A population-based study of seizures after traumatic brain injuries.
      ,
      • Cole M.
      • Spatz E.
      Seizures in chronic subdural hematoma.
      ].

      3.3 Risk factors for PTS in patients with acute subdural haematoma

      To date, there have been few studies identifying risk factors for PTS in patients with SDH. Differentiating aSDH from cSDH, the results and statistical analysis are summarized in Table 2, Table 3. Significant risk factors for ePTS in patients with aSDH were a preoperative GCS score < 8, a post-operative GCS score ≤ 8 within 24 h and the need for a craniotomy [
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      ]. Similar correlating results were reported between craniotomy and lPTS within a two-year period [
      • Temkin N.R.
      Risk factors for posttraumatic seizures in adults.
      ,
      • Englander J.
      • Bushnik T.
      • Duong T.T.
      • et al.
      Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation.
      ]. Age, haematoma size, haematoma side and midline shifts were not significant risk factors for ePTS in patients with aSDH [
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      ]. Additional risk factors such as age, black ethnicity, secondary SDH and major organ dysfunction were reported in a large population-based study, but the authors did not differentiate between types of SDH and PTS [
      • Seifi A.
      • Asadi-Pooya A.A.
      • Carr K.
      • et al.
      The epidemiology, risk factors, and impact on hospital mortality of status epilepticus after subdural hematoma in the United States.
      ].
      Table 2Risk factors for seizures in acute and mixed SDHs, odds ratio (OR), confidence intervals and p-values.
      AuthorsYearCohort informationRisk factors for ePTSRisk factors for lPTSRisk factors for unspecified PTSOR (95% CI)p-Value
      Unpaired t-test for parametric statistics, Fisher’s exact and Chi-square test for categorical variables; not significant (n.s., p>0.05).
      Rabinstein et al.
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      2010134 SDH patientsAgeN.a.n.s.
      -41 aSDH patientsSex0.865 (0.54–2.114)n.s.
      -93 acute-on-chronic SDH patientsaSDH2.593 (1.152–5,833)0.03
      CT scans:
      -Haematoma side1.493 (0.678–3.286)n.s.
      -Mean SDH volumeN.a.n.s.
      -Mean midline shiftN.a.n.s.
      Craniotomy3.85 (1.688–8.779)0.001.
      GCS score <8 preop.3.130 (1.038–9.437)0.05
      GCS score ≤8, 24 h post-op.10.544 (3.035–36.634)0.0001
      Temkin
      • Temkin N.R.
      Risk factors for posttraumatic seizures in adults.
      2003783 TBI patientsTreatmentN.a.<0.001
      -? aSDH patients-Craniotomy: 44%
      -Conservative: 19%
      -No SDH: 15%
      Englander et al.
      • Englander J.
      • Bushnik T.
      • Duong T.T.
      • et al.
      Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation.
      2003647 TBI patientsTreatment
      -276 mixed SDH-Surgery: 27.8%2.26 (1.13–4.52)0.03
      Conservative: 15.3%
      -No SDH: 9.5%0.514 (0.307–0.861)0.01
      Seifi et al.
      • Seifi A.
      • Asadi-Pooya A.A.
      • Carr K.
      • et al.
      The epidemiology, risk factors, and impact on hospital mortality of status epilepticus after subdural hematoma in the United States.
      20141,583,255 mixed SDHAge (per year)0.99 (0.99–0.99)<0.0001
      PatientsBlack2.08 (1.952–2.216)<0.0001
      -0.5% Status epilepticus1°SDH/2°SDH0.555 (0.53–0.581)<0.0001
      Major organ dysfunction
      -Haematologic1.945 (1.807–2.093)<0.0001
      -Metabolic4.185 (3.818–4.587)<0.0001
      -Renal2.263 (2.132–2.403)<0.0001
      -CNS3.348 (3.247–3.64)<0.0001
      -Respiratory6.176 (5.889–6.477)<0.0001
