The 2022 guideline from the American Heart Association (AHA)/American Stroke Association (ASA) provides recommendations for the management of patients with spontaneous intracerebral hemorrhage (sICH). In patients with spontaneous ICH without evidence of seizures, prophylactic anti-seizure medication is not beneficial to improve functional outcomes, long-term seizure control, or mortality. Previous research indicated a potential connection between the use of prophylaxis antiseizure medications like phenytoin and unfavorable outcomes in individuals with ICH. As a result, there may be an increasing tendency to turn to alternative prophylactic antiseizure drugs such as levetiracetam. Recent studies, however, have not consistently revealed clear harm or benefit associated with the use of prophylactic antiseizure drugs following spontaneous ICH, particularly concerning overall functional outcomes. Additionally, some studies have suggested that cognitive functions may be adversely impacted by the use of prophylactic antiseizure drugs after spontaneous ICH. [1]
The European Stroke Organization has also issued evidence-based guidelines in 2017 on the management of post-stroke seizures and epilepsy. In the absence of adequately powered randomized controlled trials (RCTs), there is no evidence of immediate primary prophylaxis with an antiepileptic drug (AED) compared to no treatment prevents the occurrence of acute symptomatic seizure (ASS) in ischemic stroke or intracranial (intracerebral or subarachnoidal) hemorrhage. Observational studies indicate that the likelihood of developing ASS in the majority of stroke patients is quite low, at approximately 5%. Moreover, the potential consequences of ASS appear to be relatively limited. Based on the low incidence of ASS in observational studies, the panel makes a weak recommendation against primary AED prophylaxis. If, for any reason, primary AED prophylaxis for ASS was initiated, discontinuing treatment after the acute phase is advisable, considering the relatively low long-term risk of unprovoked seizure. Furthermore, there is no reliable evidence to support the decision to start immediate and sustained prophylaxis with AED to prevent the occurrence of unprovoked post-stroke seizures. [2]
Findings from observational studies indicate that acute seizure recurrence after one ASS is also low, ranging from 10 to 20%. Thus, a weak recommendation is made, suggesting the general avoidance of secondary AED prophylaxis. However, observational studies reveal a high risk of seizure recurrence (70%) after one post-stroke unprovoked seizure. Therefore, considering secondary AED prophylaxis after a single unprovoked seizure is warranted. These guidelines offer only weak recommendations for the prevention of post-stroke acute symptomatic seizures and unprovoked seizures due to very low evidence. Adequately powered RCTs are necessary to evaluate interventions for post-stroke seizure management. [2]
A 2022 Cochrane review (N= 2 studies; 856 participants) evaluated the effectiveness of AEDs in preventing seizures after stroke, both as primary prevention for those who haven’t experienced a seizure and as secondary prevention for individuals who have already experienced a post-stroke seizure. The first study, a randomized double-blind trial, investigated valproic acid’s efficacy compared to placebo in preventing seizures within a year after stroke among 72 adults with intracerebral hemorrhage. The results did not showcase a significant difference in the risk of post-stroke seizures (relative risk [RR] 0.88; 95% confidence interval [CI] 0.35 to 2.16) or mortality (RR 1.20; 95% CI 0.40 to 3.58) between valproic and placebo groups. The second study, a randomized double-blind substudy focusing on diazepam’s role in acute stroke, compared a three-day diazepam treatment to placebo for primary seizure prevention in 784 adults with acute stroke. The overall analysis did not show a significant difference in the risk of post-stroke seizures for all stroke types or in subgroups of hemorrhagic or ischemic strokes; however, in a subgroup analysis specifically examining anterior circulation cortical infarcts, primary prophylaxis with diazepam exhibited a reduced risk of post-stroke seizures (RR 0.21; 95% CI 0.05 to 0.95). Mortality risks also did not differ significantly between the diazepam and placebo groups at two-week and three-month follow-ups. Notably, the meta-analysis conducted on these two studies revealed that AEDs were not effective in the primary prevention of post-stroke seizures (RR 0.65; 95% CI 0.34 to 1.26; moderate-certainty evidence) and the use of AEDs did not impact mortality rate among stroke patients (RR 1.03; 95% CI 0.78 to 1.36; moderate-certainty evidence). Due to these findings, it was concluded that there was insufficient evidence to recommend the routine use of AEDs for the primary and secondary prevention of seizures after a stroke. [3]
