Statins Reduce Post-Stroke Seizure Risk

Pauline Anderson

August 05, 2015

Taking a statin after a stroke, especially in the acute phase, reduces the risk for early-onset seizures and may prevent the progression of these seizures to chronic epilepsy, new research suggests.

The study, led by Jiang Guo, MD, Department of Neurology, West China Hospital of Sichuan University, Chengdu, China, was published online July 22 in Neurology.

Statins, typically used to treat high cholesterol and atherosclerotic diseases, are effective in both primary and secondary prevention of coronary heart disease and stroke, the authors write. These drugs are often given during the acute phase of a stroke.

The current analysis, a cohort study, included 1832 patients (mean age, 64.3 years) who had no history of epilepsy and were admitted to the Western China Hospital between January 2010 and August 2013 with a first-ever ischemic stroke.

Researchers used the National Institute of Health Stroke Scale (NIHSS) to categorize stroke severity as mild (less than 7), moderate (7 to 25) or severe (>25). They classified statin use into two phases: before the stroke (regular use at least 1 month before stroke) or in the acute phase (initiated within 3 days after stroke onset and continuing for at least 3 days).

In follow-up phone or face-to-face interviews, patients were asked about experiencing a seizure-like event or being diagnosed with epilepsy.

The primary outcomes were post-stroke early-onset seizure (ES) and post-stroke epilepsy (PSE). Acute ES was within 7 days of the stroke, and unprovoked late-onset seizures were more than 7 days after the stroke. PSE was defined as 2 or more unprovoked late-onset epileptic seizures after the acute phase of the stroke. Seizures were categorized as partial (simple, complex, and secondary generalized) and generalized.

Of the total sample, 14 patients used a statin before the stroke only, 1277 used a statin only in the acute phase, 114 used a statin before the stroke and in the acute phase, and 427 did not use a statin before the stroke or in the acute phase.

Among the 63 patients (3.4%) with ES, 33.3% had a simple partial seizure, 17.5% had a complex partial seizure, 11.1% had a secondary generalized attack, and 38.1% had a generalized seizure.

The analysis showed that statin use at any time compared with pre-stroke use only was associated with fewer ESs (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.19 - 0.53; P < .001). After adjustment for age, NIHSS score, hypertension, and other factors, the association remained (OR, 0.35; 95% CI, 0.20 - 0.60; P < .001).

During a mean follow-up of 2.5 years, 91 patients (5.0%) had PSE; of these, 20.9% had mainly simple partial seizures, 16.5% had mainly complex partial seizures, 17.6% had mainly secondary generalized attacks, and 45.1% had mainly generalized seizures.

The study showed that PSE was associated with less frequent use of statins (OR for anytime vs pre-stroke only, 0.64; 95% CI, 0.42 - 0.98; P = .041). However, the association did not remain after adjustments (OR, 0.81; 95% CI, 0.52 - 1.26; P = .349).

Of the 63 patients with ES, 52.4% used a statin regularly early after a stroke. After adjustments, these patients had reduced risk for PSE (OR, 0.34; 95% CI, 0.13 - 0.88; P = .026).

None of the patients used anticonvulsive drugs after a first seizure attack of PSE. This, said the authors, was due to controversy over initiating anticonvulsant therapy after a first post-stroke seizure. "To date, there remains no conclusive evidence."

Although some neurologists start antiepileptic drugs after a first acute seizure in specific conditions, there are concerns about adverse effects, poor adherence among the elderly, and interaction with other drugs, said the authors.

"Because antiepileptic therapy is long-term, most neurologists tend to be cautious and only initiate treatment after recurrent seizures" they write. "Compared with traditional antiepileptic drugs, statins have fewer side effects and drug interactions and are more tolerable for elderly patients."

Possible mechanisms of action for statins in this setting might include a decrease in glutamatergic synaptic transmission, reduction of infarction volume by anti-inflammatory and antioxidative effects, inhibition of apoptosis of neural cells, and lowering of permeability of the blood-brain barrier and brain inflammation.

"Big News"

In an accompanying editorial, Antonio Siniscalchi, MD, Department of Neurology, Annunziata, Hospital, Cosenza, Italy, and Scott Mintzer, MD, Jefferson Comprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, Pennsylvania, pointed out that efforts to prevent epilepsy have focused on patients with traumatic brain injury but that acute stroke represents another high-risk population.

Dr Siniscalchi and Dr Mintzer noted that while the study didn't find an association between acute statin use and epilepsy in all stroke patients, the risk for epilepsy was strongly reduced among patients who had had an acute seizure. These are the patients who have the greatest risk for epilepsy, they said.

"Thus, if we look for an epilepsy-preventive effect among all stroke patients we "drown out' the effect of statins, whereas we can identify their effect among those at greatest risk. The bottom line is that these results, if confirmed, will be the first-ever demonstration of antiepileptogenesis in a human clinical population," they conclude. "That's big news."

The study was nonrandomized and so was unable to exclude unmeasured confounders, including differences between those who developed acute seizure or epilepsy and those who did not, and differences in the likelihood of receiving a statin, they caution. Other limitations, they said, included a lack of subanalyses regarding the effects of statins on different types of seizures and not specifying the type and dose of statin used in relation to the risk for post-stroke seizures.

Nevertheless, they added, the data from the study support the use of statins in post-stroke patients to reduce the risk for acute seizures, especially for preventing chronic epilepsy in those who have had an acute seizure.

Further exploration into whether the coadministration of statins and anticonvulsant drugs can improve seizure control in patients with pharmaco-resistant post-stroke epilepsy is warranted, they write.

Commenting on the study for Medscape Medical News, Joseph Broderick, MD, director, University of Cincinnati Neuroscience Institute, and professor, Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Ohio, pointed out that it was carried out in a population quite different from that in the United States. He also noted that a small proportion of stroke patients in the study were receiving statin agents before the stroke. 

Dr Broderick commented that patients in the study who had seizures had much more severe strokes and were more likely to have cardioembolism. Given the occurrence of seizures, these patients would also have been more likely to have large cortical strokes, he said.

"Patients with large strokes would be much more likely to be unable to swallow during the acute post-stroke period and also less likely to survive — and thus may have been much less likely to be treated with statins," said Dr Broderick.  

"Thus, the findings of the study relating statin use to decreased seizures acutely could be explained by the confounding of much larger cortical strokes in patients more likely to have seizures who were unable to take statin agents orally, or who were likely to die and in whom statin use would be inappropriate."

A randomized trial would be needed to address this potential relationship, he said.

This work was supported by the National Natural Science Foundation of China. Dr Guo and Dr Broderick have disclosed no relevant financial relationships.

Neurology. Published online July 22, 2015. Abstract Editorial

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