Stroke Epilepsy after Thrombolysis RTPA Cortical Involvement

Description about Epilepsy after Thrombolysis

1. 1 RESULTS OF A CASE–CONTROL STUDY THE RISK OF EARLY POSTSTROKE SEIZURES: AND CORTICAL INVOLVEMENT INCREASE INTRAVENOUS THROMBOLYSIS WITH TPA JOURNAL READING STASE EPILEPSI Presenter : dr. Stefanus Erdana Putra Supervisor : Dr. dr. Diah Kurnia Mirawati , Sp.S (K). PPDS I Ilmu Penyakit Saraf Fakultas Kedokteran UNS / RSUD Dr. Moewardi 2023

2. Late PSS (onset ≥7 days from stroke) The brain has undergone changes Risk for a subsequent unprovoked seizure over the following 10 years of approximately 70% Considered as acute symptomatic seizures Not associated with alterations in the neuronal networks Low risk of long-term seizure recurrence Early PSS (onset ≤7 days from the CVA ) Not imply a diagnosis of poststroke epilepsy Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia 2010; 51:671–5 Hesdorffer DC, Benn EK, Cascino GD, Hauser WA. Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure. Epilepsia 2009;50:1102–8 [5]Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55:475–82 A single late poststroke seizure should be considered as post stroke (structural) epilepsy POSTSTROKE SEIZURES (PSS) BACKGROUND 2

3. Zhang C, Wang X, Wang Y, Zhang JG, Hu W, Ge M, et al. Risk factors for post-stroke seizures: a systematic review and meta-analysis. Epilepsy Res 2014;108:1806–16. POSTSTROKE SEIZURES (PSS) BACKGROUND Risk factor Cortical involvement Risk factor Intracerebral hemorrhage or hemorrhagic transformation of an ischemic stroke Risk factor chronic alcohol abuse Risk factor Stroke severity (i.e., National Institutes of Health Stroke Scale (NIHSS) > 15) 3 Consequence of transient cellular biochemical dysfunctions and/or h omeostatic or systemic disturbances Early PSS

4. 4 POSTSTROKE SEIZURES (PSS) BACKGROUND i.v. thrombolysis with rtPA i.v. thrombolysis and the occurrence of epileptic seizures Difference in inclusion criteria, study design, definition and type of seizures length of follow-up Found the association Carrera, 2006 Alvarez, 2013 Naylor, 2018 DeReuck, 2010 Tan, 2012 Bentes, 2017 Failed to confirm this finding Zhang C, Wang X, Wang Y, Zhang JG, Hu W, Ge M, et al. Risk factors for post-stroke seizures: a systematic review and meta-analysis. Epilepsy Res 2014;108:1806–16. Lekoubou A, Awoumou JJ, Kengne AP. Incidence of seizure in stroke patients treated with recombinant tissue plasminogen activator: a systematic review and metaanalysis. IntJStroke2017;12:923–31.

5. 5 OBJECTIVES BACKGROUND To better understand the relationship between i.v. thrombolysis and the occurrence of acute symptomatic PSS and, more generally, to identify risk factors for early PSS in patients with acute ischemic stroke.

6. 6 Retrospective case–control study Design S ingle stroke center (University of Saarland, Germany) Location January 1st, 2010 and December 31st, 2016 Date Patients with seizure which occur red during the first 7 days following ischemic stroke Cases group Patients with acute ischemic stroke who did not experienc e early PSS, who were matched with cases for age and sex Control group DESIGN AND PARTICIPANTS METHODS

7. 7 DATA COLLECTION METHODS 1 st computed tomography (CT) scan on admission 2nd CT within 24h after the admission In clinical or radiological suspicion of lacunar stroke  a MRI performed within 72h of admission Study flow Exclusion Patients with previous epilepsy Primary intracerebral hemorrhage History of brain tumor Transient ischemic attack Cerebral venous thrombosis Patients taking antiepileptic drugs Age and sex H istory of ischemic stroke Concomitant therapies Glucose, c holesterol , and sodium values on admission Blood pressure levels on admission Chronic alcoholism, hypertension, DM Data collected European Stroke Organisation Executive Committee, ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack. Cerebrovasc Dis 2008;25:457–507 Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, etal. Operational classification of seizure types by the International League Against Epilepsy:position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58:522–30.

