Authors: Naidech AM, Beaumond J, Muldoon K, et al. Prophylactic seizure medications and health-related quality of life after intracerebral hemorrhage. Crit Care Med.
Reviewed by: Lara Zimmermann, MD, Co-Director, Neurocritical Care Service, Assistant Professor of Neurological Surgery and Neurology, UC Davis School of Medicine
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Seizures are common after intracerebral hemorrhage (ICH) and are associated with cerebral edema and worse patient outcomes. Prophylactic antiseizure medication is not recommended by the AHA/ASA based on data that shows an association between poor outcome and phenytoin exposure. Nonetheless, prophylactic levetiracetam is currently used in approximately 40 percent of patients with ICH, and the potential impact of levetiracetam on cognitive function remains unknown. This study is a prospective cohort study of adults with spontaneous ICH admitted to a single academic medical center over five years (2011-2016) to evaluate the impact of prophylactic levetiracetam on cognitive function health-related quality of life (HRQoL). Adults with spontaneous ICH were prospectively identified on hospital admission. Demographic, clinical and radiographic variables as well as severity of injury (APACHE IV score) were recorded. Use of prophylactic levetiracetam was at the discretion of the treating physician. Delirium was assessed using the Confusion Assessment Method for the ICU (CAM-ICU). Patients with reduced consciousness underwent continuous electroencephalography monitoring for at least 24 hours. Each dose of levetiracetam and benzodiazepine administered during hospitalization was electronically retrieved and recorded. The primary outcome, cognitive function HRQoL, was assessed using the Neuro-Quality of Life (Neuro-QOL) test in the domains of cognitive function and mobility at one, three and 12 months after ICH. Correlations were performed using T-scores for cognitive function; mixed models was done to control for time of assessment, age and NIHSS. HRQoL analysis was referenced to the U.S. population at 50 +/- 10 with 5 point variation considered significant (one-half standard deviation).
A total of 142 patients were analyzed out of 394 patients screened; of the patients excluded from final analysis, 122 died, 91 were lost to follow-up, 24 declined permission and 15 had missing HRQoL data. For the cohort analyzed, the average age was 62 years, average NIHSS = 6 and ICH score = 0 - 2 in > 90 percent of participants. Thirty-eight patients received prophylactic levetiracetam and 104 patients received no prophylaxis. Patients treated with prophylactic levetiracetam received a median of 11 doses (7.25 – 26 doses) over five and a half days with a median of 500mg per dose. Patients who received prophylactic levetiracetam were more likely to have a lobar hematoma (71 percent vs. 18 percent, p<0.001), were older (66.9 vs. 60.6 years, p=0.02) and had a higher NIHSS score (9 vs. 6, p=0.01). APACHE IV scores, incidence of seizures (11 percent vs. 7 percent, p=0.5) and delirium (8 percent vs. 6 percent, p > 0.2) were not significantly different between groups. In mixed models, levetiracetam prophylaxis was independently associated with lower T-score in cognitive function HRQoL after controlling for age and NIHSS (5.1 points; p < 0.01) as well as after controlling for ICH score (p < 0.001). Inclusion of lobar vs non-lobar location of hematoma did not add to the final model (p>0.2). There were no associations between prophylactic levetiracetam and mobility HRQoL or modified Rankin Scale score.
This study indicates that prophylactic levetiracetam exposure after ICH is independently associated with patient reported lower cognitive function HRQoL in adults with spontaneous ICH at three months. The mechanism for this effect is unknown, but it is probably not mediated by delirium, as there was no association between prophylactic levetiracetam and delirium in this group. This finding is consonant with other research showing that phenytoin exposure is associated with worse functional outcomes after ICH and adds to the body of literature suggesting that prophylactic antiseizure medication may result in worse cognitive outcomes after hemorrhagic stroke. Limitations of this study include that a large number of eligible patients (> 60 percent) were not analyzed due to death, declined consent or other reasons.
Additionally, use of leviteracetam was up to physician discretion and, as such, patients who received the medication much more commonly had lobar hemorrhages. The authors note that lobar location did not add to the model, but given the vast differences in lobar hemorrhages between the two groups (71 percent in the levetiracetam group vs. 18 percent in the non-prophylaxis group), location remans a possible confounder as patients with lobar hemorrhages may be more likely than those with basal ganglia or cerebellar hemorrhages to have cognitive impairment regardless of seizure prophylaxis.
Hemorrhage location specificity (i.e., frontal, temporal lobe), incidence of seizures after hospital discharge and development of epilepsy are variables that likely also affect cognitive function and which were not included. Regardless, this research should raise awareness that prophylactic administration of levetiracetam in patients with spontaneous intracerebral hemorrhage may have persistent effects on cognition and these risks weighed against potential benefits of antiseizure prophylaxis for individual patients. Future randomized controlled trials are needed to better elucidate the relationship between levetiracetam and cognitive outcomes and to explore the effect that other factors such as location of ICH have on the risks and benefits of seizure prophylaxis, as well as which specific patient populations may benefit the most from these medications. #LiteratureWatch #NEWSReview #LaraZimmermann