      SDH: subdural hematoma; PTS: post-traumatic seizure; ePTS: early PTS; lPTS: late PTS; 95% CI: 95% confidence interval.
      * Unpaired t-test for parametric statistics, Fisher’s exact and Chi-square test for categorical variables; not significant (n.s., p > 0.05).
      Table 3Risk factors for seizures in chronic SDHs, odds ratio (OR), confidence intervals and p-values.
      AuthorsYearCohort informationRisk factors for ePTSRisk factors for lPTSRisk factors for unspecified PTSOR (95% CI)p-Value
      Unpaired t-test for parametric statistics, Fisher’s exact and Chi-square test for categorical variables; not significant (n.s., p>0.05). SDH: subdural hematoma; PTS: post-traumatic seizure; ePTS: early PTS; lPTS: late PTS; 95% CI: 95% confidence interval.
      Cole et al.
      • Cole M.
      • Spatz E.
      Seizures in chronic subdural hematoma.
      196150 cSDH patientsAgeN.a.n.s.
      History of epilepsyN.a.n.s.
      Hirakawa et al.
      • Hirakawa K.
      • Hashizume K.
      • Fuchinoue T.
      • et al.
      Statistical analysis of chronic subdural hematoma in 309 adult cases.
      1972309 cSDH patientsBurr hole0.453 (0.195–1.0517)0.06
      Craniotomy6.248 (2.772–14.081)0.0001
      Sabo et al.
      • Sabo R.A.
      • Hanigan W.C.
      • Aldag J.C.
      Chronic subdural hematomas and seizures: the role of prophylactic anticonvulsive medication.
      199498 cSDH patientsAge, history of trauma, Markwalder scale, location of clot, type of surgeryN.a.n.s.
      Dudekt et al.
      • Dudek H.
      • Michno T.
      • Michalski J.
      • et al.
      Late posttraumatic epilepsy in patients with an alcoholic problem treated surgically for posttraumatic chronic subdural hematomas.
      199934 cSDH patientsAlcohol abusus14.25 (1.469–138.278)0.01
      Chen et al.
      • Chen C.W.
      • Kuo J.R.
      • Lin H.J.
      • et al.
      Early post-operative seizures after burr-hole drainage for chronic subdural hematoma: correlation with brain CT findings.
      2004128 cSDH patientsCT scans:
      -Density
      Hypodense1.178 (0.133–10,471)n.s.
      (n = 1/16 seizure)
      Isodense0.198 (0.037–1.063)0.052
      (n = 2/83 seizure)
      Mixed density5.12 (1.076–24.373)<0.05
      (n = 4/29 seizure)
      -SDH side
      Right0.292 (0.034–2.502)n.s.
      Left3.802 (0.709–20.397)n.s.
      Bilateral0.529 (0.061–4.575)n.s.
      Grobelny et al.
      • Grobelny B.T.
      • Ducruet A.F.
      • Zacharia B.E.
      • et al.
      Preoperative antiepileptic drug administration and the incidence of postoperative seizures following burr hole-treated chronic subdural hematoma.
      200988 cSDH patientsAgeN.a.n.s.
      Sex (male)0.254 (0.069–0.932)0.06
      Mean GCS at admissionN.a.n.s.
      CT scans:
      -SDH side
      Right00.03
      Left2.741 (0.749–10.172)n.s.
      Bilateral1.429 (0.38–5,371)n.s
      -Mean SDH volumeN.a.n.s.
      -Mean midline shiftN.a.n.s.
      Huang et al.
      • Huang Y.H.
      • Yang T.M.
      • Lin Y.J.
      • et al.
      Risk factors and outcome of seizures after chronic subdural hematoma.
      2011100 cSDH patientsAgeN.a.n.s.
      Sex0.912 (0.179–4,654)n.s.
      Symptoms (mental change)7.224 (1.481–35.241)0.008
      Mean GCS at admissionN.a.0.008
      CT scans:
      -Density of haematoma (HU)N.a.0.051
      -Severe brain atrophy3.802 (1.032–14.012)0.05
      -Haematoma mass effectN.a.n.s.
      -Haematoma volumeN.a.n.s.
      Mean GOS at dischargeN.a.0.016
      Stroke5.347 (1.409–20.291)0.019
      * Unpaired t-test for parametric statistics, Fisher’s exact and Chi-square test for categorical variables; not significant (n.s., p > 0.05). SDH: subdural hematoma; PTS: post-traumatic seizure; ePTS: early PTS; lPTS: late PTS; 95% CI: 95% confidence interval.

