{"id":1656,"date":"2015-05-07T11:15:11","date_gmt":"2015-05-07T11:15:11","guid":{"rendered":"https:\/\/touchneurology.com\/2015\/05\/07\/experimental-and-clinical-approaches-to-recovery-after-stroke\/"},"modified":"2015-05-07T11:15:11","modified_gmt":"2015-05-07T11:15:11","slug":"experimental-and-clinical-approaches-to-recovery-after-stroke","status":"publish","type":"post","link":"https:\/\/touchneurology.com\/stroke\/journal-articles\/experimental-and-clinical-approaches-to-recovery-after-stroke\/","title":{"rendered":"Experimental and Clinical Approaches to Recovery after Stroke"},"content":{"rendered":"

Stroke is one of the leading causes of death and disability in developed and less-developed countries.1,2<\/sup> Effective therapeutic approaches to brain protection and recovery in stroke remain elusive, due to an incomplete understanding of the endogenous neurobiological processes involved in repair and a consequent inability to adequately stimulate them.3<\/sup> Many trials of neuroprotective therapies for ischaemic stroke over the past 2 decades have failed, largely due to a failure to recognise the complexity of stroke and the repair processes involved in recovery.4\u20137<\/sup> <\/p>\n

Various factors alter stroke severity, rehabilitation and outcomes. These include co-morbidities, such as diabetes and cardiovascular disease, and other factors, such as stress.8\u201312<\/sup> Imaging techniques such as positron emission tomography (PET) and animal model studies are increasing knowledge of pathophysiology and the neurorehabilitation process.13,14<\/sup> These studies also indicate targets for new drugs and alternative roles for existing therapies, particularly those that enhance brain repair processes. Furthermore, non-invasive brain stimulation (NIBS) can stimulate recovery at specific brain regions.15<\/sup> In addition, emerging biomarkers have the potential to identify risks in stroke and inform treatment strategies.16<\/sup> Adequate stroke rehabilitation services at treatment centres are critical in improving outcome but the these are often under-resourced.17<\/sup> Better outcomes in stroke can also be achieved using current best practice, the application of which can be assisted by meta-analyses of multiple clinical trials.<\/p>\n

This article presents important information on current experimental models and clinical approaches to recovery and rehabilitation after stroke, based on presentations given at the 3rd International Salzburg Conference on Neurorecovery (ISCN) in September 2014.<\/p>\n

Non-invasive Brain Stimulation in Rehabilitation after Stroke <\/b>
NIBS techniques that represent a promising new area of therapy for post-stroke recovery and affect the specific and localised interactions between the brain hemispheres that determine recovery of a patient, were reported by Professor Wolf-Dieter Heiss from Cologne, Germany. He stressed that these methods are derived from two main principles: transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS).15<\/sup> rTMS allows for very precise, focal and noninvasive electrical manipulation of nervous tissue, including the cerebral cortex, spinal roots and cranial as well as peripheral nerves.18<\/sup> The effects of NIBS, the interaction in functional networks and their reorganisation in recovery after focal brain damage can be visualised using functional imaging PET and functional magnetic resonance imaging (fMRI).13<\/sup> <\/p>\n

Within the lesional area in ischaemic stroke there is the core zone that is, for the most part, irreversibly damaged but this is surrounded by the penumbra or peri-infarct, which is ischaemic but is still potentially viable and can be recovered if reperfused rapidly.19<\/sup> Interventions enabling reperfusion can limit the spread of damage and protect neurological function. In some instances the unaffected hemisphere inhibits the recovery of ipsilateral functional networks but this effect of transcallosal inhibition can be reduced by NIBS methods, such as contralateral inhibitory rTMS.20<\/sup> <\/p>\n

Motor recovery stimulation following stroke has been mainly performed using an rTMS approach. Studies have employed diverse time windows for initiating treatment, ranging from 5 days to 7 years post-stroke.21<\/sup> In a review of 22 studies including 307 patients, motor functions improved after NIBS, clinical effects were highly variable depending on patient characteristics but all the improvements were maintained until the end of the observation periods.22,23<\/sup> In addition, early stimulation following stroke was more beneficial than late stimulation.<\/p>\n

Aphasia affects more than a third of all stroke victims and is one of the most disabling functional defects after ischaemic stroke. It improves during the first 4 weeks in one-third of patients, increasing to approximately half after 6 months. Speech and language therapy (SLT) is the only effective treatment to date, but this is usually limited in duration and intensity and should be provided early.24<\/sup> NIBS is an important approach to address aphasia: rTMS modulates cortical excitability, has been shown to suppress naming function and can facilitate language recovery in aphasic patients (see Figure 1<\/i>).20<\/sup> <\/p>\n

NIBS acts on specific networks involved in the pathophysiology of language processing and promotes adaptive cortical reorganisation after stroke. Rehabilitation of post-stroke aphasia involves two strategies: recruitment of perilesional cortical regions in the dominant (left) hemisphere and development of language ability in the non-dominant (right) hemisphere. The majority of NIBS trials in post-stroke aphasia aimed to reinforce the activity of brain regions in the left hemisphere due to more effective recovery in strokes involving this side.25<\/sup> This can be achieved using an excitatory NIBS protocol to reactivate the lesioned area or an inhibitory NIBS protocol to reduce activities in the contralesional homologous area. <\/p>\n

