Clinical Findings and Outcome after Stroke. Including a Translational Stem Cell Therapy Perspective.

Background and Purpose: Stroke is one of the dominant causes of death and adult disability in the world. There is a need for novel therapeutic approaches to improve functional recovery and outcome after stroke, and experimental studies have shown that stem cell-based therapies (SCT) hold much potential in this regard. This thesis, comprising 5 papers, aims to explore and describe clinical symptoms, lesion appearance, and outcome after stroke to provide guidance and enhance possibilities for future clinical implementation of SCT. Methods: In Paper I, a consecutive series of first-ever ischemic stroke patients (n=108) were examined ≤4 days of stroke onset regarding: (i) neuroradiological characteristics, and (ii) stroke severity measured with National Institutes of Health Stroke Scale (NIHSS). In Papers II and V, available survivors (n=84) from Paper I were assessed after 3-5 years regarding: (i) the frequency and recovery of upper extremity motor impairment (UEMI) measured with NIHSS arm and hand motor items; ii) the relation of UEMI to activity limitations measured with modifed Rankin Scale (mRS) and participation restrictions evaluated with Stroke Impact Scale (SIS); and iii) their knowledge and attitude about SCT using a questionnaire on SCT for stroke. In Papers III and IV, 10-year survivors (n=145) from a population-based group of 416 first-ever stroke patients in the Lund Stroke Register were assessed regarding: (i) functional status measured with mRS and Barthel Index (BI); (ii) patient-reported outcome using the European Quality of Life-5 Dimensions (EQ-5D) and Short-Form 36 Health Survey (SF-36), and iii) cognitive function using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), including comparisons with age- and sex-matched non-stroke control persons (n=354) from the population study Gott Aldrande i Skane.Results: In Paper I, the distance between the nearest margin of the infarct(s) to the subventricular zone (a known neurogenic area in the brain) was 0-2 mm in 51/102 patients with visible ischemic lesions on DW-MRI. Only 8 patients had infarcts predominantly confined to striatum (a commonly used lesion site in pre-clinical stroke studies with SCT), causing mild deficits with a median NIHSS of 3 (range 1-5). In Paper II, 56 (52%) of the stroke patients had UEMI (NIHSS arm/hand score ≥1) in the first days after stroke onset. Morever, 10/41 stroke survivors with UEMI at baseline and without recurrent stroke displayed residual UEMI after 3-5 years, whereas 31/41 individuals showed complete recovery. Post-stroke UEMI correlated to mRS (rs=0.49, p<0.001) and the SIS participation domain (rs=-0.38, p=0.001). In Paper III, 103 (71%) of the 10-year stroke survivors had mRS≤2, 106 (73%) had a BI score of 95-100, 105 (72%) reported no problems with self-care according to EQ-5D, and 90 (62%) had positive views about their general health status according to SF-36. In Paper IV, 75 (61%) out of 122 stroke survivors who completed the MoCA had a score of MoCA<25. The odds of having severe cognitive impairment (MMSE<23) were higher among stroke survivors than the controls (education-adjusted OR 2.48; 95% CI: 1.34-4.59; p=0.004). In Paper V, only 10 (12%) of the stroke survivors had prior knowledge of SCT, but 53 (63%) of the participants expressed positive attitudes towards SCT after having received standardized and neutral written information. Positive attitudes to SCT were associated with male gender (crude OR 3.74; 95% CI: 1.45-9.61; p=0.006) and higher degree of self-perceived stroke recovery according to the SIS (crude OR 1.02; 95% CI: 1.00-1.04; p=0.034). Conclusions: Optimized endogenous neurogenesis may have a therapeutic potential, and striatum should probably not be the primary target for SCT aiming for neuronal replacement. SCT targeting post-stroke UEMI may be clinically valuable, and UEMI recovery may be a suitable outcome in later-phase pivotal stroke trials studying the efficacy of SCT. A majority of long-term stroke survivors have a relatively good prognosis accompanied by positive self-perceptions about their health, and would probably not have been in need of SCT to improve functional outcome. However, early prognostic assessments are needed to detect stroke patients with poor expected functional recovery and outcome where SCT may be beneficial. Cognitive impairment is common among long-term stroke survivors and should be taken into account both in pre-clinical studies and in future clinical trials with SCT. Targeted patient information on SCT for stroke may be valuable to facilitate recruitment to clinical trials and reduce risks of selection bias. (Less)