      3.4 Risk factors for PTS in patients with chronic subdural haematoma

      For patients with cSDH, the risk factors for PTS were different to those for aSDH. One prospective study reported alcoholism as a risk factor for lPTS in cSDH [
      • Dudek H.
      • Michno T.
      • Michalski J.
      • et al.
      Late posttraumatic epilepsy in patients with an alcoholic problem treated surgically for posttraumatic chronic subdural hematomas.
      ]; however, since most of the studies did not distinguish between the type of PTS, we could only identify risk factors for unspecified PTS: previous stroke, specific symptoms such as change of mental status (e.g. disorientation, frontal lobe syndrome), CT findings (Hounsfield unit (HU) density, brain atrophy), craniotomy and mean Glasgow outcome scale by discharge [
      • Sabo R.A.
      • Hanigan W.C.
      • Aldag J.C.
      Chronic subdural hematomas and seizures: the role of prophylactic anticonvulsive medication.
      ,
      • Grobelny B.T.
      • Ducruet A.F.
      • Zacharia B.E.
      • et al.
      Preoperative antiepileptic drug administration and the incidence of postoperative seizures following burr hole-treated chronic subdural hematoma.
      ,
      • Hirakawa K.
      • Hashizume K.
      • Fuchinoue T.
      • et al.
      Statistical analysis of chronic subdural hematoma in 309 adult cases.
      ,
      • Huang Y.H.
      • Yang T.M.
      • Lin Y.J.
      • et al.
      Risk factors and outcome of seizures after chronic subdural hematoma.
      ,
      • Chen C.W.
      • Kuo J.R.
      • Lin H.J.
      • et al.
      Early post-operative seizures after burr-hole drainage for chronic subdural hematoma: correlation with brain CT findings.
      ,
      • Cole M.
      • Spatz E.
      Seizures in chronic subdural hematoma.
      ,
      • Dudek H.
      • Michno T.
      • Michalski J.
      • et al.
      Late posttraumatic epilepsy in patients with an alcoholic problem treated surgically for posttraumatic chronic subdural hematomas.
      ]. Furthermore, the incidence of unspecified PTS in left-sided haematoma was slightly higher but did not reach significance [
      • Sabo R.A.
      • Hanigan W.C.
      • Aldag J.C.
      Chronic subdural hematomas and seizures: the role of prophylactic anticonvulsive medication.
      ,
      • Grobelny B.T.
      • Ducruet A.F.
      • Zacharia B.E.
      • et al.
      Preoperative antiepileptic drug administration and the incidence of postoperative seizures following burr hole-treated chronic subdural hematoma.
      ,
      • Chen C.W.
      • Kuo J.R.
      • Lin H.J.
      • et al.
      Early post-operative seizures after burr-hole drainage for chronic subdural hematoma: correlation with brain CT findings.
      ]. Similarly to aSDH, age, haematoma size and midline shifts were not significant risk factors for unspecified PTS in patients with cSDH [
      • Grobelny B.T.
      • Ducruet A.F.
      • Zacharia B.E.
      • et al.
      Preoperative antiepileptic drug administration and the incidence of postoperative seizures following burr hole-treated chronic subdural hematoma.
      ,
      • Huang Y.H.
      • Yang T.M.
      • Lin Y.J.
      • et al.
      Risk factors and outcome of seizures after chronic subdural hematoma.
      ].

