What is the risk of bleeding with tissue plasminogen activator (tPA) in mimic stroke?

Risk of Bleeding with tPA in Mimic Stroke

The risk of bleeding with tissue plasminogen activator (tPA) in stroke mimics is very low, with studies showing no cases of symptomatic intracerebral hemorrhage in most cohorts and overall bleeding rates significantly lower than in true ischemic stroke patients.

Bleeding Risk in Stroke Mimics vs. True Strokes

Intracranial Hemorrhage Risk

• In a large international registry study of 429 stroke mimics treated with tPA, the rates of bleeding complications were significantly lower compared to true stroke patients 1:

  • Parenchymal hematoma: 1.2% in mimics vs. 5.1% in true strokes
  • Symptomatic intracranial hemorrhage (SICH) by NINDS criteria: 0.5% vs. 3.9%
  • SICH by ECASS II criteria: 0.2% vs. 2.1%
  • SICH by SITS-MOST criteria: 0% vs. 0.5%

• Multiple smaller studies have consistently shown minimal to no risk of symptomatic intracranial hemorrhage:

  • No cases of intracranial hemorrhage in a study of 15 stroke mimics 2
  • No intracerebral hemorrhages in a cohort of 38 stroke mimics (12% of all tPA-treated patients) 3
  • Zero cases of symptomatic intracranial hemorrhage in 56 stroke mimic patients (0%; 95% CI, 0% to 5.5%) 4

Systemic Bleeding Risk

• Systemic hemorrhage is also uncommon in stroke mimics receiving tPA:
  • Only 2 systemic hemorrhages (5.2%) reported in one cohort of 38 stroke mimic patients 3
  • The FDA label for tPA notes that serious systemic hemorrhage occurred in approximately 1.6% of patients treated with intravenous tPA in the NINDS trials 5

Common Stroke Mimics Receiving tPA

The most frequent conditions misdiagnosed as stroke and receiving tPA include:

1. Conversion/somatoform disorders (26.8-30.8%)
2. Complicated migraine (17.5-19.6%)
3. Seizures (14.2-19.6%)
4. Headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) syndrome
5. Encephalitis
6. Brain tumors

Clinical Characteristics of Stroke Mimics

Stroke mimics receiving tPA tend to have:

• Younger age (mean 53.7-56 years vs. 66-72 years in true strokes) 2, 4
• Lower baseline NIHSS scores (median 6-8 vs. 8-13 in true strokes)
• Fewer vascular risk factors
• Higher prevalence of left hemisphere symptoms (80% vs. 52.4%) 2
• Global aphasia without hemiparesis as a common presentation (54% of mimics vs. 7% of true strokes) 2

Functional Outcomes

Functional outcomes in stroke mimics receiving tPA are generally excellent:

• 84.1% achieve modified Rankin Scale (mRS) 0-1 at 3 months vs. 57.7% in true strokes 1
• 96% are functionally independent at hospital discharge (mRS 0-1) 4
• Mortality is lower in stroke mimics (2.6% vs. 5.4% in true strokes) 1

Clinical Implications

The American Heart Association/American Stroke Association guidelines acknowledge that stroke mimics are identified in approximately 3-21% of patients treated with fibrinolytics 6. Despite this relatively high rate of misdiagnosis, the guidelines note that there is "no evidence of increased fibrinolytic treatment risk" for these patients.

The safety profile of tPA in stroke mimics suggests that clinicians should not delay or withhold treatment when there is reasonable suspicion of acute ischemic stroke, as the potential benefit in true stroke outweighs the minimal risk in mimics. The 2013 AHA/ASA guidelines specifically state that "the benefit of thrombolysis in case of IS may outweigh the risks of treating an SM" 6.

Pitfalls and Caveats

1. Despite the reassuring safety profile, clinicians should still strive to accurately diagnose stroke through careful clinical assessment and appropriate imaging.

2. The FDA label for tPA lists several contraindications and cautions that should be considered regardless of whether the patient has a true stroke or mimic 5:

   • Previous hemorrhagic stroke
   • Known intracranial neoplasm
   • Active internal bleeding
   • Suspected aortic dissection
   • Severe uncontrolled hypertension (>180/110 mmHg)

3. Multimodal imaging techniques may help differentiate true strokes from mimics, but their use should not delay treatment if a patient otherwise meets criteria for tPA administration.