Pregabalin improves axon regeneration and motor outcome in a rodent stroke model.

Ischaemic stroke remains a leading cause of death and disability worldwide. Surviving neurons in the peri-infarct area are able to establish novel axonal projections to juxtalesional regions, but this regeneration is curtailed by a growth-inhibitory environment induced by cells such as reactive astrocytes in the glial scar. Here, we found that the astroglial synaptogenic cue thrombospondin-1 is upregulated in the peri-infarct area, and hence tested the effects of the anticonvulsant pregabalin, a blocker of the neuronal thrombospondin-1 receptor Alpha2delta1/2, in a mouse model of cortical stroke. Studying axonal projections after cortical stroke in mice by three-dimensional imaging of cleared whole-brain preparations, we found that pregabalin, when administered systemically for 5 weeks after stroke, augments novel peri-infarct motor cortex projections and improves skilled forelimb motor function. Thus, the promotion of axon elongation across the glial scar by pregabalin represents a promising target beyond the acute phase after stroke to improve structural and functional recovery.

Epothilones Improve Axonal Growth and Motor Outcomes after Stroke in the Adult Mammalian CNS.

Stroke leads to the degeneration of short-range and long-range axonal connections emanating from peri-infarct tissue, but it also induces novel axonal projections. However, this regeneration is hampered by growth-inhibitory properties of peri-infarct tissue and fibrotic scarring. Here, we tested the effects of epothilone B and epothilone D, FDA-approved microtubule-stabilizing drugs that are powerful modulators of axonal growth and scar formation, on neuroplasticity and motor outcomes in a photothrombotic mouse model of cortical stroke. We find that both drugs, when administered systemically 1 and 15 days after stroke, augment novel peri-infarct projections connecting the peri-infarct motor cortex with neighboring areas. Both drugs also increase the magnitude of long-range motor projections into the brainstem and reduce peri-infarct fibrotic scarring. Finally, epothilone treatment induces an improvement in skilled forelimb motor function. Thus, pharmacological microtubule stabilization represents a promising target for therapeutic intervention with a wide time window to ameliorate structural and functional sequelae after stroke.

Region-specific permeability of the blood-brain barrier upon pericyte loss.

The blood-brain barrier (BBB) regulates differing needs of the various brain regions by controlling transport of blood-borne components from the neurovascular circulation into the brain parenchyma. The mechanisms underlying region-specific transport across the BBB are not completely understood. Previous work showed that pericytes are key regulators of BBB function. Here we investigated whether pericytes influence BBB permeability in a region-specific manner by analysing the regional permeability of the BBB in the pdgf-b ret/ret mouse model of pericyte depletion. We show that BBB permeability is heterogeneous in pdgf-b ret/ret mice, being significantly higher in the cortex, striatum and hippocampus compared to the interbrain and midbrain. However, we show that this regional heterogeneity in BBB permeability is not explained by local differences in pericyte coverage. Region-specific differences in permeability were not associated with disruption of tight junctions but may result from changes in transcytosis across brain endothelial cells. Our data show that certain brain regions are able to maintain low BBB permeability despite substantial pericyte loss and suggest that additional, locally-acting mechanisms may contribute to control of transport.

Spectrum of Cav1.4 dysfunction in congenital stationary night blindness type 2.

Defective retinal synaptic transmission in patients affected with congenital stationary night blindness type 2 (CSNB2) can result from different dysfunction phenotypes in Cav1.4 L-type calcium channels. Here we investigated two prototypical Cav1.4 variants from either end of the functional spectrum. Using whole-cell and single-channel patch-clamp techniques, we provide analysis of the biophysical characteristics of the point mutation L860P and the C-terminal truncating mutation R1827X. L860P showed a typical loss-of-function phenotype attributed to a reduced number of functional channels expressed at the plasma membrane as implied by gating current and non-stationary noise analyses. This phenotype can be rationalized, because the inserted proline is predicted to break an amphipatic helix close to the transmembrane segment IIIS1 and thus to reduce channel stability and promote misfolding. In fact, L860P was subject to an increased turnover. In contrast, R1827X displayed an apparent gain-of-function phenotype, i.e., due to a hyperpolarizing shift of the IV-curve and increased single-channel activity. However, truncation also resulted in the loss of functional C-terminal modulation and thus unmasked calcium-dependent inactivation. Thus R1827X failed to support continuous calcium influx. Current inactivation curtails the dynamic range of photoreceptors (e.g., when adapting to variation in illumination). Taken together, the analysis of two representative mutations that occur in CSNB2 patients revealed fundamental differences in the underlying defect. These may explain subtle variations in the clinical manifestation and must be taken into account, if channel function is to be restored by pharmacochaperones or related approaches.

[Identification of quality indicators of stroke care]. / Identifizierung von Qualitätsindikatoren der Schlaganfallversorgung.

BACKGROUND/OBJECTIVES: The purpose of the present study was to identify existing quality indicators of stroke care and to select those that are appropriate for use in the German health care system. METHODS: A systematic literature search in databases of performance measures, clinical indicator programs, stroke guidelines and published scientific literature (published in 1993-2002) identified 151 quality indicators. This number was reduced by selecting indicators that satisfied the following quality criteria for clinical performance measures: a) consensus on the relative importance of aspects of clinical care (according to the American Heart Association/American College of Cardiology Forum), b) controllability of aspects of clinical care (according to the German "Advisory Council for the Concerted Action in Health Care") and c) internal validity (according to the stroke guideline of the Royal College of Physicians, UK). RESULTS: Of the 151 quality indicators, 31 fulfilled all three criteria for clinical performance measures. After elimination of overlapping indicators 13 quality indicators remained covering important aspects of the quality of stroke care in Germany: two of these indicators refer to the quality of structural aspects of care, six consider processes of care and five indicators are devoted to outcomes of care. These 13 indicators cover "prevention, rehabilitation, coordination and continuity of care", which are important controllable aspects of care. Whereas six indicators were considered to be highly valid, seven indicators did not convey enough information to ensure their validity. CONCLUSION: Suitable quality indicators covering several important aspects of stroke care could be selected from existing indicators for the development of an appropriate set of indicators to be used in the German health care system.

