Contactin-associated protein 2 autoantibodies can be associated with multifocal motor-like neuropathy: a case report.

Autoantibodies against contactin-associated protein 2 (CASPR2) are usually associated with autoimmune encephalitis and neuromyotonia. Their association with inflammatory neuropathies has been described in case reports albeit all with distal symmetric manifestation. Here, we report a patient who developed distal arm paresis, dominantly of the right arm, over the course of 1 year. Electroneurography showed a conduction block of motor nerve conduction, nerve ultrasonography a swelling of the right median and ulnar nerve and flow cytometry an increase in natural killer (NK cells) in the blood and natural killer T (NKT) cells in the cerebrospinal fluid (CSF), therefore indicating a multifocal motor neuropathy-like (MMN-like) phenotype. CASPR2 autoantibodies were detected in serum and CSF. Through immunotherapy with intravenous immunoglobulins the patient showed clinical and neurographic improvement. We therefore describe the first association of CASPR2 autoantibodies with a MMN-like clinical manifestation, extending the spectrum of CASPR2-associated diseases.

[de novo hATTR amyloidosis after domino transplantation of a donor's liver: a case report for the use of Patisiran]. / de novo hATTR Amyloidose nach Domino-Lebertransplantation: Ein Fallbeispiel für den Einsatz von Patisiran.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, rapidly progressing, and potentially life-threatening disease caused by one of more than 120 mutations in the transthyretin (TTR) gene. As a result of the cumulative amyloid deposits, especially in the peripheral nerves and the heart, the majority of patients develop progressive, peripheral sensorimotor polyneuropathy and biventricular cardiomyopathy over time.Since TTR - and its amyloidogenic variants too - is predominantly synthesized in the liver, early, orthotopic liver transplantation (LTx) is a treatment option that can be used to potentially stop the progression of hATTR amyloidosis.The actual case shows a patient with hepatocellular carcinoma who received the organ of a patient with hATTR as part of a domino liver transplantation. After approximately 10 years, the patient started to develop the characteristic symptoms of the metabolic disorder. Because of a further progression of the amyloidosis, therapy with the RNA interference therapeutic patisiran was initiated, which temporarily halted the progression.

[Gene therapy options for hereditary transthyretin-related amyloidosis]. / Gentherapieoptionen der hereditären Transthyretinamyloidose.

Hereditary transthyretin-related amyloidosis (ATTRv) is a rare autosomal dominant disease and is fatal if left untreated. It is caused by mutations in the transthyretin gene. All known mutations induce misfolding of the tetrameric transthyretin molecule and protein deposits in multiple organs. In peripheral nerves this result in sensorimotor and autonomic polyneuropathy and in cardiac muscle it causes cardiomyopathy. Untreated ATTRv is characterized by an irreversible and progressive course and death 7-11 years after symptom onset. Treatment options consist of TTR stabilizing drugs, such as tafamidis and active agents that selectively interfere at the mRNA level, the so-called gene silencers patisiran and inotersen. All forms of treatment aim to prevent amyloid tissue deposition in tissues and organ dysfunction. Patisiran works by RNA interference on endogenous mechanisms of gene expression. It results in the cleavage of TTR-mRNA using the cytoplasmatic RNA-induced silencing complex. Inotersen, an antisense oligonucleotide, degrades TTR-mRNA via activation of nuclear RNase H. Both mechanisms result in a significant reduction of TTR protein serum levels. The efficacy could be demonstrated by slowing or improving neuropathy progression in the phase III study APOLLO (patisiran) or the NEURO-TTR study (inotersen). Furthermore, the use of both agents led to an improvement in the quality of life in patients with ATTRv. Both forms of treatment are approved in Germany since August 2018 for polyneuropathy stages 1 and 2 according to Coutinho. The choice of treatment should be carried out individually considering drug formulation, contraindications and the necessary safety monitoring controls.

Genome silencer therapy leading to 'regression' of cardiac amyloid load on cardiovascular magnetic resonance: a case report.

