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

We congratulate Chernyshev et al. on their study concerning tissue plasminogen activator (tPA) safety in patients with stroke mimics (SM). [1] In addition to its undeniable value, some methodological issues are controversial.

It is unclear how patients were allocated in neuroimaging-negative cerebral ischemia (NNCI) and SM subgroups. The NNCI group may include TIAs and patients in whom thrombolysis succeeded. The SM group may include patients who did not have a true stroke. This determination often requires advanced parenchymal and vascular exams immediately after admission.

Chernyshev et al. reported that CT scan was the only tool for tissue evaluation before tPA, yet early vascular studies were not mentioned. If the presence of an alternative diagnosis to stroke was the only difference between SM and NNCI definitions, the under-recognition of this alternative diagnosis could misclassify SM patients into the NNCI category.

Misclassification of NNCI patients into the SM subgroup could also occur. Some strokes present with seizures, headache, confusional states, or other clinical pictures that resemble stroke-mimicking conditions. In these patients, a normal CT scan at baseline and early reperfusion may lead to a negative followup neuroimage. However, they do not have a SM.

In our opinion, the reported SM rate of 14% is very high. We reviewed the frequency and outcome of SM among 199 patients treated with IV tPA. [2] As a differential feature, we included acute ultrasonographic findings to the diagnostic algorithm. Up to 14% of patients did not show brain infarction signs at baseline and followup CT but only 2.5% were finally classified as SM. Similar SM rates have been published. [3-5] Furthermore, it would be interesting to know SM rates coming from stroke teams that routinely perform multimodal and vascular patency studies with CT or MRI before thrombolysis. These techniques are very accurate in acute stroke diagnosis.

Fortunately, SM patients are not prone to bleeding and have excellent outcomes. These are the most consistent findings of Chernyshev et al. relative to previous studies. [2-5] Although it seems reasonable to encourage neurologists to administer tPA in patients whose diagnosis is unclear, this recommendation should be approached with caution.

We agree with an expeditious policy to administer tPA. However, growing evidence suggests that baseline complementary exams of brain and vessels may add critical data. Future research must include prospective studies and better selection and classification of patients.

References

1. 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.

2. Martínez-Ramírez S, Vidal A, Querol L, et al. Frequency and ouctome of patients wrongly treated with intravenous thrombolysis. Cerebrovasc Dis 2008;25(suppl 2):27.

3. Scott PA, Silbergleit R. Misdiagnosis of stroke in tissue plasminogen activator-treated patients: characteristics and outcomes. Ann Emerg Med 2003;42:611-618.

4. Hemmen TM, Meyer BC, McClean TL, Lyden PD. Identification of nonischemic stroke mimics among 411 code strokes at the University of California, San Diego, Stroke Center. J Stroke Cerebrovasc Dis 2008;17:23-25.

5. Winkler DT, Fluri F, Fuhr P, et al. Thrombolysis in stroke mimics: frequency, clinical characteristics, and outcome. Stroke 2009;40:1522-1525.

Editor's Note: The Editorialists were offered the opportunity to respond but declined.

Disclosures: Dr. Martínez-Ramírez received funding for travel from Sanofi-Aventis and Ferrer Internacional S.A.; and receives research support from Instituto de Salud Carlos III (from the Ministerio de Sanidad y Consumo) through Ayuda Rio Hortega. Dr. Delgado-Mederos received funding for travel from Sanofi-Aventis and Ferrer Internacional S.A.; and receives research support from the Spanish Ministry of Health (Instituto Carlos III) FIS PS09/00557. Dr. Martí-Vilalta received funding for travel from Sanofi-Aventis; and receives research support from the Spanish Ministry of Health (Instituto Carlos III) FIS PI 051939. Dr. Martí-Fàbregas received funding for travel from Sanofi-Aventis, Boehringer Ingelheim, and Ferrer Internacional S.A.; and receives research support from the Spanish Ministry of Health (Instituto Carlos III) FIS PI071062. All authors are members of RETICS (RENEVAS), which warrants travel funds and research support across the Spanish territory.

