Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia

Although there is worldwide consensus among disease experts and independent regulators regarding the utility of IV tissue plasminogen activator (tPA) for acute ischemic stroke (AIS), there is concern about administering IV tPA to patients who present with clinical features suggestive of AIS but have an alternative diagnosis.¹ AIS causes neurologic deficits that commonly occur in other disorders² for which tPA has no benefit and may carry an increased risk for hemorrhage. When patients present to the emergency department (ED) with acute neurologic deficits, time is important to make a rapid evaluation if IV tPA is being considered.³ The short time window of 3 hours from symptom onset to administer tPA (per Food and Drug Administration label) may not allow physicians to make a correct diagnosis. A quick history and neurologic examination, often with the NIH Stroke Scale (NIHSS), along with a CT scan to rule out hemorrhage, comprise the main components of the evaluation. Such an approach may miss several other disorders that mimic stroke or cannot reliably differentiate conditions that masquerade as stroke, such as seizure, complicated migraine, or functional deficits. Does specificity matter in patients presenting with suspected stroke once a brain hemorrhage has been ruled out? Many would argue that it is wrong to give a treatment that is potentially dangerous to patients who do not have the target disease.⁴ Vascular imaging with CT angiography, magnetic resonance angiography, or transcranial Doppler ultrasound can visualize large artery occlusions and diffusion-weighted imaging (DWI) is highly sensitive to detect ischemic stroke, but these modalities are not universally available at primary and community hospitals.

In the absence of additional imaging, it is estimated from studies that 3%–7% of patients treated with IV tPA for assumed acute cerebral ischemia have a stroke mimic (SM).^5,6 However, these studies collectively reported 13 patients with SMs who were treated with tPA. No large study has addressed the question of safety of thrombolysis in patients with SMs or in patients who did not have an infarct on MRI and were not found to have another diagnosis aside from stroke (i.e., averted stroke). Herein, we report a retrospective study of over 100 patients who presented to our ED with symptoms concerning for acute cerebral ischemia but who ultimately were found to have an SM or who had no supporting evidence for stroke on subsequent imaging and were discharged with an averted stroke, which we call neuroimaging-negative cerebral ischemia.

METHODS

RESULTS

Over the study period, we treated 512 suspected stroke patients with full dose IV tPA (0.9 mg/kg). A total of 106 (21%) were not found to have an infarct on posttreatment DWI obtained within 1 day of hospitalization and subsequent posttreatment CT or MRI performed 24 hours after admission. Among the 106 patients, 69 had an SM (14% of the 512 patients) and 37 (7% of the 512 patients) had NNCI. Twelve patients were excluded from analysis because they did not undergo follow-up posttreatment neuroimaging. Follow-up MRI after 24 hours was done in 64% of patients, follow-up CT was done in 79%, and both a follow-up MRI and CT was done in 44% of patients.

Etiologies of SM.

Etiologies of SM are shown in the figure. The most common etiologies in the SM group were seizure (38%), complicated migraine (37%), and conversion disorder (21%). Case vignettes for each of these conditions are provided in appendix e-1 on the Neurology® Web site at www.neurology.org. In those patients diagnosed with a seizure, 2 patients presented with a history of motor activity before IV tPA administration and the rest of the patients had, during hospitalization, witnessed motor activity consistent with a seizure, an EEG showing epileptiform features explaining the presenting symptoms, or symptoms that resolved with IV Ativan but not tPA. There were single cases of aseptic meningitis, heatstroke, cardiac syncope due to arrhythmia, and spinal epidural mass.