BACKGROUND: Hereditary or variant transthyretin amyloidosis (ATTRv) is a progressive disease manifesting with neuropathy and/or cardiomyopathy. An early and accurate diagnosis of cardiac amyloidosis is a pre-requisite for timely and appropriate patient management, including anti-amyloid therapies, as it is associated with heart failure, conduction disease, and arrhythmias, leading to reduced quality of life and early death. CASE SUMMARY: We present the case of an ATTRv male patient presenting with a mixed amyloidosis phenotype (neuropathy and cardiomyopathy). Cardiac disease manifestation comprised tachyarrhythmias (atrial fibrillation) and conduction abnormalities (atrio-ventricular block) in addition to segmental left ventricular (LV) hypertrophy (septal wall) due to regionally pronounced amyloid deposits in the basal LV myocardium. Interestingly, by means of serial cardiovascular magnetic resonance (CMR) studies, we were able to demonstrate an impressive and unexpected improvement of cardiomyopathy findings within a relatively short period-of-time after the implementation of genome-silencer therapies. DISCUSSION: This is our second case report that showed ATTRv cardiomyopathy reversal under anti-amyloid therapy-documented by multi-parametric CMR. Our findings support the hypothesis that amyloid infiltration leading to cardiomyopathy is not an irreversible pathological process-but rather a dynamic one, that cannot only be stopped but even reversed (to a certain degree) by currently emerging anti-amyloid therapies. Moreover, the role of serial multi-parametric CMR imaging for surveillance of cardiomyopathy dynamics under these therapies is nicely illustrated.

Detecting myasthenia gravis as a cause of unclear dysphagia with an endoscopic tensilon test.

AIMS: The flexible endoscopic evaluation of swallowing-tensilon test (FTT) was developed to diagnose myasthenia gravis (MG) in patients with unclear pharyngeal dysphagia. The purpose of this study was to determine sensitivity and specificity of the FTT and compare its diagnostic validity with that of other diagnostic markers. METHODS: In this single-centre pragmatic clinical cohort study, a total of 100 patients with unclear pharyngeal dysphagia were eligible to undergo FTT. All patients were subjected to FTT and subsequently followed up clinically. FTT was considered positive if a significant improvement of pharyngeal swallowing function could be objectified endoscopically upon administration of edrophonium chloride. In addition, repetitive nerve stimulation test and serum MG antibody analysis were conducted. RESULTS: All subjects (mean age 62.5 ± 14.1 years, female 33) underwent FTT without any complications. According to the results of the diagnostic procedures and based on long-term clinical follow-up for at least 3 years, 51 patients were finally diagnosed with MG. The sensitivity and specificity for the FTT was 88.2% and 95.9%, respectively. Application of the Cochran's Q test showed statistically significant heterogeneity among the diagnostic tests, with results indicating FTT performance to be more accurate than the repetitive nerve stimulation results (p < 0.001) and comparable with serum antibody tests (p > 0.99). CONCLUSION: FTT has excellent clinical properties to be used routinely in the assessment of dysphagia with isolated or predominant pharyngeal muscle involvement allowing rapid and accurate diagnosis of MG.

Chance or challenge, spoilt for choice? New recommendations on diagnostic and therapeutic considerations in hereditary transthyretin amyloidosis with polyneuropathy: the German/Austrian position and review of the literature.

Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTRv) in the TTR gene. Alongside cardiac dysfunction, the disease typically manifests with a severely progressive sensorimotor and autonomic polyneuropathy. Three different drugs, tafamidis, patisiran, and inotersen, are approved in several countries, including the European Union and the United States of America. By stabilizing the TTR protein or degrading its mRNA, all types of treatment aim at preventing amyloid deposition and stopping the otherwise fatal course. Therefore, it is of utmost importance to recognize both onset and progression of neuropathy as early as possible. To establish recommendations for diagnostic and therapeutic procedures in the follow-up of both pre-symptomatic mutation carriers and patients with manifest ATTRv amyloidosis with polyneuropathy, German and Austrian experts elaborated a harmonized position. This paper is further based on a systematic review of the literature. Potential challenges in the early recognition of disease onset and progression are the clinical heterogeneity and the subjectivity of sensory and autonomic symptoms. Progression cannot be defined by a single test or score alone but has to be evaluated considering various disease aspects and their dynamics over time. The first-line therapy should be chosen based on individual symptom constellations and contra-indications. If symptoms worsen, this should promptly implicate to consider optimizing treatment. Due to the rareness and variability of ATTRv amyloidosis, the clinical course is most importantly directive in doubtful cases. Therefore, a systematic follow-up at an experienced center is crucial to identify progression and reassure patients and carriers.

Quality of life outcomes in APOLLO, the phase 3 trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis.

