The proportional recovery rule for stroke revisited

Most motor recovery occurs in the first 3 months after stroke. This is often referred to as spontaneous biological recovery (SBR), a process that has been both underinvestigated in humans and underexploited with respect to neurorehabilitation. Data from animal models suggest that SBR is attributable to a unique timelimited period of enhanced postischemic plasticity. In 2008, we defined recovery as the difference (D) between impairment in the few days after stroke and at a later time point (3 months). We reasoned that SBR, being a process, is best reflected in a change rather than in a final endpoint. Our original finding was that SBR, in the majority of patients, follows a proportional recovery rule. Impairment was measured with the Fugl-Meyer Scale (FM), which assesses the ability of the patient to move individual joints out of synergy and therefore captures both motor control and strength. For the upper limb, the maximal score is 66. The proportional recovery rule states that, at 3 months, patients should get approximately 70% of their maximum potential recovery back. So, for example, a patient with moderate hemiparesis of 46 will recover (66-46) 3 0.7, which equals 60. This rule has since been validated for motor recovery in two subsequent studies, and we have shown that it appears to also be true for aphasia recovery. Interestingly, a subset of patients with severe hemiparesis (FM <20) fails to show proportional recovery. That is to say, whereas some patients with severe hemiparesis recover proportionally as all others, some are nonrecoverers. In contrast, patients with mild-to-moderate hemiparesis always recover to nearly the same degree. Thus these two findings—the rule itself and its failure in a subset of patients with severe hemiparesis—led us to two conclusions: (1) The existence of the rule implies that current rehabilitation methods in the first 3 months after stroke have little or no impact on recovery from impairment above what is expected from SBR, and (2) there is something categorically different between severe patients who do recover and those who do not. Specifically, we conjectured that recovery requires reorganization, which takes time, but this reorganization ultimately requires access to muscles through the corticospinal tract (CST). If the CST is interrupted too much, then no amount of cortical reorganization will make a difference. Accordingly, we predicted that the dichotomy between recoverers and nonrecoverers might map onto patients who do or do not have measurable motor-evoked potentials (MEPs) using transcranial magnetic stimulation (TMS). In two studies published in this issue of Annals of Neurology, two approaches have been taken to find CST-based predictors of recovery versus nonrecovery in patients with severe hemiparesis. Before describing the two studies, it is important to first examine the proportional recovery rule itself a little more carefully given that there are potential concerns when the same measure, initial impairment (FM0), is correlated with itself plus another term, final impairment (FM1), that is, the relationship between FM0 and FM1 2 FM0. Measuring FM0 and FM1 with error, FM0 1 e0 and FM1 1 e1, can induce positive correlations between initial impairment and the change in impairment, even when there is either no true recovery or true recovery that is unrelated to initial impairment. This correlation arises from the appearance of the error e0 in measured initial impairment, FM0 1 e0, and in the measured change in impairment, D 5 (FM1 1 e1) 2 (FM0 1 e0). However, the induced correlation will be small when the variability in true initial FM0 impairment is large compared to the variance of the measurement error e0, as is the case for FM, which has good reliability. Given low measurement error variance, it is reasonable to interpret D as true biological change. In contrast, high correlations between FM1 and FM0 are expected whether or not D is related to initial impairment. Although this correlation is not spurious, given that it accurately reflects the fact that patients with lower-than-average initial FM will have lower-than-average final FM, it does not directly address recovery. For this reason, we, and others subsequently, prefer to model D rather than FM1. Finally, when using measurements that have a constrained range, it is important to consider ceiling effects. Thus far, such effects have not been observed: Substantial room for improvement remains for all but the least affected subjects. A related concern is that FM measures latent “true recovery” nonlinearly. For example, a change from FM0 5 56 to FM1 5 61 (D 5 5) may reflect the same degree of “recovery” as a change from FM0 5 36 to FM1 5 51 (D 5 15). In this hypothetical scenario, true recovery is constant (and therefore unrelated to initial impairment), but the observed data are consistent with proportional recovery. This possibility, however,