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Figure Etiologies of stroke mimics

DISCUSSION

It is of paramount importance to study the safety of IV tPA in patients with suspected acute cerebral ischemia who are ultimately found on hospital workup not to have a stroke. Within 3 hours after the onset of symptoms, it may be difficult to determine whether acute neurologic signs are due to stroke or to another cause. ED physicians are uncomfortable differentiating a hemiplegic migraine, for example, from stroke.⁴ The concern is that exposing patients who do not have ischemic stroke to an added risk of hemorrhage with tPA is inappropriate.⁴

Over a 4-year period, we discovered that 21% of our patients who had presented to our ED with symptoms suggestive of acute cerebral ischemia and had received Food and Drug Administration– approved IV tPA did not have a confirmed infarct on subsequent DWI. Among all treated patients, the incidence of SM was 14% and NNCI was 7%. Our stroke center has a wide referral base and a high volume of hyperacute patients with neurologic problems requiring emergency stroke workup to consider administration of standard of care IV tPA. The incidence of SM in our patient population is higher than other reported studies, which might reflect a greater number of patients referred and evaluated for thrombolysis, and possibly a lower threshold to treat with IV tPA at our center. Our treatment approach is to consider any patient for thrombolysis with a measurable deficit that is disabling such as a mild hemiparesis. In addition, we used serial monitoring of patients with imaging as part of the definition of SM and NNCI groups. All SM and NNCI patients had follow-up posttreatment neuroimaging. Previous studies did not consistently use posttreatment imaging as a selection criterion for SM.^5,6,8 Our method to define SM may be a limiting factor to determine the actual SM rate among hospitals without primary stroke centers.

To our knowledge, this is the largest reported series of patients with SM treated with tPA. In contrast to patients with AIS, they were younger, were more often women, and had significantly lower admission NIHSS scores. SM patients had a more favorable functional status and disposition at discharge compared with AIS patients. Other studies with a smaller sample number have not found demographic differences between AIS and SM patients.⁵ SM patients were diagnosed with a variety of territorial syndromes: right and left MCA, posterior circulation, and subcortical presentations. A prior study of 7 treated SM patients found mainly left MCA symptoms. Consistent with prior studies,^5,6,8 the main SM etiologies were seizures, migraine, and conversion disorder. However, we also treated patients with tPA who were subsequently diagnosed with aseptic meningitis, a cervical epidural mass, and cardiac syncope.

Neuroimaging before and after treatment in the absence of an alternative diagnosis other than acute cerebral ischemia allowed us to distinguish an NNCI group from the SM group. Rapid, sometimes dramatic recovery from stroke-like syndromes within 24 hours after IV thrombolysis has previously been reported.^6,9 As per the WHO criteria, acute focal deficits resolving after treatment might be described as TIAs. Such patients may have recanalized rapidly after tPA before imaging could show damage. These patients have also been described as having an averted stroke.¹⁰ Our findings are in agreement with a recent study showing that tPA was safe to administer in 23 patients with suspected cerebral ischemia who were found not to have an infarct and were diagnosed with TIA.¹⁰ Alternatively, small strokes may not be detected on neuroimaging, including DWI. False negative DWI studies have been described in acute ischemic stroke within the first 24 hours of symptom onset in which follow-up studies confirmed the “missing” infarct.¹¹ However, in our dataset, all patients had imaging not only before treatment but at least 24 hours after treatment. Given the absence of an infarct and that no diagnosis other than averted stroke could be found, we believed this condition merited its own category separate from SM. Pretreatment vascular studies and perfusion imaging would have been helpful to better define if NNCI patients had evidence for ischemia or evidence for recanalization after thrombolysis. It is also possible that some patients in this group had a nonischemic etiology that was not found during hospitalization.

Despite finding that we gave IV tPA to 14% of patients with suspected acute cerebral ischemia who were ultimately diagnosed with an SM, we found no instances of symptomatic or systemic hemorrhage despite a range of nonstroke diagnoses. It may not be surprising to have found no instances of sICH in these patients since they did not have a stroke. Patients treated with IV tPA for acute myocardial infarction have less than 1% incidence of intracerebral hemorrhage, and the tPA dose for stroke is lower.¹² The patient who presented with a cervical epidural mass and acute focal deficits required surgery, during which it was found that the mass had bled after tPA. However, we believe the patient's symptoms did not worsen because of the hemorrhage. Most patients with SM and NNCI had shorter hospital stays, significant improvement on the NIHSS score, and excellent functional outcomes.