[Critical appraisal of stroke guidelines]. / Methodische Qualität von Leitlinien zur Schlaganfallversorgung.

BACKGROUND: Despite the increasing burden of disease and known deficiencies of actual stroke care there is a lack of evidence-based stroke guidelines in Germany. For future guideline development and implementation in Germany, critically appraising internationally available guidelines might be useful. OBJECTIVES: To identify and evaluate published evidence-based German and English language stroke/cerebrovascular disorder guidelines using the established "German Guideline Appraisal Instrument". METHODS: Systematic literature search (published in 1992-2002) using Medline and English-/German language guideline databases. A total of 626 hits resulted in 54 guideline articles. 13 articles (from Australia, Germany, the United Kingdom, Singapore and the USA) fulfilled specific inclusion criteria (recommended for countrywide implementation, complete guidelines for prevention and/or diagnostic/treatment and/or rehabilitation). The systematic guideline appraisal consisted of a) the assessment of the methodological quality using the established "German Guideline Appraisal Instrument" attributing scores and ranking the guidelines according to their overall quality; b) the systematic documentation of appraisal using structured abstracts. RESULTS: The methodological quality of "content and form" (10-17 of a total of 17 points) of the 13 guidelines was comparable. Regarding the domains of the "quality of the development process" (the guidelines achieved 4-15 of 17 points) and "guideline applicability" (0-3 of 6 points), though, the appraised guidelines varied impressively. The 6 best guidelines (> or = 25 of a total of 40 points) were characterized by explicitly linking recommendations and supporting evidence, by expert reviews of the guidelines prior to publication, and the provision of instructions for guideline implementation. CONCLUSION: None of the 13 appraised guidelines covered all key methodological quality criteria. The analysis shows, however, that it should be possible to compile a methodologically sound stroke guideline by using those parts of the different appraised guidelines that fitted the quality criteria best.

Does age influence early recovery from ischemic stroke? A study from the Hessian Stroke Data Bank.

Age is the most important risk factor for developing a stroke. In addition, age may also influence stroke recovery. To allow structured discharge planning, it may be important to consider the influence of age on stroke recovery during the early phase. We studied the effect of patient age on early stroke recovery in a cohort of 2219 unselected stroke patients. Data on functional status (Barthel Index Score) were collected prospectively within 24h after admission, after one week and at discharge for 2219 acute stroke patients treated in 1999 and 2000 at 7 neurological departments in the county of Hesse, Germany. Multiple regression analyses were used to test for an association between age, relative recovery and speed of recovery of ADL after stroke. More than half of the patients (58 %) improved in functional status during hospitalization. 37 % had no change in Barthel Index score and only a small number of patients (5 %) deteriorated during this period. Relative improvement decreased with increasing age: patients younger than 55 years showed an improvement of 67 % of the maximum possible improvement compared whith only 50 % for patients above 55 years (adjusted R(2) = 0.120, beta(age) = -0.130, p < 0.001). Age only had a small effect on the speed of recovery. For younger patients functional recovery was slightly faster (adjusted R(2) = 0.256, beta(age) = -0.080, p < 0.001). Despite its strong influence on case fatality, age is a poor predictor of functional recovery during the very early phase after stroke. Resulting functional recovery depends much more on the extent of the initial disability. Advanced age should not be regarded as a limiting factor in the early rehabilitation of stroke patients.

Timecourse of health-related quality of life as determined 3, 6 and 12 months after stroke. Relationship to neurological deficit, disability and depression.

OBJECTIVE: To study the timecourse of health-related global and domain-specific quality of life (QOL) in patients presenting with stroke or transient ischemic attacks (TIA) up to one year after the ischemic event. Variables were identified that may predict poststroke life satisfaction. PATIENTS AND METHODS: In this prospective study, a cohort of 183 stroke/TIA patients was followed up at 3, 6, and 12 months. A total of 144 survivors completed the follow-up (65 women, 79 men, mean age 65.3 years). Health-related QOL was assessed by the Short Form 36 (SF-36) questionnaire, the neurological status by the European Stroke Scale (ESS). Disability was evaluated by using the Barthel index and the modified Swedish Stroke Registry Follow-up Form; depression was scored by the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: One year after stroke/TIA, 66 % of patients reported a worsening of life satisfaction compared with the prestroke level. The SF-36 physical component summary was reduced throughout the observation period. The SF-36 mental component summary deteriorated between the 6- and 12-months follow-up from 52.2 +/- 7.1 to 50.6 +/- 7.1 (p < 0.05). The SF-36 domains "physical functioning", "social functioning" and the MADRS scores both showed a significant deterioration between 6 and 12 months poststroke (p < 0.05). In contrast, the neurological status and the degree of disability remained stable. Male sex, absence of diabetes, and normal MADRS scores at 3 and 6 months postinsult were identified as predictors of favorable QOL after 1 year (p < 0.05). CONCLUSIONS: Despite stable neurologic function and disability, global as well as domain-specific measures of QOL deteriorated over the 12-months observation period in a cohort of stroke survivors.