We read the article by Chernyshev et al. [1] and the accompanying editorial by Saver et al. [2] with great interest. There have been few reports [3-5] regarding the safety of IV tPA in patients who presented with stroke- like symptoms but ultimately diagnosed with another condition.

The healthy brain—when treated with IV tPA—has a low risk of bleeding and this favors aggressive therapy in this group of patients. We identified 14 (4.3%) cases of stroke mimics from 321 patients treated with IV tPA from 2000 to 2009. Among them, 12 (85.7%) were female; six (50%) patients presenting with non-dominant hemisphere symptoms; and seven (58%) had complete resolution of the symptoms. There were no intracranial hemorrhages in this group.

We agree with Chernyshev et al.'s initial hypothesis that it is reasonable to treat these patients aggressively assuming that the patient may have treatable stroke, even if non-stroke etiology is suspected. Their data, along with our data, may confirm that this aggressive therapy is fairly safe.

Stroke may be suspected because patients are often scared and may exaggerate their deficits. Often, there is not ample time to perform additional imaging (MRI) to confirm the diagnosis of stroke in patients with psychogenic etiologies of acute neurologic deficit. Physicians have to make treatment decisions based on limited information in a short period of time.

When the history and exam are consistent with the diagnosis of stroke and the patient meets all inclusion and exclusion criteria, some patients with stroke mimics would be unnecessarily treated with IV tPA yet the risk of serious complications would be low.

References

1. 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.

2. Saver JL, Barson WG. Swift or sure? Neurology 2010;74:1336-1339.

3. Mouradian MS, Rodgers J, Kashmere J, et al. Can rt-PA be administered to the wrong patient? Two patients with Somatiform disorder. The Canadian Journal of Neurological sciences 2004;31:99-101.

4. Uchino K. Transient Ischemic attack after tissue plasminogen activator: Aborted stroke or unnecessary stroke therapy? Cerebrovasc Dis 2010;29:57-61.

5. Winkler DT, Fluri F, Fuhr P, et al. Thrombolysis in stroke mimics: frequency, clinical Charachteristics, and outcome. Stroke 2009;40:1522-1525.

Editor's Note: The Editorialists were offered the opportunity to respond but declined.

Disclosures: Dr. Mathiesen has received honoraria for speaking on speakers bureau for National Stroke Association, American Association Neuroscience Nurses, and Medivance Corporation. Dr. Castaldo has received honoraria for speaking on the speakers bureau for Merck and Galaxo Corporations. Drs. Isayev, Conahan and Jenny report no disclosures.

We thank Martinez-Ramirez et al. and Isayev et al. for their comments and inquiries. Martinez-Ramirez et al. question whether our patients were correctly assigned to SM and NNCI groups. Although not included in this paper, we routinely perform vascular studies in all admitted patients with suspected stroke by ultrasound, CT angiography, or MR angiography.

Within 3 hours of symptom onset, we typically obtain a CTA with CT if the patient does not have contraindications. Vascular data were taken into consideration in formulating a diagnosis for all patients in this study. However, documenting a vascular occlusive lesion is not sufficient to distinguish an SM versus an NNCI patient because an NNCI patient, by definition, has an averted stroke from recanalization.

The final diagnosis of all our patients was made at hospital discharge when all available data were collected. We doubt SM patients were misclassified as NNCI patients or vice-versa. The diagnosis of NNCI vs SM depends on clinical judgment and cannot be distinguished by imaging alone. While multimodal CT and MRI are invaluable in assisting the clinician formulate an assessment of a patient with a neurological disorder, they do not always identify small vessel strokes, particularly in the posterior circulation. It should be noted that clinicians cannot fully rely on imaging to make a diagnosis.

Disclosures: See original article for full disclosure list.