What is the approach to using thrombolytics, such as alteplase (tissue plasminogen activator), in patients with mild stroke symptoms, as indicated by low National Institutes of Health Stroke Scale (NIHSS) scores?

Recent Trials on Low NIHSS and Thrombolytic Treatment

Key Clinical Recommendation

For patients with mild stroke (NIHSS 0-5), treatment with IV alteplase within 3 hours may be considered when symptoms are judged as potentially disabling, but treatment risks must be carefully weighed against possible benefits, as the evidence remains uncertain and recent trials have not demonstrated clear superiority over antiplatelet therapy. 1

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Major Recent Trials and Evidence

PRISMS Trial Context

• The Potential of rtPA for Ischemic Strokes with Mild Symptoms (PRISMS) trial randomized patients with mild stroke to thrombolysis versus aspirin and did not show benefit from thrombolysis 2
• This trial specifically enrolled patients with nondisabling neurologic deficits 2
• The negative results from PRISMS have significantly influenced current clinical uncertainty about treating mild strokes 2

MRI-Based Selection Study (2019)

• A retrospective analysis of 121 patients with NIHSS ≤5 who received thrombolysis after MRI screening showed excellent safety with symptomatic intracranial hemorrhage (sICH) rate <1% 2
• 74% achieved favorable 90-day outcome (mRS 0-1) in the overall cohort 2
• Among 81 PRISMS-eligible patients (nondisabling deficits), none experienced sICH and 84% had favorable outcomes 2
• This suggests MRI selection may identify patients who benefit more safely from thrombolysis 2

NIHSS 0-2 vs 3-5 Comparison Study (2023)

• A prospective registry study of 236 patients compared outcomes in NIHSS 0-2 (n=80) versus NIHSS 3-5 (n=156) groups treated with alteplase 3
• Patients with NIHSS 0-2 had significantly better functional outcomes at discharge (81.3% vs 48.7%, adjusted OR 0.40) compared to NIHSS 3-5 3
• No increase in sICH or mortality was observed in either group 3
• Independent predictors of excellent outcomes included non-disabling stroke (aOR 0.06) and prior statin therapy (aOR 3.46) 3

Lower Dose Alteplase Study (2020)

• A pooled analysis of 3,479 patients examined whether lower doses of alteplase could benefit specific subgroups 4
• For patients with moderate stroke (NIHSS 5-14), lower dose alteplase showed significant sICH reduction (OR 0.13,95% CI 0.02-0.68) with comparable efficacy (OR 1.23,95% CI 0.71-2.13) compared to standard dose 4
• For mild stroke (NIHSS ≤4), the difference in sICH risk was not statistically significant (OR 2.71,95% CI 0.80-7.69) 4
• This suggests that stroke severity should guide dosing considerations 4

Non-Disabling Mild Stroke Study (2023)

• A retrospective analysis of 319 highly selected patients with non-disabling AIS (NIHSS 0-5) compared alteplase-treated versus untreated patients 5
• No difference in 3-month favorable outcomes was found: 82.3% in treated vs 86.1% in untreated patients 5
• Hemorrhagic complications and mortality were infrequent and unaffected by alteplase treatment 5
• This study suggests alteplase, while safe, offers no clear clinical advantage in non-disabling mild stroke 5

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Current Guideline Recommendations

Within 0-3 Hour Window

• Treatment of patients with mild ischemic stroke symptoms that are judged as nondisabling may be considered (Class IIb; LOE C-LD) 1
• Treatment risks should be weighed against possible benefits 1
• The guidelines explicitly state that "more study is needed to further define the risk-to-benefit ratio" 1

Within 3-4.5 Hour Window

• For otherwise eligible patients with mild stroke, IV alteplase may be as effective as treatment in the 0-3 hour window and may be a reasonable option (Class IIb; LOE B-NR) 1
• Treatment risks should be weighed against possible benefits 1
• In ECASS III, only 128 patients with NIHSS 0-5 were included, and they were not analyzed separately 1
• Registry data (SITS-ISTR and GWTG) showed similar good functional outcomes and sICH risk in mild stroke treated in both time windows 1

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Critical Clinical Considerations

Defining "Disabling" vs "Non-Disabling"

• The distinction between disabling and non-disabling symptoms is crucial but remains subjectively defined 1, 2, 5
• One study operationalized non-disabling as: ≤1 point in vision, language, neglect, or single limb items, and 0 points in consciousness 5
• Patients with truly non-disabling deficits may not benefit from alteplase despite its safety 5

