The research, conducted at the Chinese People’s Liberation Army General Hospital in Beijing and published in BMC Cancer, examined the records of pediatric patients with hematologic malignancies who developed PRES during chemotherapy between January 2011 and December 2024. Over that fourteen-year window, nineteen children met the criteria for the syndrome, and seventeen of them experienced seizures. The team, led by Lin-Yan Hu, Chen Feng, and senior authors Xiu-Yu Shi and Li-Ping Zou, focused on a specific clinical question: among children who needed ongoing antiseizure therapy after their acute episodes, which medication could be given without sabotaging the cancer treatment itself? Their answer, drawn from a small but carefully documented cohort, was topiramate, a drug with a pharmacological profile that largely sidesteps the metabolic machinery chemotherapy depends on.

To understand why this matters, it helps to consider the biology of the problem. Most chemotherapy agents are metabolized by the cytochrome P450 enzyme family in the liver, a system that also processes many older antiseizure medications. Drugs such as phenytoin, carbamazepine, and phenobarbital are potent inducers of these enzymes, meaning they can accelerate the breakdown of chemotherapeutic agents and reduce their effectiveness below therapeutic thresholds. In a child fighting acute lymphoblastic leukemia or Burkitt lymphoma, that interaction is not a theoretical concern; it can mean the difference between remission and relapse. Even newer agents like levetiracetam, which has become the default choice in many oncology settings because of its benign interaction profile, carry practical challenges, including behavioral side effects in children and dosing adjustments in kidney impairment, which is common in PRES itself.

Topiramate occupies an unusual niche in this landscape. Chemically a sulfamate-substituted monosaccharide, it dampens neuronal excitability through several mechanisms at once: it blocks voltage-gated sodium channels, enhances the inhibitory action of GABA at certain receptors, antagonizes the AMPA subtype of glutamate receptor, and modulates calcium channels. Crucially, it is largely eliminated unchanged by the kidneys rather than extensively metabolized by cytochrome P450 enzymes, which means it exerts minimal induction or inhibition on the pathways that clear chemotherapy drugs. This pharmacokinetic invisibility is precisely what makes it attractive for oncology patients, and it is the theoretical foundation on which the Beijing team built their clinical experience.

The study’s design was straightforward and descriptive. The researchers defined clear criteria for initiating maintenance antiseizure therapy: children who suffered more than two seizures within twenty-four hours, or more than three seizures within three days, were considered at sufficiently high risk of further episodes to warrant ongoing medication. Of the eleven children who met these thresholds, eight received topiramate at a median dose of three milligrams per kilogram per day, while three received levetiracetam at a median of thirty-five milligrams per kilogram per day. Six additional children who experienced only a single seizure did not receive maintenance therapy, reflecting a deliberate strategy of reserving long-term drugs for those with demonstrated recurrence risk.

The outcomes, though drawn from a small sample, tell a striking story. All eight children treated with topiramate completed their planned chemotherapy courses, and no serious adverse events attributable to antiseizure medications were documented anywhere in the cohort. One child in the topiramate group required the drug to be reintroduced after an initial discontinuation and went on to develop secondary epilepsy, a reminder that PRES can leave lasting neurological scars even when the acute imaging findings appear reversible. In the levetiracetam group, the picture was more sobering: one child died from cancer relapse after persistent neurological deficits made it impossible to tolerate further chemotherapy. Among the six children with single seizures who received no maintenance therapy, two likewise died of relapse after being unable to continue treatment.

These numbers must be interpreted with great care, and the authors are refreshingly candid about that. The study is retrospective, meaning the researchers looked backward at records rather than assigning treatments prospectively, and it was not randomized. The choice of topiramate versus levetiracetam was made by treating clinicians, likely influenced by each child’s specific circumstances, introducing selection bias that no statistical adjustment can fully remove. With only nineteen patients in total and just eleven on maintenance therapy, the study lacks the statistical power to demonstrate that topiramate improves survival or chemotherapy completion rates. The authors explicitly frame their findings as hypothesis-generating and descriptive, a scientific way of saying that the results are intriguing enough to justify further study but not definitive proof of benefit.

Nevertheless, the consistency of the signal is worth pausing on. In a population where the inability to tolerate chemotherapy is often the proximate cause of death, the observation that every topiramate-treated child completed their planned cancer treatment is clinically meaningful, even if causation cannot be established. The median dose used, three milligrams per kilogram per day, is modest by epilepsy standards, suggesting that seizure control in PRES may require less aggressive dosing than chronic epilepsy. The absence of serious adverse events is also notable, given that topiramate is known to cause cognitive slowing, kidney stones, and metabolic acidosis in some patients, side effects that could theoretically compound the toxicities of intensive cancer therapy.

