Hidden Time Bias May Skew Evidence on Seizure Prevention After Brain Hemorrhage

A sharp-eyed statistical critique published in the journal Neurocritical Care is challenging how researchers interpret one of the most debated questions in stroke medicine: whether giving prophylactic antiseizure medication to patients with lobar intracerebral hemorrhage actually prevents seizures. In a letter to the editor, Goh Kobayashi of Eiju General Hospital in Tokyo, together with Taisuke Shibata and Atsushi Shiraishi of Kameda Medical Center in Chiba, Japan, argue that a subtle but powerful methodological flaw known as immortal time bias may have distorted the conclusions of a widely discussed observational study on the topic.

The study under scrutiny, led by Banker and colleagues and published online in December 2025, examined patients with lobar intracerebral hemorrhage, a form of bleeding stroke that occurs in the lobes of the brain rather than deep structures such as the basal ganglia or thalamus. Lobar hemorrhages are strongly associated with cerebral amyloid angiopathy, an age-related condition in which amyloid protein deposits weaken vessel walls, and they carry a particularly high risk of subsequent seizures. Because clinical seizures can worsen outcomes after hemorrhagic stroke, physicians have long debated whether to prescribe preventive antiseizure drugs even in patients who have never seized, despite growing concern that these medications may themselves be harmful.

That concern was echoed in 2025 clinical practice guidelines from the Neurocritical Care Society, authored by Frontera and colleagues, which recommended against routine prophylactic antiseizure medication for most patients with nontraumatic intracerebral hemorrhage, citing trials suggesting possible harm, particularly with older agents such as phenytoin. Against this backdrop, observational studies comparing treated and untreated patients carry enormous weight. If such studies are methodologically sound, they can suggest when cautious prophylaxis might still help selected patients; if they are flawed, they can mislead clinicians and guideline developers alike.

The letter by Kobayashi and colleagues centers on the mechanics of immortal time bias, a problem first articulated in detail by epidemiologist Samy Suissa in a landmark 2008 paper in the American Journal of Epidemiology. The bias arises whenever a study classifies patients by a treatment that can only be started after they have survived for some period, yet counts that survival period as if it belonged to the treated group. Patients who die early, before ever receiving the drug, are automatically assigned to the untreated comparison group, even if they would have received the medication had they lived longer. The treated group thus appears to be populated by people who, by construction, could not die during the time window in question. They are, in a literal sense, immortal within that interval, and any apparent survival advantage may reflect nothing more than the way time was allocated.

In the context of lobar intracerebral hemorrhage, the problem is especially acute because the timing of antiseizure medication initiation is tightly linked to disease trajectory. Sicker patients, those with larger hemorrhages, deeper depressions of consciousness, or impending withdrawal of life-sustaining therapy, often die or transition to comfort care before prophylaxis is ever considered. Survivors who stabilize, by contrast, are the ones who live long enough to be started on medication. If the original analysis grouped patients from the moment of admission according to whether they ultimately received prophylaxis, while allowing the days before treatment to count toward the treated group’s follow-up time, the comparison would systematically favor the treated cohort for reasons unrelated to any pharmacological benefit.

Recent work has clarified just how pervasive and structurally varied this bias can be. In 2025, Hernán, Sterne, Higgins, Shrier, and Hernández-Díaz published a formal structural description in the journal Epidemiology showing how different causal structures generate immortal time, emphasizing that the bias is not a statistical nuisance to be adjusted away but a design-level misalignment between the question being asked and the analysis being performed. Their companion concept, the target trial, introduced by Hernán and colleagues in the Journal of Clinical Epidemiology in 2016, urges observational researchers to first specify the randomized trial they would ideally conduct, including a clearly defined time zero at which eligibility and treatment assignment both begin, and then emulate that design as faithfully as the data allow.

Applying that framework to seizure prophylaxis after lobar hemorrhage reveals the core difficulty: treatment is not assigned at a single moment but initiated at heterogeneous times, often days into the hospital course. Modern methods exist to handle this. The clone-censor-weight approach, increasingly used in pharmacoepidemiology and described in accessible detail by Gaber and colleagues in Cancer Medicine in 2024, creates artificial copies of each patient at time zero, one assigned to each treatment strategy, and then censors the copies when they deviate from their assigned strategy, using inverse probability weighting to correct for the informative censoring that results. This preserves the integrity of time zero and prevents the spurious survival advantage that plagues naive comparisons.

The exchange between the letter writers and the authors of the original study, with a formal response also published in Neurocritical Care, illustrates a broader and increasingly visible shift in how the medical literature polices itself. Methodological letters were once relegated to statistical footnotes; today, as large observational datasets drive clinical guidelines in neurocritical care, they sit at the center of practice-defining debates. The authors of the letter report no funding and no conflicts of interest and disclose that language-model tools were used only to refine phrasing and check citation consistency, with all content verified by the authors themselves. Their intervention does not claim that prophylactic antiseizure medication is definitively harmful or beneficial after lobar hemorrhage; it claims something more fundamental, that the existing estimate cannot be trusted until the time-zero problem is resolved.

For clinicians, the practical message is one of humility: observational evidence suggesting that prophylaxis is safe or effective in lobar hemorrhage should be weighed carefully against the randomized-trial signals of harm that shaped current guidelines. For researchers, the letter is a template for how to interrogate pharmacoepidemiologic analyses in acute neurology, where treatment timing, mortality, and disease severity are deeply entangled. As big-data studies continue to fill the evidence gaps left by trials that are difficult to conduct in critically ill stroke patients, the battle against immortal time bias, fought in the pages of methodological letters like this one, may prove as consequential for patient care as any new drug.

Subject of Research: Immortal time bias in observational studies of prophylactic antiseizure medication after lobar intracerebral hemorrhage

Article Title: Addressing Immortal Time Bias in Estimating the Effect of Prophylactic Antiseizure Medication after Lobar Intracerebral Hemorrhage

Article References: Kobayashi, G., Shibata, T., & Shiraishi, A. (2026). Addressing Immortal Time Bias in Estimating the Effect of Prophylactic Antiseizure Medication after Lobar Intracerebral Hemorrhage. Neurocritical Care. https://doi.org/10.1007/s12028-026-02643-8

Image Credits: AI Generated

DOI: 10.1007/s12028-026-02643-8

Keywords: immortal time bias, lobar intracerebral hemorrhage, antiseizure medication, seizure prophylaxis, neurocritical care, observational study design, target trial emulation, clone-censor-weight method, epidemiology, stroke, cerebral amyloid angiopathy, clinical guidelines