      3.5 Prophylactic antiepileptic treatment in acute subdural haematomas

      To date, there has only been one recently published retrospective study by Radic et al. [
      • Radic J.A.
      • Chou S.H.
      • Du R.
      • et al.
      Levetiracetam versus phenytoin: a comparison of efficacy of seizure prophylaxis and adverse event risk following acute or subacute subdural hematoma diagnosis.
      ] evaluating prophylactic antiepileptic treatment in patients with aSDHs. In this study, levetiracetam and phenytoin were compared and were shown to have equal efficacy in reducing PTSs (OR 1.3, 95% CI 0.7–2.4, p = ns), whereas levetiracetam had a significantly lower adverse event profile (OR 0.1, 95% CI 0.1–0.4, p < 0.0001). Interestingly, in just one subgroup with midline shift in the CT scan, the levetiracetam group had a higher risk of electrographic epileptic seizures than the phenytoin group (OR n.a., p = 0.03). Similar results regarding the benefit of prophylactic AEDs (phenytoin or levetiracetam) in reducing PTSs were reported in the past; however, they did not distinguish between the different TBI entities [
      • Haltiner A.M.
      • Temkin N.R.
      • Dikmen S.S.
      Risk of seizure recurrence after the first late posttraumatic seizure.
      ,
      • Temkin N.R.
      • Dikmen S.S.
      • Wilensky A.J.
      • et al.
      A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures.
      ,
      • Temkin N.R.
      Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta analysis of controlled trials.
      ,
      • Zafar S.N.
      • Khan A.A.
      • Ghauri A.A.
      • et al.
      Phenytoin versus leviteracetam for seizure prophylaxis after brain injury—a meta analysis.
      ,
      • Szaflarski J.P.
      • Sangha K.S.
      • Lindsell C.J.
      • et al.
      Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis.
      ].

      3.6 Prophylactic antiepileptic treatment in chronic subdural haematomas

      For patients with cSDHs, there are controversial statements in terms of prophylactic anticonvulsive medication. A retrospective study focusing on surgically treated patients with cSDHs showed effective reduction of seizures by using prophylactic phenytoin medication (OR 0.1, 95% CI 0.0–0.4, p = 0.0002); however, the benefit in terms of outcome is not precisely described [
      • Sabo R.A.
      • Hanigan W.C.
      • Aldag J.C.
      Chronic subdural hematomas and seizures: the role of prophylactic anticonvulsive medication.
      ]. Another study identified prophylactic AED treatment as a predictor of lower seizure incidence in cSDHs (OR 0.2, 95% CI 0.1–0.7, p = 0.013), but the outcome at discharge did not differ (OR n.a., p = ns). In contrast, a retrospective study showed no benefit in patients treated prophylactically with AEDs (OR 1.3, 95% CI 0.4–3,9, p = ns) [
      • Rubin G.
      • Rappaport Z.H.
      Epilepsy in chronic subdural haematoma.
      ]. Due to the variable incidence of epileptic seizures in patients with cSDHs, there is currently no consensual recommendation for the use of prophylactic AEDs in these patients [
      • Rubin G.
      • Rappaport Z.H.
      Epilepsy in chronic subdural haematoma.
      ,
      • Ohno K.
      • Maehara T.
      • Ichimura K.
      • et al.
      Low incidence of seizures in patients with chronic subdural haematoma.
      ].