8. 8 DATA COLLECTION METHODS 1 Acute stroke localization and stroke etiology  Trial of ORG10172 in Acute Stroke Treatment (TOAST) classification 2 Stroke severity  NIHSS and Rankin scale on admission, before eventual recanalization therapy 3 Intravenous thrombolysis with rtPA or other reperfusion therapies according to European and German guidelines 4 The seizure type described according to the most recent classification by the ILAE European Stroke Organisation Executive Committee, ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack. Cerebrovasc Dis 2008;25:457–507 Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, etal. Operational classification of seizure types by the International League Against Epilepsy:position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58:522–30.

9. 9 STATISTICAL ANALYSIS METHODS Descriptive statistics Q uantitative variables Median and IQR Qualitative variables Absolute and relative frequencies Comparation Dichotomous variables chi-square test Quantitative variables Mann–Whitney U test Risk factors : OR with 95% CI 1 st : univariate logistic regression (p<0.05) 2 nd : multiple logistic regression analysis using forward Wald (p-value cut off 0.05 for inclusion) and backward Wald elimination (p-value cut off 0.1 for exclusion)

10. Cases Mean±SD Controls Mean±SD Statistical significance (p value) Age (years) 72.94 ± 9 72.557 ± 13 0.816 Male gender 55.7% 55.7% 1 Prior ischemic stroke 28 (35.4%) 45 (28.5%) 0.274 Concomitant therapies Statins 36 (45.6%) 52 (33.1%) 0.974 Antiplatelets 36 (45.6%) 52 (33.1%) 0.262 Anticoagulans 13 (16.5%) 28 (17.7%) 0.808 Alcoholism 8 (10.1%) 10 (6.3%) 0.298 Hypertension 69 (87.3%) 135 (85.4%) 0.691 Systolic blood pressure at admission 151 ± 29 148 ± 30 0.317 Diabetes mellitus I nsulin dependent 11 (13.9%) 30 (19%) 0.395 Not In sulin dependent 19 (24.1%) 28 (17.7%) Blood sugar at admission(mg/dL) Median: 134 [IQR: 109–172] Median: 123 [IQR: 103–160] 0.048 Sodium levels at admission (mmol/L) 141 ± 11 140 ± 4 0.612 Total cholesterol levels (mg/dL) 173 ± 45 178 ± 46 0.660 10 Table 1. Clinical characteristics of participants RESULT

11. Cases N (%) Controls N (%) Statistical significance (pvalue) Large artery disease 22 (27.8%) 34 (21.5 % ) 0.087 Cardiac embolism 31 (39.2%) 63 (39.9 % ) Small vessel disease 1 (1.3%) 14 (8.9 % ) Other determined etiology 1 (1.3%) 8 (5.1 % ) Undetermined etiology (cryptogenic) 23 (29.1%) 39 (24.7 % ) Unavailable information 1 (1.3%) (0%) Total 79 (100%) 158 (100%) Stroke localization Cortical 54 (68.4%) 73 (46.2%) 0.002 Subcortical 18 (22.8%) 42 (26.6%) Lacunar 7 (8.9%) 40 (25.3%) Stroke severity NIHSS Median: 7 [IQR: 3–16] Median: 4 [IQR: 2–8] 0.010 Rankin score Median: 4 [IQR: 2–5] Median: 3 [IQR: 2–4] 0.007 11 Table 2. Stroke characteristics RESULT

12. Recanalization therapy Cases N (%) Controls N (%) Statistical significance (p - value) Intravenous thrombolysis 25 (31.6%) 26 (16.5%) 0.007 Intraarterial thrombolysis 7(8.9 %) 5 (3.2%) 0.059 Mech anical thrombectomy Successful 16 (20.3%) 25 (15.8%) 0.327 Not successful 5 (6.3%) 5 (3.2%) 12 Table 3. Reperfusion therapies RESULT

13. 13 Risk Factor Analysis RESULT Univariate Analysis : blood sugar levels on admission (OR: 1.005; 95% CI: 1.000 to 1.009; p = 0.044), stroke localization (lacunar stroke: OR: 0.237; 95% CI: 0.098–0.568; p = 0.001), NIHSS (OR: 1.034; 95% CI: 1.008–1.061; p = 0.010), Rankin score (OR: 1.242; 95% CI: 1.028–1.500; p = 0.025), i.v. thrombolysis with rtPA (OR: 2.350; 95% CI: 1.247–4.430; p = 0.008) Multiple logistic regression : after forward and backward variable selection cortical stroke localization (OR: 2.49; 95% CI: 1.35–4.59; p= 0.003) i.v. thrombolysis (OR: 2.26; 95% CI: 1.16–4.43; p = 0.017)

