Appendix e-1 Seizure at Onset

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Appendix e-1
Seizure at Onset

A seizure at the onset of stroke-like symptoms was initially considered a contraindication to IV rtPA, and is still listed as a formal contraindication in the Alteplase insert. This is based on the difficulty of differentiating stroke from Todd’s paralysis. However, these entities are not mutually exclusive: seizures can occur at the onset of an acute ischemic stroke. Little data exists to establish how frequently this occurs, but one study reported acute seizures in approximately 6% of patients presenting with a stroke.1 Furthermore, a recent study showed that rtPA was safe when administered to patients with stroke mimics (n = 69, including 38% of cases in which the mimic was a seizure), with no cases of hemorrhage.2 Current AHA guidelines state that “a patient with a seizure at the time of onset of stroke may be eligible for treatment as long as the physician is convinced that residual impairments are secondary to stroke and not a postictal phenomenon”.3

In a review of 499 acute stroke patients, the off-label administration of thrombolysis was not associated with poorer clinical outcomes, but this study only included 7 patients with seizure at symptom onset. Multimodality brain imaging has guided the decision of administering rtPA in some series.4 In one retrospective study of 326 patients who underwent CT angiogram (CTA), an arterial occlusion was found in 5 of 9 patients with a seizure at onset.5 CT or MR perfusion studies may also be useful in selecting patients for treatment.
In summary, evidence suggests that a seizure at onset of symptoms should not be considered an absolute contraindication to giving IV rtPA to acute stroke patients.
Severe Hypoglycemia or Hyperglycemia

Blood glucose is one of the few mandatory laboratory values deemed necessary when evaluating a stroke patient. The Alteplase insert states that “due to the increased risk for misdiagnosis of acute ischemic stroke, special diligence is required in making this diagnosis in patients whose blood glucose values are <50 mg/dL (2.7 mmol/L) or >400 mg/dL (22.2 mmol/L)”. These values are consensus-driven, likely derived from the NINDS trial.6 Thus, the concern over administering IV rtPA to these patients is mainly because of the possibility that the glucose derangement may be mimicking a stroke. Although hypoglycemia presenting with focal neurological deficits is well described,7-9 this is very rare and symptoms more commonly include altered consciousness or seizures. In one report of 1460 stroke patients, only 0.5% had symptoms mimicking stroke secondary to an abnormal blood glucose concentration.9

Beyond this concern about misdiagnosis, an additional issue is the possibility that hyperglycemia itself exerts adverse effects on the brain. There is some data to suggest that rtPA is not as effective in the setting of hyperglycemia with poorer chances of recanalization, documented after IV thrombolysis and endovascular therapy in hyperglycemic patients. Hyperglycemia in the first few hours after an ischemic stroke has been associated with poorer clinical outcomes and increased risk of ICH. 12-14 However, in an analysis of serum glucose levels at baseline and at 24 hours in patients studied in the ECASS-2 trial, it was persistent or delayed hyperglycemia at 24 hours (rather than hyperglycemia at baseline only) that was associated with adverse outcomes such as worse rates of improvement, increased rates of mortality, and parenchymal hemorrhage.15 Whether these associations are merely epiphenomena of stroke severity or truly represent causal relationships is uncertain.
Thus, there is not sufficient evidence at this point in time to support the exclusion of patients with hypoglycemia or hyperglycemia from receiving IV rtPA for acute stroke symptoms, unless normalization of the blood sugar level is promptly followed by major neurological improvement.
Recent Myocardial Infarction

Myocardial infarction (MI) within the preceding 3 months is a contraindication to giving IV rtPA for acute ischemic stroke according to the most recent AHA guidelines, but not in the European guidelines. Most clinical trials excluded patients with recent MI, though a specific definition of MI is usually lacking. Equally lacking is high-level evidence to support this exclusion criterion. The concern about giving rtPA to these patients is the potential for myocardial hemorrhage predisposing to myocardial wall rupture, and tamponade. Wall rupture is a rare complication of MI and is becoming even less frequent as immediate intervention has become standard for ST segment elevation MI (STEMI). Wall rupture only happens after transmural infarction and usually occurs within 2-5 days of STEMI. Among patients treated with thrombolysis for MI, the incidence of cardiac rupture is estimated to be 1-8%. whereas the risk in non-thrombolyzed patients with MI is estimated to be 1-5%.18 See the e-Appendix for cases of patients with recent MI who received thrombolysis for stroke