This study has important limitations including its retrospective design and single center experience from a comprehensive stroke center. Therefore, extrapolating the results to community hospitals with lower volumes of stroke patients must be done with caution. The small sample size may possibly introduce sample and selection bias. In the National Institute of Neurological Disorders and Stroke trial,⁷ the rate of ICH in the treated group was 6.41% (95% CI 3.69%–9.13%). Thus, the margin of error with a 95% CI was 2.72%. The sample size needed to obtain this rate is 312. Thus, while our sample of 405 AIS patients is adequate to observe the same rate of ICH as in the National Institute of Neurological Disorders and Stroke trial with at least 95% confidence, the sample size in our study of SM and NNCI patients was not powered to detect such a difference. Thus, this retrospective study is vulnerable to type II error. Certain patients were excluded from our analysis if they were unable to undergo MRI secondary to large body size or presence of implants. While our study suggests that the safety risk is low in patients who later turn out to have an SM, our data should not be used to excuse a less than thorough evaluation. All patients enrolled in this study and treated with tPA met published Food and Drug Administration and American Heart Association guidelines for treatment, and we do not advocate that these criteria should be shortcut. However, even if these criteria are followed, the diagnosis of stroke will remain based on clinical judgment. Our data would support that if the clinician thinks that the patient may be experiencing a stroke, and the patient meets accepted guidelines, the patient should be treated.

Overall, our data together with others^5,6,10 support administering IV tPA to patients presenting in the 3-hour window with suspected AIS, even when alternate etiologies are being considered. Taken collectively, the preponderance of data from this study and the literature suggests that delaying IV tPA administration in the ED in order to obtain further investigations beyond cranial CT in the form of imaging or EEG may not be warranted, even if the diagnosis ultimately is not AIS. However, some centers are able to rapidly obtain additional testing such as CT angiography with CT or even an MRI in the ED setting. Because the risk of emergently treating SMs such as migraine are low, and there is loss of potential benefit in withholding treatment if the patient is indeed having a stroke, we favor IV tPA treatment if the patient meets Food and Drug Administration and American Heart Association criteria for thrombolysis. Subsequent studies after tPA initiation can be performed to better clarify the etiology in cases where the diagnosis is uncertain. Further prospective investigations are needed to establish the safety of thrombolysis in SM and NNCI.

DISCLOSURE

Dr. Chernyshev, Dr. Martin-Schild, Dr. Albright, Dr. Barreto, Dr. Misra, and Dr. Acosta report no disclosures. Dr. Grotta serves on a scientific advisory board for Lundbeck, Inc.; serves on the editorial board of the International Journal of Stroke; holds US Patents 6,500,834, 6,503,915, and 6,503,916 (issued: 1/7/03): A Composition and Method for Treatment of Cerebral Ischemia and received a license fee payment from InnerCool technology; receives royalties from the publication of Acute Stroke Care: A Manual from the University of Texas–Houston Stroke Team (Cambridge, 2007) and Stroke: Pathophysiology, Diagnosis, and Management (Churchill Livingstone, 2004); has received speaker honoraria for lectures not sponsored by industry; and receives research support from the NIH/NINDS (P50 NS 044227 [PI], R01 NS052971 [Co-I], P01 NS046588-02 [Co-I], and T32-NS0074212-11 [PI]) and from the Burnett Family Stroke Fund, and from the Harold Farb Research Fund. Dr. Savitz serves on a scientific advisory board for Grupo Ferrer Internacional S.A.; has received travel expenses and/or honoraria for lectures or educational activities not funded by industry; serves as an Associate Editor of Experimental and Translational Stroke Medicine; has received honoraria from Johnson & Johnson; and receives research support from Athersys, the NIH R21NS064316 (PI) and R21 HD060978 (PI), the American Heart Association, and the Howard Hughes Medical Institute.