      4. Discussion

      In the present study, we report a systematic review of the incidence and risk factors of PTS as well as prophylactic AED treatment in patients with SDHs. Overall, SDHs, especially aSDHs, were associated with high incidence of PTS [
      • Hamasaki T.
      • Yamada K.
      • Kuratsu J.
      Seizures as a presenting symptom in neurosurgical patients: a retrospective single-institution analysis.
      ,
      • Annegers J.F.
      • Hauser W.A.
      • Coan S.P.
      • et al.
      A population-based study of seizures after traumatic brain injuries.
      ]. The incidence of ePTS in patients with aSDHs was approximately 28% and in patients with cSDHs 10%. Furthermore, the incidence of lPTS in patients with aSDHs was 43% within 2 years of follow-up whereas in patients with cSDHs it was only 5.3% within 3 years of follow-up, indicating a lower risk of developing epilepsy.
      Depending on the type of SDH (acute vs. chronic), there are different risk factors likely to cause PTSs: in patients with aSDHs, in particular for ePTSs, risk factors were mainly dependent on the severity of the TBI as graded by the preoperative GCS score and the 24-h post-operative GCS score, both below 8, as well as the need for a craniotomy [
      • Annegers J.F.
      • Hauser W.A.
      • Coan S.P.
      • et al.
      A population-based study of seizures after traumatic brain injuries.
      ,
      • Wiedemayer H.
      • Triesch K.
      • Schafer H.
      • et al.
      Early seizures following non-penetrating traumatic brain injury in adults: risk factors and clinical significance.
      ,
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      ,
      • Haltiner A.M.
      • Temkin N.R.
      • Dikmen S.S.
      Risk of seizure recurrence after the first late posttraumatic seizure.
      ,
      • Frey L.C.
      Epidemiology of posttraumatic epilepsy: a critical review.
      ].
      In the case of lPTSs, craniotomy was found to be the most important risk factor. Compared to ePTSs, the recurrence rate of seizures was shown to be much higher in patients with lPTSs [
      • Hart Y.M.
      • Sander J.W.
      • Johnson A.L.
      • et al.
      National General Practice Study of Epilepsy: recurrence after a first seizure.
      ,
      • Hesdorffer D.C.
      • Benn E.K.
      • Cascino G.D.
      • et al.
      Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure.
      ]. An increased risk of lPTS compared to the normal population persisted for at least 20 years. [
      • Annegers J.F.
      • Hauser W.A.
      • Coan S.P.
      • et al.
      A population-based study of seizures after traumatic brain injuries.
      ,
      • Wiedemayer H.
      • Triesch K.
      • Schafer H.
      • et al.
      Early seizures following non-penetrating traumatic brain injury in adults: risk factors and clinical significance.
      ]. Additionally, the recurrence of lPTS was related to the severity of the aSDH. Sixty-nine per cent of the patients with aSDHs and skull fractures developed secondary PTS within 6 months and 86% within 2 years [
      • Haltiner A.M.
      • Temkin N.R.
      • Dikmen S.S.
      Risk of seizure recurrence after the first late posttraumatic seizure.
      ].
      As a pathophysiological mechanism for the high epileptogenity of aSDH it is postulated that the haematoma itself irritates the cortical surface with blood compounds and later with its degradation products [
      • Frey L.C.
      Epidemiology of posttraumatic epilepsy: a critical review.
      ]. In particular, the decomposition of haemoglobin on the cortical surface is highly epileptogenic [
      • Haltiner A.M.
      • Temkin N.R.
      • Dikmen S.S.
      Risk of seizure recurrence after the first late posttraumatic seizure.
      ,
      • Hammond E.J.
      • Ramsay R.E.
      • Villarreal H.J.
      • et al.
      Effects of intracortical injection of blood and blood components on the electrocorticogram.
      ]. Thus, blood evacuation through craniotomy or craniectomy might reduce the risk of PTS; however, intracranial surgery was found to be an independent predictor of lPTS [
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      ,
      • Englander J.
      • Bushnik T.
      • Duong T.T.
      • et al.
      Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation.
      ,
      • Hirakawa K.
      • Hashizume K.
      • Fuchinoue T.
      • et al.
      Statistical analysis of chronic subdural hematoma in 309 adult cases.
      ]. Englander et al. [
      • Englander J.
      • Bushnik T.
      • Duong T.T.
      • et al.
      Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation.
      ] speculate that the correlation between surgery and PTS might be explained by sudden decompression through craniotomy that might cause an additional intraparenchymal injury through a sudden negative deceleration. Consequently, this might promote neuronal damage and lead to the creation of an epileptogenic focus [
