Thrombolytic Therapy in Epilepsy

By:  John Paisley

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Stroke interventions can involve either thrombolytic therapy, an IV medication, mechanical thrombectomy, a surgical procedure, or combination therapy. There have been concerns expressed by several research articles that thrombolytic therapy has a potential association with post-stroke epilepsy and seizure formation. Recent research models suggest that neither thrombolytic therapy nor mechanical thrombectomy correlates with heightened risks of acute symptomatic seizures or post-stroke epilepsy. While ongoing research and debate continue, refraining from thrombolytic therapy due to seizure or epilepsy concerns is not advised. Thrombolytic therapy’s benefit in reducing stroke severity and mortality have been well-established through research over the past decades.

Introduction to reperfusion interventions

Following a stroke diagnosis, three interventions are available to directly treat blood clots. All three have specific exclusion criteria and time windows. The three interventions are thrombolytic therapy, mechanical thrombectomy, and both interventions combined. The use of both interventions, mechanical thrombectomy-intravenous thrombolysis, abbreviated MT-IVT, is another area of high research to determine if combined therapy has better outcomes than each treatment individually, with current research showing promising results (Zheng et al., 2023).

Thrombolytic therapy refers to a clot-dissolving medication administered through an IV line. This therapy is typically recommended for administration within 3-4.5 hours of stroke symptom onset (Pan & Shi, 2021; Hack et al., 2008). Due to patient safety concerns, exclusion criteria for this medication have been placed to ensure that patient risk is limited (Demaerschalk et al., 2015; Jauch et al., 2013). As such, dissolving a blood clot in a patient’s brain can be lifesaving; however, dissolving a blood clot near a recent surgery site can be life-threatening.

Mechanical thrombectomy refers to the direct removal of a blood clot through device assistance. The time window for mechanical thrombectomy tends to be longer than thrombolytic therapy since the mechanical thrombectomy equipment can estimate the individual tissues’ benefit rather than relying on an inflexible onset window. This option has limitations, as only comprehensive stroke centers have the capability for this procedure (Debabrata & Bhaumik, 2022; Albers et al., 2018; Nogueira et al., 2017).

Animal studies, and previous studies

The relationship between thrombolytic therapy and epilepsy has been the subject of extensive investigation over the past few decades. Ongoing research has raised concerns about the potential for thrombolytic therapies to exacerbate seizure activity and worsen stroke tissue damage compared to control groups.

In animal research studies, thrombolytic therapies administered to rats have been associated with higher neuronal injury volume (infarction volume) compared to control and knockout rats (Wang et al., 1998). Moreover, experimental research has associated the biochemical pathways of thrombolytic therapies, such as tissue Plasminogen Activator (tPA), with disruptions of the blood-brain barrier (BBB), decreased seizure thresholds, and cellular toxicity (Yepes et al., 2008; Jin et al., 2010; Tan et al.,2012; Niego & Medcalf, 2014).

Patient-care literature has also discussed the potential development of epilepsy as a side effect of thrombolytic therapy. Additionally, considerations have been raised suggesting that seizure activity might serve as an indicator of the success of thrombolytic therapy (Hafeez et al., 2007; Rodan et al.,2006; Brondani et al., 2020).

Alternate considerations

Some of these findings have faults that we can observe, requiring further research to clarify. In the case of animal testing, there are genetic and physiologic differences between rats and humans. While animal testing is a safe alternative to patient-care research, animal results alone should not equate to patient-care results.

For instance, the study reporting increased brain infarct size in rats warrants further investigation due to potential inaccuracies. Another independent study highlighted additional genetic mutations in the rat strain used, raising doubts about the accuracy of the previous findings (Szabo et al., 2016).

Exploring the molecular actions of tPA, this chemical is also naturally produced in the body. While its role in stroke treatment has been extensively studied, ongoing research is exploring its broader functions. Notably, its impact on the BBB appears to be part of its regulatory activities promoting brain homeostasis (Leybaert et al., 2004; Fredriksson et al., 2017). Current biochemical research supports the notion that tPA acts to facilitate seizure activity due to tPA’s effect on the BBB (Marchi et al., 2011). Contrary to initial assumptions, a following study found that tPA’s over-expression (over-production) results in an increased risk for seizure activity rather than tPA itself. Moreover, animal testing following post-stroke tPA administration failed to establish a definitive association with tPA and seizure or epilepsy development (Tan et al., 2012).

In the patient care literature, associations with seizure treatment may have skewing data. For instance, some studies exclude patients based on specific criteria omitting certain demographic groups. These exclusion criteria often limit the inclusion of individuals from lower socioeconomic backgrounds, those with mental health conditions, and patients who have experienced acute symptomatic seizures. It’s worth noting that acute symptomatic seizures, while not typically diagnosed as epilepsy alone, are of particular concern in thrombolytic therapy research (Burneo et al.,2019; Hurford & DPhil, 2020). Additionally, some studies fail to consider stroke severity, an important factor associated with epilepsy and seizure development (Brigo et al., 2020; Alvarez et al., 2013; Zöllner et al., 2020a).

Reperfusion syndrome and newer research models

One key point of interest in patient-care-centered research is reperfusion syndrome. Widely studied in cardiology and vascular surgery, reperfusion syndrome refers to the adverse effects that occur once a previously blocked blood vessel becomes unblocked. The oxygen deprivation of the surrounding tissue results in a buildup of toxic materials. Once the blockage is cleared, these toxic materials are free to flow into surrounding tissues, resulting in secondary injury (Ikhlas & Atherton, 2023).

This reactive process adds another layer of consideration to stroke therapy research, making it challenging to compare the direct effects of thrombolytic therapies or mechanical thrombectomy. Furthermore, it adds the question: Does reperfusion syndrome contribute to seizure and epilepsy formation? Newer research models have incorporated two methods to combat this issue. These newer models compare the three previously mentioned stroke interventions to patient populations who did not receive these therapies with similar conditions, enabling comparison of their respective impacts with statistical correction for confounding variables. This methodology can assist in determining questions such as: How do the outcomes of thrombolytic therapies compare to mechanical thrombectomy in different patient populations? How do thrombolytic therapies compare to mechanical thrombectomy on post-stroke epilepsy rates?

Our current understanding

Using the newer research model to investigate stroke interventions, present studies support the idea that neither mechanical thrombectomy nor thrombolytic therapy correlate with elevated risks of acute symptomatic seizures or the development of post-stroke epilepsy (Ferreira-Atuesta et al., 2021; Zöllner et al., 2020b; Mushannen et al., 2021; Kohlhase et al., 2022; Gasparini et al., 2019; Alain et al., 2020). While thrombolytic therapy is still a debated topic among specialists, most articles agree that stroke severity, hemorrhagic stroke, and area of stroke are independent risk factors for epilepsy and seizure formation post-stroke (Zöllner et al., 2020a; Nandan et al., 2023; Thevathasan et al., 2018; Bladin et al., 2000; Inatomi et al., 2023).

Lastly, while epilepsy formation related to thrombolytic therapy is still debated, abstaining from thrombolytic therapy solely due to this concern is not recommended. Thrombolytic therapy has been shown to reduce stroke severity and decrease mortality in patients who meet the recommended medication criteria (Demaerschalk et al., 2015). Furthermore, stroke care has been heavily researched to ensure both monitoring and exclusion criteria for thrombolytic care are safe and reduce patient risk.


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