By: John Paisley
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.
Resources:
Albers, G. W., Marks, M. P., Kemp, S., Christensen, S., Tsai, J. P., Ortega-Gutierrez, S., McTaggart, R. A., Torbey, M. T., Kim-Tenser, M., et al. 2018. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa1713973
Alvarez, V., Rossetti, A. O., Papavasileiou, V., & Michel, P. (2013). Acute seizures in acute ischemic stroke: does thrombolysis have a role to play?. Journal of neurology. https://doi.org/10.1007/s00415-012-6583-6
Bladin, C. F., Alexandrov, A. V., Bellavance, A., Bornstein, N., Chambers, B., Coté, R., Lebrun, L., Pirisi, A., & Norris, J. W. (2000). Seizures after stroke: a prospective multicenter study. Archives of neurology, 57(11), 1617–1622. https://doi.org/10.1001/archneur.57.11.1617
Brigo, F., Schneider, M., Wagenpfeil, G., Ragoschke-Schumm, A., Fousse, M., Holzhoffer, C., Nardone, R., Faßbender, K., & Lochner, P. (2020). Intravenous thrombolysis with tPA and cortical involvement increase the risk of early poststroke seizures: Results of a case-control study. Epilepsy & behavior : E&B, 104(Pt B), 106312. https://doi.org/10.1016/j.yebeh.2019.04.056
Brondani, R., Almeida, A., Cherubini, P., Secchi, T., Oliveiera, M., Martins, S., Bianchin, M. 2020. Risk Factors for Epilepsy After Thrombolysis for Ischemic Stroke: A Cohort Study. Frontiers: Epilepsy. https://doi.org/10.3389/fneur.2019.01256
Burneo, J. G., Antaya, T. C., Allen, B. N., Belisle, A., Shariff, S. Z., & Saposnik, G. (2019). The risk of new-onset epilepsy and refractory epilepsy in older adult stroke survivors. Neurology, 93(6), e568–e577. https://doi.org/10.1212/WNL.0000000000007895
Chakraborty, D., & Bhaumik, S. 2022. Mechanical Thrombectomy- Where Do We Stand Now?. Annals of Indian Academy of Neurology. https://doi.org/10.4103/aian.aian26322
Demaerschalk, B., Kleindorfer, D., Adeoye, O., Demchuk, A., Fugate, J., Grotta, J., et al. 2015. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke. American Heart Association: Stroke. https://doi.org/10.1161/STR.0000000000000086
Ferreira-Atuesta, C., Döhler, N., Erdélyi-Canavese, B., Felbecker, A., Siebel, P., Scherrer, N., Bicciato, G., Schweizer, J., Sinka, L., Imbach, L., Katan, M., Abraira, L., Santamarina, E., Álvarez-Sabín, J., Winklehner, M., von Oertzen, T., Wagner, J., Gigli, G. L., Serafini, A., Janes, F., Merlino, G., Valente, M., Gregoraci, G., Conrad, J., Evers, S., Lochner, P., Roell, F., Brigo, F., Bentes, C., Peralta, A., Pinho e Melo, T., Keezer, M., Duncan, J., Sander, J., Tettenborn, B., Koepp, M., & Galovic, M. 2021. Seizures after Ischemic Stroke: A Matched Multicenter Study. Annals of Neurology. https://doi.org/10.1002/ana.26212
Fredriksson, L., Lawrence, D. A., & Medcalf, R. L. (2017). tPA Modulation of the Blood-Brain Barrier: A Unifying Explanation for the Pleiotropic Effects of tPA in the CNS. Seminars in thrombosis and hemostasis. https://doi.org/10.1055/s-0036-1586229
Hacke, W., Kaste, M., Bluhmki, E., Brozman, M., Dávalos, A., Guidetti, D., Larrue, V., Lees, K. R., Medeghri, Z., Machnig, T., Schneider, D., von Kummer, R., Wahlgren, N., Toni, D., & ECASS Investigators (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. The New England journal of medicine. https://doi.org/10.1056/NEJMoa0804656
Hafeez, F., Razzaq, M. A., Levine, R. L., & Ramirez, M. A. (2007). Reperfusion seizures: a manifestation of cerebral reperfusion injury after administration of recombinant tissue plasminogen activator for acute ischemic stroke. Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association. https://doi.org/10.1016/j.jstrokecerebrovasdis.2007.07.007
Hurford, R., DPhil, L. 2020. Journal Club: Risk of new-onset epilepsy and refractory epilepsy in older adult stroke survivors. Neurology Journals. https://doi.org/10.1212/WNL.000000000000894
Ikhlas M, Atherton NS. 2023. Vascular Reperfusion Injury. PubMed: Pearls. https://www.ncbi.nlm.nih.gov/books/NBK562210/
Inatomi, Y., Nakajima, M., & Yonehara, T. (2023). Cortical Involvement of a Recent Infarct Contralateral to Early Focal Seizures in Ischemic Stroke. Internal medicine (Tokyo, Japan). https://doi.org/10.2169/internalmedicine.0120-22
Jauch, E., Saver, J., Adams, H., Bruno, A., Connors, J., Demaerschalk, B., Khatri, P., et al. 2013. Guidelines for the Early Management of Patients With Acute Ischemic Stroke. American Heart Association: Stroke. https://doi.org/10.1161/STR.0b013e318284056a
Jin, R., Yang, G., & Li, G. (2010). Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiology of disease. https://doi.org/10.1016/j.nbd.2010.03.008