There are a handful of case reports of elderly women treated with IV rtPA for stroke who developed cardiac rupture and hemopericardium. Only one of these 5 patients had a well-documented recent MI – a 93 year-old woman who presented with concurrent STEMI.19 Another had coronary artery bypass grafting surgery 16 days before, and another had dyspnea several days prior to presentation with nonspecific changes on electrocardiogram.20 Four of the five were fatal.19-21 Sudden hypotension, occurring approximately 30 minutes to 2 hours after completion of rtPA should raise suspicion for this complication.
Pathologically, myocardial fibrosis and scarring is complete by week 6-7 after an MI. Thus, it has been suggested that the time after an MI to be considered as a contraindication for IV thrombolysis in patients with stroke should be shortened to 7 weeks.18 Patients with non-STEMI, particularly those that do not involve the anterior cardiac wall, may be at lower risk for this complication, but there are no solid data to estimate risks or guide treatment in this subset of patients.
In summary, there is a lack of high-quality evidence to guide clinicians evaluating patients with acute ischemic stroke and recent MI within the time-window for IV thrombolysis. Specifically, there are no sufficient data to pinpoint a specific time-frame in which the risk of rupture of the cardiac wall after IV thrombolysis outweighs the benefit of the therapy. Patients who have suffered a recent STEMI involving the anterior cardiac wall are at highest risk of myocardial rupture. If the stroke is severely disabling, these patients may be better candidates for mechanical embolectomy, which confers a lower risk of systemic hemorrhage.

References for Appendix e-1

1. Shinton RA, Gill JS, Melnick SC, Gupta AK, Beevers DG. The frequency, characteristics and prognosis of epileptic seizures at the onset of stroke. J Neurol Neurosurg Psychiatry 1988;51:273-276.

2. Chernyshev OY, Martin-Schild S, Albright KC, et al. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology 2010;74:1340-1345.

3. Adams HP, Jr., del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007;38:1655-1711.

4. Selim M, Kumar S, Fink J, Schlaug G, Caplan LR, Linfante I. Seizure at stroke onset: should it be an absolute contraindication to thrombolysis? Cerebrovasc Dis 2002;14:54-57.

5. Sylaja PN, Dzialowski I, Krol A, Roy J, Federico P, Demchuk AM. Role of CT angiography in thrombolysis decision-making for patients with presumed seizure at stroke onset. Stroke 2006;37:915-917.

6. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-1587.

7. Vanpee D, Donckier J, Gillet JB. Hemiplegia hypoglycaemia syndrome. European journal of emergency medicine : official journal of the European Society for Emergency Medicine 1999;6:157-159.

8. Foster JW, Hart RG. Hypoglycemic hemiplegia: two cases and a clinical review. Stroke 1987;18:944-946.

9. Berkovic SF, Bladin PF, Darby DG. Metabolic disorders presenting as stroke. The Medical journal of Australia 1984;140:421-424.

10. Ribo M, Molina C, Montaner J, et al. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke 2005;36:1705-1709.

11. Hallevi H, Barreto AD, Liebeskind DS, et al. Identifying patients at high risk for poor outcome after intra-arterial therapy for acute ischemic stroke. Stroke 2009;40:1780-1785.

12. Bruno A, Levine SR, Frankel MR, et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002;59:669-674.

13. Demchuk AM, Morgenstern LB, Krieger DW, et al. Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke 1999;30:34-39.

14. Alvarez-Sabin J, Molina CA, Ribo M, et al. Impact of admission hyperglycemia on stroke outcome after thrombolysis: risk stratification in relation to time to reperfusion. Stroke 2004;35:2493-2498.

15. Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-II trial. Stroke 2008;39:2749-2755.

16. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457-507.

17. Becker RC, Hochman JS, Cannon CP, et al. Fatal cardiac rupture among patients treated with thrombolytic agents and adjunctive thrombin antagonists: observations from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9 Study. J Am Coll Cardiol 1999;33:479-487.

18. De Silva DA, Manzano JJ, Chang HM, Wong MC. Reconsidering recent myocardial infarction as a contraindication for IV stroke thrombolysis. Neurology 2011;76:1838-1840.

19. Dhand A, Nakagawa K, Nagpal S, et al. Cardiac rupture after intravenous t-PA administration in acute ischemic stroke. Neurocrit Care 2010;13:261-262.

20. Kasner SE, Villar-Cordova CE, Tong D, Grotta JC. Hemopericardium and cardiac tamponade after thrombolysis for acute ischemic stroke. Neurology 1998;50:1857-1859.

21. Kremen SA, Wu MN, Ovbiagele B. Hemopericardium following intravenous thrombolysis for acute ischemic stroke. Cerebrovasc Dis 2005;20:478-479.

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