The broader context makes this work part of a growing recognition that PRES in children with cancer deserves dedicated research rather than extrapolation from adult neurology. The syndrome arises when chemotherapy-induced hypertension, electrolyte disturbances, and direct endothelial toxicity overwhelm the autoregulatory capacity of the brain’s posterior circulation, leading to vasogenic edema visible on magnetic resonance imaging. Most children recover fully if the syndrome is recognized promptly and blood pressure is controlled, but the seizure burden during the acute phase can be substantial, and the question of how long to continue antiseizure drugs afterward remains unresolved worldwide. Guidelines are sparse, and practice varies widely between centers, which is precisely why even small descriptive studies like this one fill an important gap.

What happens next will determine whether topiramate’s pharmacokinetic advantages translate into real clinical benefit. The authors call for prospective validation, ideally a multicenter trial that randomizes children with PRES-related seizures to different maintenance regimens and tracks chemotherapy tolerance, seizure recurrence, and long-term neurological outcomes. Until such evidence exists, the Beijing experience offers pediatric oncologists and neurologists a reasoned option to consider when the interaction profile of standard antiseizure drugs threatens to undermine cancer therapy. It is a modest finding in a rare and complicated corner of medicine, but for the families of children facing both cancer and seizures simultaneously, even a modest finding can point toward a safer path through an already perilous journey.

Subject of Research: Use of topiramate as maintenance antiseizure therapy in children with hematologic malignancies who develop posterior reversible encephalopathy syndrome during chemotherapy

Article Title: Topiramate use for maintenance antiseizure therapy in children with hematologic malignancies experiencing posterior reversible encephalopathy syndrome during chemotherapy: a single-center retrospective study

Article References: Hu, L.-Y., Feng, C., Cai, R.-Y., Li, Y., Chai, L.-N., He, W., Chen, J., Wan, L., Yang, G., Shi, X.-Y., & Zou, L.-P. (2026). Topiramate use for maintenance antiseizure therapy in children with hematologic malignancies experiencing posterior reversible encephalopathy syndrome during chemotherapy: a single-center retrospective study. BMC Cancer. https://doi.org/10.1186/s12885-026-16999-9

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16999-9

Keywords: posterior reversible encephalopathy syndrome, PRES, topiramate, levetiracetam, anti-seizure medications, pediatric oncology, hematologic malignancies, chemotherapy, seizures, drug interactions, cytochrome P450, retrospective study

The dispute began when the authors of a letter to the editor pointed out a subtle but potentially consequential flaw in how the original study assigned patients to treatment groups. In the study, patients were classified as receiving prophylaxis only if they were seizure-free from the moment their symptoms began until they reached the hospital and treatment was started. That classification, the letter writers argued, creates a hidden asymmetry. A patient who seized in the minutes or hours between symptom onset and hospital arrival could never be counted in the prophylaxis group, because the treatment window had already closed. Such patients would automatically land in the no-prophylaxis group, inflating that group’s seizure rate and making the medication appear more protective than it truly is. This is the classic structure of immortal time bias, dressed in the specific clothing of emergency stroke care.

The research team, led by Margaret Banker of the Department of Preventive Medicine and Andrew M. Naidech of the Department of Neurology at Northwestern University Feinberg School of Medicine, responded with a combination of empirical data and formal sensitivity analysis. Their first line of defense was timing. The team had prospectively recorded the interval between symptom onset and initial presentation, whether that presentation occurred at their own facility or at a referring hospital. The median interval turned out to be 4.3 hours, with an interquartile range of 1.1 to 11.5 hours. In other words, the window during which an early seizure could occur before any treatment decision was possible is, for most patients, relatively brief. That brevity matters, because the magnitude of immortal time bias depends directly on how much unobservable time exists between the true start of follow-up and the moment treatment could logically begin.

Still, the researchers acknowledged that the critics’ proposed remedies, including a target trial emulation with clone-censor weighting, would be the gold standard approach for this kind of question. Such methods construct hypothetical randomized trials from observational data by cloning every patient into multiple treatment strategies and censoring each clone at the moment it deviates from its assigned strategy. The problem, the team explained, is practical rather than conceptual: those analyses require knowing the exact time of the first seizure, and that information was not captured. Time of symptom onset is a standard NIH Common Data Element for stroke research, but time of seizure is not a common data element in epilepsy care, so it never appeared on the case report forms. The researchers agreed that future studies should record both timestamps to enable the more rigorous analytic frameworks their critics favor.

Unable to run the ideal analysis, the team did the next best thing: they systematically dismantled the bias from both directions. The potential misclassification, they reasoned, could arise in two distinct ways. First, a seizure might occur almost immediately after symptom onset, before the patient could possibly reach a hospital and be offered prophylaxis. Second, a seizure might occur after a longer delay, but the patient might arrive so late that the treatment decision window had effectively passed. Each scenario implies a different pattern of misclassification, and each can be probed by excluding the patients most likely to embody it.