      • Seifi A.
      • Asadi-Pooya A.A.
      • Carr K.
      • et al.
      The epidemiology, risk factors, and impact on hospital mortality of status epilepticus after subdural hematoma in the United States.
      ]. On the other hand, the high incidence of PTS after craniotomy might also be explained by the simple fact that the craniotomy itself is a surrogate marker of the severity of a brain injury, which accompanies structural parenchyma damage, which is known to be epileptogenic.
      Unfortunately, a substantial number of studies dealing with cSDHs did not differentiate between the types of PTS. Therefore we had to summarize the risk factors for unspecified PTSs in cSDHs. In contrast to aSDHs, the main risk factors were alcohol abuse, specific symptoms such as mental disorders, previous strokes and CT abnormalities (Hounsfield Unit density irregularities, brain atrophy). Similarly to aSDHs, other risk factors for PTSs in cSDHs were craniotomy and low GCS at patient discharge. Alcoholism as a patient-related risk factor was known to be an important predictor of lPTS. A recent meta-analysis by Samokhvalov et al. [
      • Samokhvalov A.V.
      • Irving H.
      • Mohapatra S.
      • et al.
      Alcohol consumption, unprovoked seizures, and epilepsy: a systematic review and meta-analysis.
      ] reported a strong correlation between alcohol use and seizures with a pooled OR of 2.19 across all studies. A pathophysiological mechanism for lPTS in patients with chronic alcoholism was suspected to involve multiple head traumas, structural changes such as brain atrophy, changes in neurotransmitter pathways and metabolic changes, thereby lowering the convulsive threshold [
      • Seifi A.
      • Asadi-Pooya A.A.
      • Carr K.
      • et al.
      The epidemiology, risk factors, and impact on hospital mortality of status epilepticus after subdural hematoma in the United States.
      ,
      • Samokhvalov A.V.
      • Irving H.
      • Mohapatra S.
      • et al.
      Alcohol consumption, unprovoked seizures, and epilepsy: a systematic review and meta-analysis.
      ,
      • Dam A.M.
      • Fuglsang-Frederiksen A.
      • Svarre-Olsen U.
      • et al.
      Late-onset epilepsy: etiologies, types of seizure, and value of clinical investigation, EEG, and computerized tomography scan.
      ]. Interestingly, older age was not a significant risk factor despite the fact that brain atrophy was a significant parameter for epileptic seizure [
      • Sabo R.A.
      • Hanigan W.C.
      • Aldag J.C.
      Chronic subdural hematomas and seizures: the role of prophylactic anticonvulsive medication.
      ,
      • Grobelny B.T.
      • Ducruet A.F.
      • Zacharia B.E.
      • et al.
      Preoperative antiepileptic drug administration and the incidence of postoperative seizures following burr hole-treated chronic subdural hematoma.
      ,
      • Huang Y.H.
      • Yang T.M.
      • Lin Y.J.
      • et al.
      Risk factors and outcome of seizures after chronic subdural hematoma.
      ,
      • Cole M.
      • Spatz E.
      Seizures in chronic subdural hematoma.
      ]. In this context, it seems to be important not to classify general brain atrophy as a predictor of seizures, but to evaluate the cause of brain atrophy, such as alcohol consumption or previous stroke [
      • Huang Y.H.
      • Yang T.M.
      • Lin Y.J.
      • et al.
      Risk factors and outcome of seizures after chronic subdural hematoma.
      ]. Furthermore, HU density of SDH was related to seizure occurrence in cSDH. Patients with mixed-density haematomas were more prone to seizures than patients with low-isodense haematomas. A pathophysiological explanation could be that blood degradation products may lead to fibrinogen degradation products, which contribute to membrane formation as well as irritation of the brain parenchyma. On the other hand, high activation of tissue plasminogen activators may lead to more rebleeding and consequently to a larger haematoma mass effect [
      • Brodersen P.
      • Gjerris F.
      Regional cerebral blood flow in patients with chronic subdural hematomas.
      ,
      • Chen C.W.
      • Kuo J.R.
      • Lin H.J.
      • et al.
      Early post-operative seizures after burr-hole drainage for chronic subdural hematoma: correlation with brain CT findings.
      ,
      • Lim D.J.
      • Chung Y.G.
      • Park Y.K.
      • et al.
      Relationship between tissue plasminogen activator, plasminogen activator inhibitor and CT image in chronic subdural hematoma.
      ,
      • Nomura S.
      • Kashiwagi S.
      • Fujisawa H.
      • et al.
      Characterization of local hyperfibrinolysis in chronic subdural hematomas by SDS-PAGE and immunoblot.