14. 14 STUDY RESULT DISCUSSION Cortical involvement and i.v. thrombolysis are independent risk factors An increased risk of early PSS was not explained by age or sex, concomitant drugs, diabetes or alcoholism, sodium and cholesterol levels, blood pressure on admission, stroke etiology or severity, and hemorrhagic transformation or hemorrhage following i.v. thrombolysis. Intravenous thrombolysis with/without subsequent mechanical thrombectomy represents the current standard of care of patients with an acute ischemic stroke

15. 15 1 U pregulation of matrix metalloproteinase 2 L oss of inhibitory interneurons using gamma-aminobutyric acid (GABA) 3 Enhanced disruption of the blood–brain barrier 4 Direct neurotoxic effects by excitotoxicity 5 Excessive nitric oxide formation 6 Recanalization with free-radical production Tan ML, Ng A, Pandher PS, Sashindranath M, Hamilton JA, DavisSM, et al.Tissue plasminogen activator does not alter development of acquired epilepsy. Epilepsia 2012;53:1998–2004. Lekoubou A, Awoumou JJ, Kengne AP. Incidence of seizure in stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta analysis. IntJStroke2017;12:923–31 Possible neurotoxic effects of tPA NEUROTOXIC EFFECTS DISCUSSION

16. Activation of brain - derived neurotrophic factor P roposed neuroprotective effects include the following 16 NEUROPROTECTIVE EFFECTS DISCUSSION Inhibition of apoptosis (at low concentrations) Stabilization of neuronal energy supply during metabolic stress Tan ML, Ng A, Pandher PS, Sashindranath M, Hamilton JA, DavisSM, et al.Tissue plasminogen activator does not alter development of acquired epilepsy. Epilepsia 2012;53:1998–2004. Lekoubou A, Awoumou JJ, Kengne AP. Incidence of seizure in stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta analysis. IntJStroke2017;12:923–31

17. 17 ASSOCIATION DISCUSSION S ome of them showed a significant association with early or late PSS , some others not Clinical studies Lekoubou A, Awoumou JJ, Kengne AP. Incidence of seizure in stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta analysis. IntJStroke2017;12:923–31 An incidence of early seizure per 1000 of 34 (95% CI: 22–50) among patients receiving rtPA compared with 36 (95% CI: 25–48) among patients not undergoing this reperfusion treatment. S ystematic review Authors : there is an “inconclusive suggestion that rates are similar inrecombinant tissue plasminogen activator-treated and recombinant tissue plasminogen activator naïve patients” Need for large prospective studies to better elucidate the association between rtPA and the occurrence of PSS

18. 18 CASE CONTROL STUDY DISCUSSION Case Control + More appropriate and sensitive than a prospective cohort study to investigate the association between a certain exposure and a rare event Superior to prospective studies in detecting a possible association between reperfusion therapies and early PSS. + - Prone to biases and our results should be interpreted with some caution, particularly because of the retrospective nature of the study

19. 19 STROKE SEVERITY DISCUSSION F ound to be associated with seizures only in the univariate analysis 1 2 The i.v. thrombolysis was performed more frequently in most severe cases  selection bias 3 More frequently in the first years of the study period but unlikely to have occurred in most recent years 4 Pa tients with reperfusion therapies are frequently evaluated in the emergency department earlier  ascertainment bias Stroke severity

20. 20 CORTICAL STROKE INVOLVEMENT DISCUSSION 1 Cortical stroke involvement was also associated with the occurrence of early PSS 2 Consistent with data from epidemiological studies 3 Cortical localization is a major risk factor for seizure occurrence 4 The role of the neocortex in seizure generation Beghi E, D'Alessandro R, Beretta S, Consoli D, Crespi V, Delaj L, et al. Incidence and predictors of acute symptomatic seizures after stroke. Neurology 2011;77:1785–93.

21. CONCLUSION 21 There is a possible association between i.v. thrombolysis or cortical stroke localization and the occurrence of early PSS 1 This association was not explained by stroke etiology or severity, nor by hemorrhagic transformation or hemorrhage following i.v. thrombolysis. 2 Further studies are required to draw definite conclusions on the relationship between different reperfusion therapies and the occurrence of early PSS and poststroke epilepsy. 3

22. THANK YOU 22