A 2021 meta-analysis evaluated the efficacy of seizure prophylaxis following ICH. A total of 8 studies were included for analysis (N= 2,852 participants). Among patients who received prophylactic seizure medications, phenobarbital was the most frequently administered (37%), despite being used in only one study, followed by levetiracetam (30%), valproate (21%), and phenytoin (8%). Antiseizure medication was not associated with a significant reduction in any seizure occurrence in patients with spontaneous ICH at the longest follow-up period (odds ratio [OR] 0.708; 95% CI 0.438 to 1.143; p= 0.158; I2= 34%). These findings were confirmed in subgroup analyses and meta-regression analyses. Additionally, seizure prophylaxis did not prevent seizure occurrence within 14 days of ICH (OR 0.66; 95% CI 0.21 to 2.08; p= 0.48; I2= 35%). Similarly, another 2021 meta-analysis evaluated the use of seizure prophylaxis following ICH, specifically with phenytoin. A total of 11 studies were included for analysis (N= 4,268 participants). In this analysis, seizure prophylaxis with phenytoin was not associated with any poor functional outcome at the time of longest follow-up (OR 1.2; 95% CI 0.9 to 1.6; p= 0.22; I2= 61%). Meta-analysis of 6 studies (n= 3,481 participants) also found no association between seizure prophylaxis and poor functional outcome, defined as a modified Rankin scale score of 4-6 at 90-day follow-up (OR 1.4; 95% CI 0.8 to 2.4; p= 0.24). Sensitivity analyses found no changes in results with removal of certain studies. These analyses are limited by the lack of high-quality studies included, with the majority of studies being observational in nature. [4], [5]
A 2021 decision analysis model evaluated which of the four seizure prophylaxis strategies provides the greatest net benefit for patients with sICH. The study included four approaches to antiseizure drug strategies: a conservative approach involving short-term (7-day) secondary early-seizure prophylaxis with long-term therapy following late seizures, a moderate approach comprising long-term secondary early seizure prophylaxis or late-seizure therapy, an aggressive approach entailing long-term primary prophylaxis, and lastly, a risk-guided strategy involving short-term secondary early-seizure prophylaxis for low-risk patients (2HELPS2B score, 0), short-term primary prophylaxis for higher-risk patients (2HELPS2B score, ≥1), and long-term secondary therapy for late seizures. The 2HELPS2B score estimates the early-seizure risk for hospitalized patients by considering electroencephalography (EEG) findings and one clinical factor. [6]
In this decision analysis, models were employed to stimulate four prevalent scenarios. The first scenario involves a 60-year-old man with a low risk of early seizures (≤7 days after stroke) at 10% and late seizures at either 3.6% or 9.8%, along with an average risk of short-term (9%) and long-term (30%) adverse drug reactions (ADR). For this scenario, the preferred strategy was the risk-guided approach, which resulted in 8.12 quality-adjusted life years (QALYs). This choice surpassed the conservative strategy (8.08 QALYs), the moderate strategy (8.07 QALYs), and the aggressive strategy (7.88 QALYs). [6]
The second scenario involved an 80-year-old woman, characterized by a low risk of early seizures (10%) and late seizures (either 3.6% or 9.8%), along with high short-term (24%) and long-term (80%) risks of ADR. In this case, the preferred strategy was the conservative approach, yielding 2.18 QALYs. This choice outperformed the risk-guided strategy (2.17 QALYs), the moderate strategy (2.09 QALYs), and the aggressive strategy (1.15 QALYs). [6]
Scenario 3 involved a 55-year-old man with a high risk of early seizures (19%) and late seizures (either 34.8% or 46.2%), along with low short-term (9%) and long-term (30%) risks of ADR. In this scenario, the preferred strategy was the aggressive approach, yielding 9.21 QALYs. This choice was preferred over the risk-guided strategy (8.98 QALYs), the moderate strategy (8.93 QALYs), and the conservative strategy (8.77 QALYs). [6]
Lastly, scenario 4 was a 45-year-old woman characterized by a high risk of early seizures (19%) and late seizures (either 34.8% or 46.2%), along with high short-term (18%) and long-term (60%) risks of ADR. In this scenario, the preferred strategy was the risk-guided approach, resulting in 11.53 QALYs. This choice outperformed the conservative strategy (11.23 QALYs), the moderate strategy (10.93 QALYs), and the aggressive strategy (8.08 QALYs). Sensitivity analyses indicated a preference for short-term strategies, specifically conservative and risk-guided approaches, across various scenarios. Additionally, the risk-guided strategy demonstrates comparable or superior performance compared to alternative strategies in most settings. This decision analysis model indicates the dominance of short-term (7-day) prophylaxis over long-term therapy following sICH. The consideration of the 2HELPS2B score to guide clinical decisions regarding the initiation of short-term primary versus secondary early seizure prophylaxis is recommended for all patients after sICH. [6]
