Objective:

To review the early thoughts and research on thrombolysis as an acute intervention for Acute Ischemic Stroke (AIS).

Background:

The pathophysiology of AIS was first reported by Johann Jacob Wepfer in 1658 based on autopsy studies. The advent of cerebral angiography in the early 1900’s initially made it possible to visualize intracranial vessel occlusion in live patients. Development of biological agents with thrombolytic activity raised interest as a possible AIS treatment.

Design/Methods:

We conducted a PubMed search to historically review the earliest research and thoughts on thrombolysis for AIS.

Results:

Perhaps the earliest trial of thrombolytic treatment for AIS was reported by Sussman and Fitch in 1958 with 3 patients treated by intravenous fibrinolysin. One had some clinical and angiographic improvement of a middle cerebral artery occlusion and the authors astutely noted shorter duration of symptoms and likely embolic nature of the stroke as key factors. Trials of IV streptokinase in 1964 and urokinase in 1976 demonstrated no clinical improvement and available autopsy results suggested increased hemorrhage leading to increased mortality. The first major publication regarding CT for stroke was in 1975 and increasing availability dramatically changed the landscape and allowed improved patient selection. Subsequent trials of streptokinase, urokinase and recombinant tissue Plasminogen Activator (rtPA) in the European Cooperative Acute Stroke Study (ECASS) trial were negative. The National Institute of Neurological Disorders and Stroke (NINDS) trial in 1995 demonstrated a clinical benefit of rtPA in the treatment of AIS within 3 hours of symptoms onset. Subsequent research has led to eligibility expansion and tenecteplase as an alternative agent.

Conclusions:

True to the initial conclusions of Sussman and Fitch in 1958, key paradigms for successful pharmacological stroke treatment—such as the importance of time from symptom onset and makers of disease severity—remain crucial factors for advancing, patient selection, and drug development in thrombolytic reperfusion therapy.