      ].
      The diagnosis of seizures depends on either clinical seizure manifestation or seizure patterns on an EEG. In particular, subclinical seizures are one of the problems leading to delayed treatment and worse outcome. Several case reports described epileptiform abnormalities such as periodic lateralized epileptiform discharges (PLEDs), which are periodic spikes or sharp waves occurring in 1–3 s intervals, in patients with SDH [
      • Rudzinski L.A.
      • Rabinstein A.A.
      • Chung S.Y.
      • et al.
      Electroencephalographic findings in acute subdural hematoma.
      ,
      • Westmoreland B.F.
      Periodic lateralized epileptiform discharges after evacuation of subdural hematomas.
      ,
      • Chu N.S.
      Acute subdural hematoma and the periodic lateralized epileptiform discharges.
      ,
      • Mehryar G.R.
      • McIntyre H.B.
      Periodic lateralized epileptiform discharges associated with subdural hematoma.
      ]. PLEDs might be a sign of a continuum between ictal and interictal status and could be a biomarker of an increased probability of the occurrence of subclinical seizures [
      • Westmoreland B.F.
      Periodic lateralized epileptiform discharges after evacuation of subdural hematomas.
      ]. A retrospective study reported very high incidence of EEG abnormalities (e.g. slowing, asymmetries, epileptiform discharges, PLEDs) on EEGs in 21 out of 24 patients (87%) with aSDHs [
      • Rudzinski L.A.
      • Rabinstein A.A.
      • Chung S.Y.
      • et al.
      Electroencephalographic findings in acute subdural hematoma.
      ], implying that the occurrence of PTSs in patients with aSDHs might be higher than noticed in routine clinical treatmentin clinical routine. EEG abnormalities and the occurrence of PTSs were associated with unfavourable functional outcome and impairment of quality of life [
      • Rabinstein A.A.
      • Chung S.Y.
      • Rudzinski L.A.
      • et al.
      Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.
      ,
      • Rudzinski L.A.
      • Rabinstein A.A.
      • Chung S.Y.
      • et al.
      Electroencephalographic findings in acute subdural hematoma.
      ]. Currently, the use of AEDs in patients with recurrent PTSs might be advisable, but there is no consensus on the use of prophylactic AEDs.
      Initially, the benefit of prophylactic AEDs was described in patients with TBI. Temkin et al. [
      • Temkin N.R.
      • Dikmen S.S.
      • Wilensky A.J.
      • et al.
      A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures.
      ] analysed, in a double-blind fashion, the occurrence of PTSs after TBI in 404 patients either treated with phenytoin or placebo and found that patients undergoing prophylactic phenytoin treatment had significantly fewer ePTSs than placebo-treated patients with 0.25 RR (4% vs. 14%). A previous study had shown no significant difference between those groups; however, the incidence of PTS was very low, making an interpretation of the effect of phenytoin difficult (4% PTS after TBI) [
      • Cole M.
      • Spatz E.
      Seizures in chronic subdural hematoma.
      ]. A meta-analysis comparing AEDs reported a promising effect of phenytoin- and carbamazepine-induced reduction of ePTS after TBI. However, the incidence of lPTS was not significantly reduced by using prophylactic AEDs [
      • Haltiner A.M.
      • Temkin N.R.
      • Dikmen S.S.
      Risk of seizure recurrence after the first late posttraumatic seizure.
      ,
      • Temkin N.R.
      Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta analysis of controlled trials.
      ,
      • Young B.
      • Rapp R.P.
      • Norton J.A.
      • et al.
      Failure ofprophylactically administered phenytoin to prevent late posttraumatic seizures.
      ]. One study observing the use of phenytoin even reported delay in functional recovery after brain damage; therefore, the American Academy of Neurology recommended prophylactic use of phenytoin within the first 7 days after TBI to decrease the risk of PTS, but not beyond 7 days [
      • Chang B.S.
      • Lowenstein D.H.
      • Quality Standards Subcommittee of the American Academy of Neurology
      Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain injury: report of the Quality Standards Subcommittee of the American Academy of Neurology.
      ,
      • Naidech A.M.
      • Kreiter K.T.
      • Janjua N.
      • et al.
      Phenytoin exposure is associated with functional and cognitive disability after subarachnoid hemorrhage.
      ]. Meanwhile, phenytoin has mostly been replaced by new-generation AEDs like levetiracetam, since phenytoin has significantly more side effects, such as hepatic cytochrome P450 induction, cutaneous reaction, cardiac complication, thrombocytopenia and drugs interaction, which led in one study to a discontinuation rate of 40% [