Professor Heiss concluded that further developments are needed to firmly establish NIBS protocols in the treatment of stroke. These include larger-scale brain-stimulation studies for post-stroke recovery, as well as early intervention, ideally within the first 2 weeks post-stroke in stroke units rather than rehabilitation centres. Furthermore, NIBS should always be combined with rehabilitation and pharmacological therapy. Future studies should directly compare tDCS and rTMS or excitatory versus inhibitory protocols. The trials should also further explore advantages of contralateral inhibitory protocols that include better localised stimulation site but have no direct infarct influence and no risk of seizures. <\/p>\n

Co-morbidity and Stroke Outcomes <\/b>
Stroke patients have many co-morbidities, which can influence prognosis8 and should be taken into account during evaluation and treatment, as emphasised by Professor Jaakko Tuomilehto from Helsinki, Finland, and Krems, Austria. Appropriate measures must be undertaken to properly evaluate co-morbidity bias in the clinical trials. A recent systematic literature review of 26 studies (acute myocardial infarction n=8; heart failure n=11; stroke n=7) that measured co-morbidity in cardiovascular research concluded that \u201c\u2026measurement of co-morbidity remains limited to a list of conditions without stated rationale or standards, increasing the likelihood that the true impact is underestimated\u201d.26<\/sup> <\/p>\n

The importance of co-morbidity was emphasised in an analysis of a cohort of 451 patients with ischaemic stroke, which revealed an interesting correlation between stroke outcomes and periventricular white matter disease (PVWMD).27<\/sup> Severe PVWMD was significantly associated with poor functional outcome at 3 months, independent of other factors, such as diabetes and age. Outcome at 3 months was also a significant predictor of long-term mortality and functional recovery. <\/p>\n

The investigation of patients with ischaemic stroke in neurologic rehabilitation (INSIGHT) registry was the first to provide large-scale data on patients with acute stroke (<3 months) who survived the initial phaseof high risk and were undergoing neurological in-patient rehabilitation (n=1,167).28<\/sup> Analysis of registry data demonstrated a significant association between microalbuminuria (MAU) and polyvascular disease and supported previous findings that MAU predicts cardio-\/cerebrovascular events in patients recovering from ischaemic stroke. MAU could therefore be used as a biomarker during neurological in-patient rehabilitation, identifying patients with increased risk of recurrent events. <\/p>\n

Acute ischaemic stroke (AIS) and diabetes appear to be correlated in both children and adults. This was emphasised in a study in Finland in which the cumulative incidence of stroke in childhood onset type 1 diabetes patients with nephropathy was 20 % at age >40.29<\/sup> In the Nationwide Inpatient Sample, hospital admissions in the US for AIS between 1996 and 2007 decreased but there was a steep rise in the proportion with comorbid diabetes (from one in five to almost one in three).12<\/sup> <\/p>\n

Finally, Professor Tuomilehto concluded that these examples and others suggest that co-morbidities should be taken into account in the evaluation and treatment of stroke patients. <\/p>\n

Organisation of Stroke Rehabilitation Services <\/b>
Professor Michael Brainin reported that the use of health care resources for stroke rehabilitation has been greatly influenced by local availability but is often under-resourced.17<\/sup> This was emphasised by the GAIN trial that assessed 1,422 patients (from 19 countries), which found that any link between resources used and outcomes is unclear and showed a threefold variation in the average number of days in hospital\/institutional care (20 to 60 days).30<\/sup> Additionally, there was no relationship between health care resource use and survival or activities of daily living (ADL) at 3 months. <\/p>\n

In Austria and Germany, a phase system has been developed that involves institutional rehabilitation linked directly with acute stroke care.31<\/sup> This system is based on a continuous flow of competences from acute treatment (Phase A) to outpatient and community rehabilitation (Phase E) and has been used to justify the establishment of large rehabilitation clinics. In some Western countries, stroke units are now considered essential platforms on which other important therapeutic means are delivered and around which the major progress in stroke management has been made in recent years. In other Western countries, however, outpatient rehabilitation centres play major roles. The Cochrane Outpatient Service Trialists systematic review showed that therapy for patients with stroke who live at home could prevent deterioration in ADLs (absolute reduction in risk of deterioration was seven per 100 patients) but concluded that the best delivery model could not be identified.32<\/sup> <\/p>\n

Early mobilisation post-stroke has been regarded by many physicians as an important element of rehabilitation services. This is supported by animal models of stroke recovery and currently available clinical data that suggest that spontaneous biological recovery occurs very early and lasts probably up to 3 months post-stroke. Findings of the recently completed AVERT study, however, appear to be contrary to this principle (see Figure 2<\/i>).33,34<\/sup> This study followed-up patients who received very early mobilisation\/higher treatment dose, within 24 hours of their stroke (n=1,054) compared with patients who received \u2018usual care\u2019 (n=1,050) consisting of an early, lower dose out-of-bed activity regimen. Three months after stroke, fewer patients in the very early mobilisation group had favourable outcomes than those in the \u2018usual care\u2019 group (46 % versus 50 %; p=0.005). These results suggest that \u2018usual care\u2019 is preferable to very early mobilisation\/higher dose intervention, but clinical recommendations on this require more investigation and analysis. <\/p>\n

Major efforts are in progress to classify and unify stroke rehabilitation services worldwide and build on the 2004 WHO International Classification of Functioning, Disability and Health for Stroke, which defines the spectrum of post-stroke disabilities.35<\/sup> Additionally, the Global Stroke Community Advisory Panel recently developed guidelines that identified promising areas of stroke rehabilitation:36\u201338<\/sup> <\/p>\n