Wagging the dog--moving closer to features defined by basic scientists, the protection of prodromal transient ischaemic attacks reveals itself.

The ability of organs to integrate a stressful stimulus into a protective response, upon subsequent more profound stress, is an essential and adaptive feature of evolution. Commonly referred to in the basic science literature as ‘ischaemic pre-conditioning’, this protective effect of a minor insult upon the subsequent injury from a more severe event involves endogenous mechanisms in cells and tissue which ultimately increase cell survival. These processes are not, in fact, limited to ischaemic injuries. Rather, low-level exposure to stresses as varied as amyloid beta peptide, oxidized lipids and other stressors are all capable of inducing protection against subsequent injury. The multimodal nature of pre-conditioning speaks to two important considerations. First, these protective pathways are probably highly evolutionarily conserved; secondly, harnessing endogenous protective pathways could potentially allow us to develop therapies which would probably be well tolerated and capable of reducing multiple types of injuries. In fields such as cardiology, pulmonology and nephrology, pre-conditioning tissue chemically and surgically is an area of active clinical investigation, with ongoing trials in each discipline [1]. In neurology, by contrast, only a handful of clinical studies have been presented on this topic, and a consensus has not yet developed that transient ischaemic attacks (TIAs) provide protection against strokes. Whilst several previous publications in stroke strongly suggest a protective period associated with TIA preceding stroke, the protective period remains elusive [2]. Lacunar strokes, which often involve white matter, may not have a similar capacity for ischaemic pre-conditioning [3]. In this month’s issue of the European Journal of Neurology, a team lead by Sheng-di Chen performed a retrospective analysis of 120 patients diagnosed with acute non-lacunar strokes, with or without prodromal TIA(s) [4]. The authors did not find a beneficial effect on the NIHSS differences between admission to discharge when all patients were grouped, but a subgroup of patients with multiple TIAs or TIAs longer than 4 min scored more favourably. This work enhances prior studies in elucidating the spatial and temporal limitations of the protective window provided by pre-conditioning and reminds us of the need for increased understanding of the nature and consequences of TIAs. Given the addition of another cohort supporting pre-conditioning protection by TIA, has the debate been settled? We suspect not, although the evidence for pre-conditioning by TIA’s has been advanced by this work. The available literature has not produced a consensus on the consequences of prodromal TIAs. There remains no definitive study on the topic, with the large cohort size, subject standardization, and imaging data required to build a consensus. The work by Chen and colleagues, however, is one of only a very few studies that begins to build a bridge to the basic science understanding of a phenomenon shown to provide powerful protection in some settings. Modelling of CNS pre-conditioning suggests the robust forms of pre-conditioning protection that are observed in cerebral cortical perfusion models. We have strong evidence that uncontrolled blood sugar or exposure to sulfonylureas to treat diabetes can block the experimentally induced protection [5]. By excluding patients with lacunar TIAs and strokes, the report by Chen’s team provides a valuable exclusion criterion that may explain, at least in part, why some previous studies have not confirmed neuro-protection by TIA’s occurring prior to a stroke [3]. The regional specificity of the ischaemic pre-conditioning effect has been defined, but the temporal specificity of protection has been addressed, without a clear consensus. In basic science models, a much stronger and reproducible effect is observed when TIA-like injury is followed by 24-h prior to stroke [6]. Moreover, the very rapid protection observed in mildly ischaemic peripheral tissue, which has been capitalized on in clinical trials, may not be present in neural tissues. The limited duration of protection has been reported in several studies in which a prodromal TIA <4 weeks prior to stroke is associated with a decrease in infarct volume [7]. Schaller et al. [8] suggested that several TIAs within the week prior to a stroke were strongly associated with a better outcome. The larger issue to be discussed in understanding the protective effect of a TIA would be to imitate the protective effect by introduction of small molecule therapies which regulate targets like heat-shock proteins that play a critical role in ischaemic pre-conditioning [9]. Obviously, no one is going to ‘prescribe’ a TIA for a patient prior to experiencing a stroke, but we may learn to mimic the biochemical effects of a TIA. This research also has implications for the general management of TIA’s. Although an estimated 5% of patients who present with TIAs suffer strokes within 48 h of their initial ischaemic insult [10], there continues to be a failure to rally around TIA as a emergent condition. Without a biomarker of TIA, there continues to be a strong debate over what constitutes a TIA. At present, the paucity of small molecule therapies to protect the brain against stroke may encourage the misperception that little can be performed to protect the brain. The recent EXPRESS study suggested that up to 80% of strokes can be prevented by the emergent evaluation and treatment of patients with TIA [11], yet rapid response systems for TIA are just now being implemented. In a similar vein, fewer than 3% of patients with ischaemic strokes receive IV tPA under the very short window which this drug can be administered, despite the proved benefit of this treatment [12]. We hope the publication by the Chen team will promote an appreciation of the highly at risk population of TIA patients who might have the additional biological advantage of experiencing pre-conditioning protection. These patients are highly underutilized for clinical and basic science investigation and may present our best opportunity to understand and capitalize on the brain’s natural defensive capabilities.