To address the first scenario, the researchers re-ran their analysis after excluding patients who presented very rapidly, within one, two, or four hours of symptom onset. These exclusions remove precisely the patients who could have seized before prophylaxis was even a possibility. The results barely moved. Across all three exclusion windows, the association between prophylactic antiseizure medication and reduced seizure risk remained essentially unchanged, suggesting that immediate pre-hospital seizures were not driving the observed effect. To address the second scenario, the team performed the mirror-image analysis, excluding patients who presented late, after six, eight, or ten hours. If delayed presentations were allowing extra time for early seizures to accumulate in the no-prophylaxis group, removing those patients should have attenuated the association. It did not. The direction and magnitude of the effect held steady, indicating that the findings are robust to how quickly or slowly patients reached medical care.

The researchers then went a step further, deploying a quantitative bias analysis, a technique that asks a deceptively simple question: how wrong would the data have to be to erase the finding? They calculated how many patients with seizures, falsely classified as not receiving prophylaxis, would need to be hypothetically reassigned to the prophylaxis group before the adjusted odds ratio crossed the null and the association vanished. The answer was striking: roughly forty percent. Only when approximately two in five of the seizure patients in the no-prophylaxis group were assumed to be misclassified did the protective signal disappear entirely. A misclassification rate of that scale, arising solely from seizures occurring in the narrow pre-hospital window, struck the authors as implausible given the observed presentation times. Their conclusion was unambiguous: the results are robust.

Beyond the statistical sparring, the exchange touches on a genuine clinical dilemma. Prophylactic antiseizure medication after lobar intracerebral hemorrhage remains controversial, because antiseizure drugs carry their own risks, and the evidence base for preventive use has long been thin. The researchers expressed appreciation for the call to conduct a prospective, randomized trial, but they were candid about its prospects. They themselves proposed exactly such a study, the Seizure Prophylaxis in Lobar ICH Treatment trial, known by the acronym SPLIT, but it was not given sufficient priority for funding. Meanwhile, the PEACH trial, a randomized, double-blind, placebo-controlled phase 3 study of prophylactic levetiracetam in acute intracerebral hemorrhage conducted in France, was halted due to low recruitment. The randomized evidence that clinicians and guideline writers crave may simply never materialize, leaving well-designed observational analyses as the best available evidence.

That reality shapes the research agenda going forward. The authors suggested that future work will likely focus on identifying which patients are most likely to experience a subsequent seizure, so that prophylaxis can be targeted to those who stand to benefit rather than applied indiscriminately. Their own data point to one such criterion: acute lobar intracerebral hemorrhage, in which bleeding occurs in the brain’s outer lobes rather than deep structures, appears to be a reasonable trigger for considering antiseizure prophylaxis. Lobar hemorrhages are known to carry a higher risk of post-hemorrhagic seizures than deep hemorrhages, plausibly because cortical blood irritates the brain’s electrical circuitry in ways that deep bleeds do not.

The broader lesson of the exchange extends well beyond this single clinical question. Immortal time bias has quietly distorted findings across the medical literature, from studies of cancer screening to intensive care interventions, and the letter-and-response format on display here represents peer review functioning as intended. Critics identified a real methodological vulnerability; the original authors responded not with dismissal but with layered sensitivity analyses, quantitative bias assessment, and an honest accounting of what their data could and could not support. The work was supported by the National Institutes of Health under grant R01NS117608, and both the original study and the rebuttal are open access, allowing clinicians, statisticians, and patients to examine the evidence directly. For now, the association between prophylactic antiseizure medication and fewer seizures after lobar brain hemorrhage stands, tested against one of epidemiology’s most persistent traps and emerging, by the authors’ account, intact.

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

Article Title: Response to: “Addressing Immortal Time Bias in Estimating the Effect of Prophylactic Antiseizure Medication After Lobar Intracerebral Hemorrhage”

Article References: Banker, M., & Naidech, A. M. (2026). Response to: “Addressing Immortal Time Bias in Estimating the Effect of Prophylactic Antiseizure Medication After Lobar Intracerebral Hemorrhage”. Neurocritical Care. https://doi.org/10.1007/s12028-026-02642-9

Image Credits: AI Generated

DOI: 10.1007/s12028-026-02642-9

Keywords: immortal time bias, intracerebral hemorrhage, antiseizure medication, seizure prophylaxis, neurocritical care, lobar hemorrhage, observational study, sensitivity analysis, quantitative bias analysis, levetiracetam, PEACH trial, epilepsy