A 2021 analysis evaluated the impact of three anticonvulsant prophylaxis strategies on QALYs among patients with an incident acute ischemic stroke (AIS). The three strategies evaluated were as follows: 1) long-term primary prophylaxis; 2) short-term secondary prophylaxis after an early seizure with lifetime prophylaxis if persistent or late seizures developed; and 3) long-term secondary prophylaxis if either early, late, or persistent seizures developed. Four base cases were utilized to determine effects of the strategies on QALYs: 1) female patients aged 40 with a 2% or 11% lifetime risk of a late seizure and a 33% lifetime risk of an ADR; 2) male aged 65 with a 6% or 29% late seizure risk and 60% ADR risk; male aged 50 with an 18% or 65% late seizure risk and 33% ADR risk; and 4) female aged 80 with a 29% or 83% late seizure risk and 80% ADR risk. Across all four cases, primary prophylaxis yielded the lowest number of QALYs compared with secondary prophylaxis. Under scenarios in which patients had higher ADR risks, strategy 2 led to the most QALYs. Based on the analysis results, it was determined that short-term therapy with continued anticonvulsant prophylaxis only after post-ischemic stroke seizures arise is preferred over long-term primary prophylaxis. [7]
A 2019 meta-analysis assessed whether the use of AEDs for primary seizure prevention among adults with spontaneous intracerebral hemorrhage had an impact on the risk of adverse outcomes and clinically relevant seizures in this patient population. A total of 7 studies comprising 3,241 patients were included for the analysis of the primary outcome, which focused on assessing poor outcomes during long-term follow-up after spontaneous intracerebral hemorrhage. Notably, the majority of these studies (5/7) utilized the modified Rankin Scale (with a score >3) to define poor clinical outcomes. The analysis revealed no significant association between AED treatment and poor clinical outcomes at the longest recorded follow-up time (OR 0.99; 95% CI 0.66 to 1.49; p= 0.96). For the secondary outcome analysis on clinical seizures during follow-up, 4 studies involving 1861 patients were included. However, there was a high variability in defining early and late seizures in the evaluated studies, and continuous electroencephalographic monitoring was not consistently used. The pooled information regarding clinically evident seizures at the longest follow-up showed no association between AED use for primary prevention and the occurrence of seizures (OR 0.89; 95% CI 0.52 to 1.51; p= 0.66). This result remained consistent in sensitivity analysis and when focusing on short-term clinical seizures. However, insufficient data were available to assess other secondary outcomes such as modified Rankin Scale scores at hospital discharge or AED toxicity during follow-up. Overall, these findings suggest that AEDs for primary prevention in adults with spontaneous intracerebral hemorrhage did not lead to improved neurological function. [8]
A 2019 meta-analysis assessed the effect of AEDs on seizure prevention and short and long-term functional outcomes in patients with acute ICH. A total of six studies were included (two retrospective cohort studies, two prospective cohort studies, and two RCTs). No significant evidence was found linking the use of AEDs after ICH to functional outcomes in both short-term and long-term periods ≥ 3 months to one year (odds ratio [OR] 1.53; 95% CI 0.81 to 2.88; p= 0.18; I2= 81.7%). In the subset of studies with a 3-month follow-up, there was similarly no statistically significant association between AED use and function outcomes (OR 1.70; 95% CI 0.88 to 3.28; p= 0.11; I2= 84.7%). [9]
Only one study investigated the association between AED use and seizure prevention. In this prospective study involving 761 patients, the lobar location of the ICH emerged as the sole independent risk factor for clinical seizures within the first 30 days after ICH, with an adjusted OR (aOR) of 2.8 (95% CI 1.63 to 4.82). Prophylactic phenobarbital was associated with a decreased risk of clinical seizures during the initial 30 days after ICH, with an aOR of 0.58 (95% CI 0.39 to 0.87). However, it is important to interpret this finding cautiously, given that the study was non-randomized and observational. The overall findings suggest that the use of prophylactic AEDs was not associated with improved short- and long-term outcomes after acute ICH, which also supports the AHA/ASA guideline recommendation against prophylactic AEDs. [9]