Risk of Vessel Occlusion with Mild Symptoms

• Some patients with MCA occlusion present with NIHSS ≤3 6
• A 2004 study identified 5 patients with MCA occlusion and NIHSS ≤3, all of whom were functionally independent at 3 months without thrombolysis 6
• Caution should be exercised in considering thrombolytic therapy in these patients 6
• Perfusion imaging may be required to identify truly "at risk" mild stroke populations 6

Safety Profile

• Symptomatic ICH rates in mild stroke are consistently low (<1-2%) across recent studies 3, 2, 5
• Mortality is infrequent and not increased by alteplase in mild stroke populations 3, 5
• MRI screening may further improve safety by identifying patients with hemorrhagic transformation risk 2

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Clinical Decision Algorithm

Step 1: Assess Stroke Severity and Disability

• If NIHSS 0-2 with non-disabling symptoms: Consider dual antiplatelet therapy (aspirin + clopidogrel) for 21 days as an alternative to thrombolysis 1
• If NIHSS 3-5 with potentially disabling symptoms: Proceed to Step 2
• If NIHSS 0-5 with clearly non-disabling symptoms (isolated sensory deficit, mild dysarthria without functional impact): Alteplase may not offer clinical advantage 5

Step 2: Time Window Assessment

• Within 3 hours: Alteplase may be considered (Class IIb) but weigh risks vs benefits 1
• Within 3-4.5 hours: Alteplase may be reasonable (Class IIb) with similar risk-benefit profile to 0-3 hour window 1

Step 3: Consider Advanced Imaging

• If available, obtain MRI with DWI and MRA to assess infarct size and vessel status 2
• Patients with large vessel occlusion despite mild symptoms may warrant more aggressive consideration of treatment 6
• Perfusion imaging can identify patients with at-risk tissue who may benefit more from intervention 6

Step 4: Risk Stratification

• Prior statin therapy predicts better outcomes (aOR 3.46) 3
• Hyperglycemia >11.1 mmol/L substantially increases sICH risk (36% in one series) 7
• Consider lower dose alteplase (0.6 mg/kg) for NIHSS 5-14 if concerned about bleeding risk, though this is not standard practice 4

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Common Pitfalls to Avoid

Pitfall 1: Treating All Mild Strokes Uniformly

• Not all mild strokes are the same: Distinguish between disabling and non-disabling deficits 1, 5
• A patient with isolated mild dysarthria may not benefit, whereas one with mild hemiparesis affecting dominant hand may be significantly disabled 5

Pitfall 2: Ignoring Vessel Status

• Do not assume mild symptoms mean small vessel disease 6
• Some patients with MCA occlusion present with NIHSS ≤3 and may have good collaterals 6
• Consider non-invasive angiography (CTA/MRA) to assess for large vessel occlusion 7, 6

Pitfall 3: Delaying Decision-Making

• Time is critical even in mild stroke 7
• Do not delay treatment to obtain extensive imaging if patient is otherwise eligible 7
• However, brief MRI screening (if immediately available) may improve patient selection 2

Pitfall 4: Overlooking Alternative Therapies

• Dual antiplatelet therapy (aspirin + clopidogrel) is a reasonable alternative for minor stroke within 24 hours (Class IIa) 1
• This may be preferred for truly non-disabling deficits where thrombolysis offers no clear advantage 5

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Nuances in the Evidence

Divergent Findings

• MRI-selected patients showed excellent outcomes (84% favorable) 2, while unselected non-disabling stroke patients showed no benefit from alteplase 5
• This suggests patient selection criteria significantly impact outcomes 2, 5
• The PRISMS trial's negative results contrast with observational data showing safety 2, 5

Severity Subgroups

• NIHSS 0-2 patients have better outcomes than NIHSS 3-5 regardless of treatment 3
• The benefit of alteplase may be more apparent in NIHSS 3-5 than 0-2 3
• Moderate stroke (NIHSS 5-14) may benefit from lower dose alteplase with reduced bleeding risk 4

Quality of Evidence

• Current guidelines rate the evidence as Class IIb (may be considered/reasonable) with Level of Evidence C-LD to B-NR 1
• This reflects genuine clinical equipoise and the need for individualized decision-making 1
• The most recent high-quality evidence (PRISMS trial) was negative 2, supporting a cautious approach