The principle of thrombolysis is based on reperfusion of the ischemic penumbra, the consequence of which is the arrest of infarct growth [15-17]. The prevailing theory states that thrombolysis mediates its action by recanalization, which in turn, is strongly associated with tissue reperfusion [18,19]. This is supported by imaging and angiographic studies demonstrating the correlation between recanalization with reduction in mortality and improved long term functional outcome [20-28]. The DEFUSE study demonstrated that in patients with an ischemic penumbra, 56% of those that showed evidence of early reperfusion had a favourable outcome [16].

Table 1. Various definitions of rapid recovery.

Conversely, in the cohort without early reperfusion only 19% showed a good functional outcome, a finding mirrored in numerous studies [31,32]. As recovery is strongly associated with vessel recanalization, it stands to reason that early recovery is likely a consequence of early recanalization.

However, recent research has cast doubts over the role of recanalization as the sole determinant of early recovery. Alexandrov et al. showed that of 73 patients that experienced early recanalization post thrombolysis, 37% showed no early improvement, and 23% had suboptimal outcomes at 3 months [33]. Similar discordance has been shown in intra-arterial and mechanical retrieval studies where despite early recanalization rates of 70% and 81% respectively, only 34% and 25% of patients experienced a good outcome [34,35]. This demonstrates that a proportion of patients with early recanalization do not have early recovery, suggesting that there are other factors at play. The literature provides two major hypotheses that perhaps give some explanation for the discrepancy: 1) despite early recanalization, there is a lack of perfusion downstream; and 2) despite early recanalization, early recovery is delayed due to “stunning”.

Recanalization does not definitively imply effective reperfusion. In fact, there are numerous means in which recanalization of the primary arterial occlusive site can result in failure of distal reperfusion such as downstream embolization, blockage of microcirculation with nonreflow phenomenon, or rapid infarction before recanalization [22,36,37]. The latter concept warrants some mention as it has had the most examination in the literature. Rapid infarction implies the loss of salvageable ischaemic tissue at the time of recanalization, resulting in non-nutritional reperfusion [22,36]. It is believed that the persistence of collateral supply protects this area from rapid infarction and in doing so allows early recanalization to facilitate early recovery [22,38-40]. It follows that early recanalization without coordination of such factors will not manifest in effective reperfusion and subsequent early recovery or recovery at all.

Alexandrov et al. proposes that this lack of correlation between early recanalization and early recovery may be attributed to the “stunned brain” hypothesis [33]. This theory describes prolonged functional deficit despite reperfusion, due to transient “stunning” after ischaemic insult [41,42]. It has been suggested that the stunning itself may be caused by resolving oedema, reperfusion injury, or delayed improvement of microcirculation in ischemic tissues [43-45]. Proponents of this hypothesis cite the select patient set who despite recanalization have poor short outcomes, but in the long term have favourable functional gains [33].Thus despite early recanalization, the recovery which theoretically should be early, may be delayed.

A low baseline NIHSS score has been shown to be a clinical predictor of rapid neurological recovery. Machumpurath et al. [7] showed that those with baseline NIHSS scores of less than 12 were three times more likely to have early recovery than their more severely affected counterparts. This has been mirrored in other trials [8,12,50].

One mechanism explaining this finding centers on the view that the NIHSS score is a surrogate marker of clot burden [51]. Larger clots would intuitively be less likely to lyse with IV tPA. It follows then that patients presenting with a high NIHSS score and therefore a greater clot burden, would be less susceptible to thrombolysis.

Advancing age is a key risk factor for stroke, and yet thrombolysis in this demographic is associated with poorer outcomes in comparison to the younger patient set [52-54]. IV tPA in the elderly population is associated with less functional gain, an increased risk of Intra-cerebral Haemorrhage (ICH) and a higher rate of mortality [52-54]. Of note, increasing age is also associated with a lower probability of rapid neurological recovery [8]. Dharmasoraja et al. revealed that those less than 70 years of age are twice as likely to experience rapid recovery [8]. Similar results have been reproduced by Brown, Blinzler, Boddu and Machumpurath [6,7,12,55]. This is an intuitive finding reflected in the wider literature regarding age and outcome post stroke.

Hyperglycaemia is a poor prognostic predictor for rapid neurological recovery [7,11,12]. Machumpurath et al. showed that patients with hyperglycaemia on admission were 2.8 times less likely to experience rapid neurological recovery than their normoglycemic counterparts, a finding that was mirrored in other trials [7,9,11]. In fact, hyperglycemia has been associated with not only lower recanalization rates, but lower rates of rapid neurological recovery despite recanalization [56]. Moreover, the deleterious effects of hyperglycemia on stroke outcome as a whole are well documented [2,9,57-60].

Numerous mechanisms have been proposed to explain these findings. Diabetics and patients presenting with hyperglycemia have elevated serum levels of plasminogen activator inhibitor type 1 (PAI-1), a rapid endogenous inhibitor of tPA implicated in lowering levels of active tPA [61-63]. It follows that elevated levels of PAI-1 have been shown to be predictive of not only poor response to thrombolysis and failure of clot lysis, but also worse long term outcomes [61-65]. Although not directly pertaining to thrombolysis, there are two other major mechanisms in the literature explaining this interaction. The first suggests that hyperglycemia itself exacerbates brain injury via intracellular acidosis and increased free radical production, which despite recanalization may render the ischemic penumbra unsalvageable [66]. The second hypothesizes that increased glucose levels are a reflection of stress response and cortisol activation and/or damage to areas involved in glucose regulation [57,67].