      • Zafar S.N.
      • Khan A.A.
      • Ghauri A.A.
      • et al.
      Phenytoin versus leviteracetam for seizure prophylaxis after brain injury—a meta analysis.
      ,
      • Allen J.P.
      • Ludden T.M.
      • Burrow S.R.
      • et al.
      Phenytoin cumulation kinetics.
      ].
      Comparing levetiracetam and phenytoin, levetiracetam appeared to have a similar efficacy in reducing PTSs with significantly lower complication rates (except for gastrointestinal problems) and better long-term outcome [
      • Szaflarski J.P.
      • Sangha K.S.
      • Lindsell C.J.
      • et al.
      Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis.
      ,
      • Radic J.A.
      • Chou S.H.
      • Du R.
      • et al.
      Levetiracetam versus phenytoin: a comparison of efficacy of seizure prophylaxis and adverse event risk following acute or subacute subdural hematoma diagnosis.
      ,
      • Zafar S.N.
      • Khan A.A.
      • Ghauri A.A.
      • et al.
      Phenytoin versus leviteracetam for seizure prophylaxis after brain injury—a meta analysis.
      ,
      • Szaflarski J.P.
      • Sangha K.S.
      • Lindsell C.J.
      • et al.
      Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis.
      ,
      • Lim D.A.
      • Tarapore P.
      • Chang E.
      • et al.
      Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study.
      ]. In addition, levetiracetam is not subject to therapeutic drug-level monitoring, as phenytoin is [
      • Zafar S.N.
      • Khan A.A.
      • Ghauri A.A.
      • et al.
      Phenytoin versus leviteracetam for seizure prophylaxis after brain injury—a meta analysis.
      ,
      • Szaflarski J.P.
      • Sangha K.S.
      • Lindsell C.J.
      • et al.
      Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis.
      ], leading to better compliance. However, prophylactic AEDs are only used in the short term; hence the results should be interpreted with caution in case of extrapolating the data into long-term treatment.
      Unfortunately, there is currently no prospective, randomized study describing the use of prophylactic AEDs in patients with exclusively SDHs. In the case of aSDHs, prophylactic AED treatment such as levetiracetam seems to be beneficial in reducing PTSs and improving functional outcome. In the case of cSDHs, several retrospective studies reported contrary results, but one should note that no differentiation between high-risk and low-risk patients was made when administering prophylactic AEDs [
      • Sabo R.A.
      • Hanigan W.C.
      • Aldag J.C.
      Chronic subdural hematomas and seizures: the role of prophylactic anticonvulsive medication.
      ,
      • Rubin G.
      • Rappaport Z.H.
      Epilepsy in chronic subdural haematoma.
      ,
      • Ohno K.
      • Maehara T.
      • Ichimura K.
      • et al.
      Low incidence of seizures in patients with chronic subdural haematoma.
      ].
      The present study has limitations that should be addressed. First, the incomplete recruitment due to our inclusion and exclusion criteria caused a selection bias. Second, most of the studies were of a retrospective nature and had small sample sizes. Third, there were limited data for certain subgroups, leading to imputation of missing values. Despite the limitations, our study is the first systematic review to summarize specific seizure occurrence in SDHs, and the results were able to consistently illustrate the correlation between SDHs and PTSs.

      5. Conclusion

      The overall incidence of ePTS and lPTS was higher in patients with aSDHs than in those with cSDHs. Risk factors for PTSs in aSDHs were preoperative and 24 h post-operative low GCS and craniotomy, whereas in cSDHs the risk factors were alcohol abuse, change of mental status, previous stroke and haematoma density on the CT. The results of our study suggest, first, differentiating the type of SDH, and secondly, summarizing the risk factors for ePTSs and lPTSs in order to decide either for or against the use of prophylactic AEDs. In patients with severe aSDHs, a prophylactic anticonvulsive treatment might be considered for a limited, short period of time, e.g. 1 week. In patients with cSDHs, the decision to apply prophylactic AEDs should be made individually depending on the cumulative risk factors. To verify the beneficial effect of prophylactic AEDs, further randomized controlled studies are warranted in the future.

       Ethical publication statement

      We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

       Funding source

      This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

      Acknowledgements

      We thank Marina Heibel and Anne Sicking for their excellent technical support.

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