Kohlhase, K., Tako, L. M., Zöllner, J. P., Golbach, R., Pfeilschifter, W., Steinmetz, H., Rosenow, F., & Strzelczyk, A. (2022). Mechanical thrombectomy does not increase the risk of acute symptomatic seizures in patients with an ischaemic stroke: a propensity score matching study. Journal of neurology. https://doi.org/10.1007/s00415-022-10968-5
Lekoubou, A., Fox, J., & Ssentongo, P. (2020). Incidence and Association of Reperfusion Therapies With Poststroke Seizures: A Systematic Review and Meta-Analysis. Stroke. https://doi.org/10.1161/STROKEAHA.119.028899
Leybaert, L., Cabooter, L., & Braet, K. (2004). Calcium signal communication between glial and vascular brain cells. Acta neurologica Belgica. https://pubmed.ncbi.nlm.nih.gov/15508267/
Marchi, N., Tierney, W., Alexopoulos, A. V., Puvenna, V., Granata, T., & Janigro, D. (2011). The etiological role of blood-brain barrier dysfunction in seizure disorders. Cardiovascular psychiatry and neurology. https://doi.org/10.1155/2011/482415
Mushannen, T., Aleyadeh, R., Siddiqui, M., Saqqur, M., Akhtar, N., Mesraoua, B., Jerdi, S. A., Melikyan, G., Shaheen, Y., Qadourah, H., Chagoury, O., Mahfoud, Z. R., & Haddad, N. 2021. Effect of Reperfusion Therapies on Incidence of Early Post-Stroke Seizures. Frontiers. https://doi.org/10.3389/fneur.2021.758181
Nandan, A., Zhou, Y., Demoe, L., Waheed, A., Jain, P., Widjaja, E. 2023. Incidence and risk factors of post-stroke seizures and epilepsy: systematic review and meta-analysis. Sage Journals. https://doi.org/10.1177/03000605231213231
Niego, B., & Medcalf, R. L. (2014). Plasmin-dependent modulation of the blood-brain barrier: a major consideration during tPA-induced thrombolysis?. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. https://doi.org/10.1038/jcbfm.2014.99
Nogueira, R. G., Jadhav, A. P., Haussen, D. C., Bonafe, A., Budzik, R. F., Bhuva, P., et al. 2017. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa1706442
Pan, Y., Shi, G. 2021. Silver Jubilee of Stroke Thrombolysis With Alteplase: Evolution of the Therapeutic Window. Frontiers. https://doi.org/10.3389/fneur.2021.593887
Rodan, L. H., Aviv, R. I., Sahlas, D. J., Murray, B. J., Gladstone, J. P., & Gladstone, D. J. (2006). Seizures during stroke thrombolysis heralding dramatic neurologic recovery. Neurology. https://doi.org/10.1212/01.wnl.0000247231.25231.2e
Szabo, R., Samson, A. L., Lawrence, D. A., Medcalf, R. L., & Bugge, T. H. (2016). Passenger mutations and aberrant gene expression in congenic tissue plasminogen activator-deficient mouse strains. Journal of thrombosis and haemostasis : JTH. https://doi.org/10.1111/jth.13338
Tan, M., Ng, A., Pandher, P., Sashindranath, M., Hamilton, J., David, S., O’Brien, T., Medcalf, R., Yan, B., Jones, N. (2012). Tissue plasminogen activator does not alter development of acquired epilepsy. Epilepsia. https://doi.org/10.1111/j.1528-1167.2012.03635.x
Thevathasan, A., Naylor, J., Churilov, L., Mitchell, P. J., Dowling, R. J., Yan, B., & Kwan, P. (2018). Association between hemorrhagic transformation after endovascular therapy and poststroke seizures. Epilepsia, 59(2), 403–409. https://doi.org/10.1111/epi.13982
Wang, Y. F., Tsirka, S. E., Strickland, S., Stieg, P. E., Soriano, S. G., & Lipton, S. A. (1998). Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. https://doi.org/10.1038/nm0298-228
Yepes, M., Roussel, B. D., Ali, C., & Vivien, D. (2009). Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends in neurosciences. https://doi.org/10.1016/j.tins.2008.09.006
Zheng, M., Li, L., Chen, L., Li, B., & Feng, C. (2023). Mechanical thrombectomy combined with intravenous thrombolysis for acute ischemic stroke: a systematic review and meta-analyses. Scientific reports, 13(1), 8597. https://doi.org/10.1038/s41598-023-35532-7
Zöllner, J. P., Misselwitz, B., Kaps, M., Stein, M., Konczalla, J., Roth, C., Krakow, K., Steinmetz, H., Rosenow, F., & Strzelczyk, A. (2020a). National Institutes of Health Stroke Scale (NIHSS) on admission predicts acute symptomatic seizure risk in ischemic stroke: a population-based study involving 135,117 cases. Scientific reports. https://doi.org/10.1038/s41598-020-60628-9
Zöllner, J. P., Misselwitz, B., Mauroschat, T., Roth, C., Steinmetz, H., Rosenow, F., & Strzelczyk, A. (2020b). Intravenous thrombolysis or mechanical thrombectomy do not increase risk of acute symptomatic seizures in patients with ischemic stroke. Scientific reports. https://doi.org/10.1038/s41598-020-78012-y
Gasparini, S., Ascoli, M., Brigo, F., Cianci, V., Branca, D., Arcudi, L., Aguglia, U., Belcastro, V., Ferlazzo, E. 2019. Younger age at stroke onset but not thrombolytic treatment predicts poststroke epilepsy: An updated meta-analysis. Epilepsy & Behavior. https://doi.org/10.1016/j.yebeh.2019.106540
