Short-term Approach Best for Seizure Prevention After ICH

Short-term, 7-day prophylactic regimens are superior to longer-term strategies for preventing seizures following spontaneous intracerebral hemorrhage (sICH), new research shows.

Investigators created a model that simulated common clinical scenarios to compare four antiseizure drug strategies ― conservative, moderate, aggressive, and risk-guided. They used the 2HELPS2B score as a risk stratification tool to guide clinical decisions.

The investigators found that the short-term, early-seizure prophylaxis strategies “dominated” long-term therapy under most clinical scenarios, underscoring the importance of early discontinuation of antiseizure drug therapy.

“The main message here was that strategies that involved long-term antiseizure drug prescription (moderate and aggressive) fail to provide better outcomes in most clinical scenarios, when compared to strategies using short-term prophylaxis (conservative and risk-guided),” senior investigatoror Lidia M. V. R. Moura, MD, MPH, assistant professor of neurology, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

The study was published online July 26 in JAMA Neurology.

Common Complication

“Acute asymptomatic seizures (early seizures ≤7 days after stroke) are a common complication of sICH,” the authors note.

Potential safety concerns have prompted recommendations against the use of antiseizure medications for primary prophylaxis. However, approximately 40% of US patients with sICH do receive prophylactic levetiracetam before seizure development. For these patients, the duration of prophylaxis varies widely.

“Because seizure risk is a key determinant of which patient groups might benefit most from different prophylaxis strategies, validated tools for predicting early…and late…seizure risks could aid physicians in treatment decisions. However, no clinical trials or prospective studies have evaluated the net benefit of various strategies after sICH,” the investigators note.

“Our patients who were survivors of an intracerebral hemorrhage motivated us to conduct the study,” said Moura, who is also director of the MGH NeuroValue Laboratory.

“Some would come to the clinic with a long list of medications; some of them were taking antiseizure drugs for many years, but they never had a documented seizure.” These patients did not know why they had been taking an antiseizure drug for so long.

“In these conversations, we noted so much variability in indications and variability in patient access to specialty care to make treatment decisions. We noted that the evidence behind our current guidelines on seizure management was limited,” she added.

Moura and her colleagues were “committed to improve outcome for people with neurological conditions by leveraging research methods that can help guide providers and systems, especially when data from clinical trials is lacking,” so they “decided to compare different strategies head-to-head using available data and generate evidence that could be used in situations with many trade-offs in risks and benefits.”

To investigate, the researchers used a simulation model and decision analysis to compare four treatment strategies on the basis of type of therapy (primary vs secondary prophylaxis), timing of event (early vs late seizures), and duration of therapy (1 week [short-term] vs indefinite [long-term] therapy).

These four strategies were as follows:

  • Conservative: short-term (7-day) secondary early-seizure prophylaxis with long-term therapy after late seizure

  • Moderate: long-term secondary early-seizure prophylaxis or late-seizure therapy

  • Aggressive: long-term primary prophylaxis

  • Risk-guided: short-term secondary early-seizure prophylaxis among low-risk patients (2HELPS2b score, 0), short-term primary prophylaxis among patients at higher risk (2HELPS2B score ≥1), and long-term secondary therapy for late seizure

The decision tree’s outcome measure was the number of expected quality-adjusted life-years (QALYs).

Primary prophylaxis was defined as “treatment initiated immediately on hospital admission.” Secondary prophylaxis was defined as “treatment started after a seizure” and was subdivided into secondary early-seizure prophylaxis, defined as treatment started after a seizure occurring in the first 7 days after the stroke, or secondary late-seizure therapy, defined as treatment started or restarted after a seizure occurring after the first poststroke week.

Incorporate Early-Risk Stratification Tool

The researchers created four common clinical scenarios and then applied the decision-making model to each. They found that the preferred strategies differed, depending on the particular scenario.

Scenario Preferred Strategy (QALYs)
  • 60-year-old man

  • Low risk of early (10%) and late (3.6% or 9.8%) seizures

  • Average risk of short- (9%) and long-term (30%) adverse drug reaction (ADR)s

  • Risk-guided (8.13)

  • Conservative (8.08)

  • Moderate (8.07)

  • Aggressive (7.88)

  • 80-year-old woman

  • Low risk of early (10%) and late (3.6% or 9.8%) seizures

  • High risk of short- (24%) and long-term (80%) ADRs

  • Conservative (2.18)

  • Risk-guided (2.17)

  • Moderate (2.09)

  • Aggressive (1.15)

  • 55-year-old man

  • High risk of early (19%) and late (34.8% or 46.2%) seizures

  • Low risk of short- (9%) and long-term (30%) ADRs

  • Aggressive (9.21)

  • Risk-guided (8.98)

  • Moderate (8.93 QALYs)

  • Conservative (8.77 QALYs)

  • 45-year-old woman

  • High risk of early (19%) and late (34.8% or 46.2%) seizures

  • High risk for short- (18%) and long-term (60%) ADRs

  • Risk-guided (11.53)

  • Conservative (11.23)

  • Moderate (10.93)

  • Aggressive (8.08)


Sensitivity analyses revealed that short-term strategies, including the conservative and risk-guided approaches, were preferable in most cases, with the risk-guided strategy performing comparably or even better than alternative strategies in most cases.

“Our findings suggest that a strategy that incorporates an early-seizure risk stratification tool (2HELPS2B) is favored over alternative strategies in most settings,” Moura commented.

“Current services with rapidly available EEG may consider using a 1-hour screening with EEG upon admission for all patients presenting with sICH to risk-stratify those patients, using the 2HELPS2B tool,” she continued. “If EEG is unavailable for early-seizure risk stratification, the conservative strategy seems most reasonable.”

“Potential Fallacies”

Commenting on the study for Medscape Medical News, José Biller, MD, professor and chairman, Department of Neurology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, called it a “well-written and intriguing contribution [to the field], with potential fallacies.”

The bottom line, he said, is that only a randomized, long-term, prospective, multicenter, high-quality study with larger cohorts can prove or disprove the investigators’ assumption.

The authors acknowledge that a limitation of the study was the use of published literature to obtain data to estimate model parameters and that they did not account for other possible factors that might modify some parameter estimates.

Nevertheless, Moura said the findings have important practical implications because they “highlight the importance of discontinuing antiseizure medications that were started during a hospitalization for sICH in patients that only had an early seizure.”

It is “of great importance for all providers to reassess the indication of antiseizure medications. Those drugs are not free of risks and can impact the patient’s health and quality of life,” she added.

The study was supported by grants from the National Institutes of Health (NIH). Moura reported receiving funding from the Centers for Disease Control and Prevention, the NIH, and the Epilepsy Foundation of America (Epilepsy Learning Healthcare System) as the director of the data coordinating center. The other authors’ disclosures are listed on the original article. Biller is the editor-in-chief of the Journal of Stroke and Cerebrovascular Diseases and a section editor of Up To Date.

JAMA Neurol. Published online July 26, 2021. Abstract

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