Time to treatment is a surprising anomaly. While the fundamental NINDS trial showed the efficacy of thrombolysis to be within three hours of symptom onset, further research has demonstrated a favourable outcome in the 3 - 4.5 hour time window [1,2]. However, it remains that a shorter time to treatment is still associated with better long term outcomes. Lees et al. in their pooled analysis of the ECASS III and EPITHET trials showed that the a favourable three month outcome was inversely proportional to time to treatment with the odds ratio decreasing from 2.55 for 0 - 90 min to 1.22 for 271 - 360 min [68]. While the impact of this predictor is well documented for 3-month outcomes, the effect of time to treatment on rapid neurological recovery has been consistently inconclusive with a large number of studies showing no significant association [6,7,9,11,12,50]. The literature has yet to propose a convincing explanation.

It is well known that atrial fibrillation (AF) is associated with poor prognostic outcome in stroke [69,70]. Studies have shown that thrombolysis in this patient set is associated with poorer long term outcomes [71]. However, studies examining the influence of AF on early recovery post thrombolysis show mixed results. Kimura et al. suggests that AF significantly reduces the likelihood of early recanalization which in turn is associated with poor early recovery [72]. Similarly Blinzler and Dharmasaroja showed that early neurological recovery is more likely in patients without AF [8,55]. While such findings are significant, other studies have shown no correlation between AF and early recovery, emphasizing the need for further examination before any conclusions can be made [6,7, 9-11,73].

The level of disability and likelihood of functional dependence emphasize the significant cost of non-recovery to the individual. A study by Hong and Saver showed that in patients who benefit from thrombolytic intervention there is an associated 4.4 years gain in disability adjusted life years [74]. Examining the cost effectiveness of thrombolysis, Fagan et al. showed that while thrombolysis increased hospitalization costs by 1.7 million per 1000, it reduces rehabilitation and nursing home costs by 1.4 million and 4.8 million respectively [75].

Although the benefit to patients and the community is not in question, the economic burden is still significant, and innovations to reduce the cost of thrombolytic therapy are welcome. One facet of this economic burden is the cost of monitoring during and post thrombolysis. The NIHSS score, the current gold standard for measuring stroke related deficit, involves measuring 15 different components of neurological dysfunction. While undoubtedly effective, monitoring by NIHSS requires a clinician trained in assessment, over numerous time periods pre and post administration of thrombolytic. It has been suggested that automated continuous monitoring of function, in particular motor recovery, can provide a similar measure of outcome with vastly reduced costs [76-78]. Devices such as accelerometers have been shown to be a reliable method of monitoring not only upper and lower limb motor function but also motor hemi-neglect and the integrity of the corticospinal tract [78-80]. In acute stroke these measures have shown moderate to strong correlations with gold standard scores such as NIHSS and the Fugal Meyer assessment arm section [81]. However studies have shown that this correlation disappears with three month outcome scores such as the modified Rankin scale and Barthel Index [82]. Nonetheless, continuous motor measurements have been shown to be reliable in measuring improvement of function in the subacute phase of recovery [78]. This can thus be a valuable tool as unlike current measures it allows direct comparison of acute and subacute functional gains while requiring less skilled clinician assessment.

Rapid neurological recovery predicting favourable outcome has numerous clinical and therapeutic implications, one of which is improved patient selection. This would allow the proportion of patients least likely to respond to IV tPA to be treated with one of many more aggressive therapies. This has been an area of considerable study, looking at different intravenous agents and endovascular intervention.

Tenecteplase (TNK) is being presently studied as an alternative to standard IV tPA for acute ischemic stroke [83]. Initially explored in animal models [84,85], TNK is now validated for use in intravenous thrombolysis for myocardial infarction [86-88]. In fact, clinical pilot studies have demonstrated that TNK efficacy is comparable with tPA in acute ischemic stroke [89]. A promising development, TNK still awaits investigation by a large randomised control trial [83].

Other alternatives with greater evidence for practice include endovascular therapies. Intra-arterial (IA) thrombolysis has been shown to result in higher rates of recanalization when compared with IV tPA studies, but reduced morbidity and mortality at three months only when compared with placebo [90-93]. Indeed, there is no robust evidence of the benefit of endovascular procedures over conventional IV tPA treatment, and as such it is not approved for direct use in patients eligible for IV tPA [94-97]. However select non-responders, that is, patients that fail to respond with IV tPA, are subsequently offered IA “rescue therapy”. This has shown considerable promise. Rubiera et al. showed that 40% of non-responders that received “rescue therapy” were functionally independent at 3 months as compared with only 14.9% of non-responders that were not offered any further therapy [97]. Nonetheless, these therapies have yet to be fully investigated. In particular, the optimal dose for IA therapy is yet to be validated, and there has not been a large randomised study directly comparing IV vs IA thrombolysis [98-100].

Rapid neurological recovery, within the context of these emerging therapies, has implications on treatment. Intravenous tPA is a validated therapy for acute ischemic stroke, and rapid neurological recovery represents the subset with the greatest positive response. Patient selection using the clinical predictors of rapid neurological recovery would permit identification of patients with the greatest potential for benefit from IV tPA. Conversely, the patients least likely to respond to conventional IV tPA (non-responders) could then be treated with more aggressive adjunctive therapies as a first line before they needed “rescuing”, potentially leading to enhanced outcomes.

Lastly, this concept of patient selection could perhaps be extended further. Intravenous tPA is not a therapy without adverse effects (clinically significant side effects include intracerebral haemorrhage, systemic haemorrhage, re-occlusion and anaphylaxis). If further research were to focus on predictors of early recovery to accurately delineate the patient group of non-responders, such patients who stand to have the least benefit need not be exposed to the risks of therapy.