Introduction: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, fatal, multisystem disease leading to deteriorating quality of life (QOL). The impact of patisiran on QOL in patients with hATTR amyloidosis with polyneuropathy from the phase 3 APOLLO study (NCT01960348) is evaluated.Methods: Patients received either patisiran 0.3 mg/kg (n = 148) or placebo (n = 77) intravenously once every three weeks for 18 months. Multiple measures were used to assess varying aspects of QOL.Results: At 18 months, compared with placebo, patisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score; (least squares [LS] mean difference: -21.1; p = 1.10 × 10-10; improved across all domains), EuroQoL 5-dimensions 5-levels (LS mean difference: 0.2; p = 1.4 × 10-12), EuroQoL-visual analog scale (LS mean difference: 9.5; p=.0004), Rasch-built Overall Disability Scale (LS mean difference: 9.0; p = 4.07 × 10-16) and Composite Autonomic Symptom Score-31(COMPASS-31; LS mean difference: -7.5; p=.0008). Placebo-treated patients experienced rapid QOL deterioration; treatment effects for patisiran were observed as early as 9 months. At 18 months, patisiran improved Norfolk QOL-DN total score and three individual domains as well as COMPASS-31 total scores relative to baseline. Consistent benefits were also observed in the cardiac subpopulation.Conclusion: The benefits of patisiran across all QOL measures and the rapid deterioration observed with placebo, highlight the urgency in early treatment for patients with hATTR amyloidosis with polyneuropathy.

Comparing Plasma Exchange to Escalated Methyl Prednisolone in Refractory Multiple Sclerosis Relapses.

Intravenous methyl prednisolone (IVMPS) represents the standard of care for multiple sclerosis (MS) relapses, but fail to improve symptoms in one quarter of patients. In this regard, apart from extending steroid treatment to a higher dose, therapeutic plasma exchange (TPE) has been recognized as a treatment option. The aim of this retrospective, monocentric study was to investigate the efficacy of TPE versus escalated dosages of IVMPS in refractory MS relapses. An in-depth medical chart review was performed to identify patients from local databases. Relapse recovery was stratified as "good/full", "average" and "worst/no" according to function score development. In total, 145 patients were analyzed. Good/average/worst recovery at discharge was observed in 60.9%/32.6%/6.5% of TPE versus 15.2%/14.1%/70.7% of IVMPS patients, respectively. A total of 53.5% of IVMPS patients received TPE as rescue treatment and 54.8% then responded satisfactorily. The multivariable odds ratio (OR) for worst/no recovery was 39.01 (95%-CI: 10.41-146.18; p ≤ 0.001), favoring administration of TPE as first escalation treatment. The effects were sustained at three-month follow-ups, as OR for further deterioration was 6.48 (95%-CI: 2.48-16.89; p ≤ 0.001), favoring TPE. In conclusion, TPE was superior over IVMPS in the amelioration of relapse symptoms at discharge and follow-up. This study provides class IV evidence supporting the administration of TPE as the first escalation treatment to steroid-refractory MS relapses.

[Transthyretin Familial Amyloid Polyneuropathy - Disease Profile of a Multisystem Disorder]. / Transthyretin-assoziierte familiäre Amyloidpolyneuropathie.

Transthyretin-related Familial Amyloid Polyneuropathy (ATTR Amyloidosis, former FAP, here called TTR-FAP) is a rare, progressive autosomal dominant inherited amyloid disease ending fatal within 5 - 15 years after final diagnosis. TTR-FAP is caused by mutations of transthyretin (TTR), which forms amyloid fibrils affecting peripheral and autonomic nerves, the heart and other organs. Due to the phenotypic heterogeneity and partly not specific enough clinical symptoms, diagnosis of TTR-FAP can be complicated. False diagnoses can include idiopathic polyneuropathy, chronic inflammatory demyelinating polyneuropathy, diabetic neuropathy as well as paraneoplastic syndrome. Hence, it is assumed that many cases remain unreported. Early and correct diagnosis of TTR-FAP is crucial, since appropriate therapeutic options exist. TTR-FAP should always be differentially diagnosed, when apart from a progressive peripheral polyneuropathy, additional symptoms as autonomic dysfunction, cardiomyopathy, gastrointestinal disorders, unexpected loss of weight, carpal tunnel syndrome, restrictions of renal function, epileptic fits, and corneal and vitreous body clouding occur. Histological evidence of amyloid and successive immunohistochemical evidence of transthyretin as well as genetic testing for transthyretin mutations, lead to an accurate diagnosis.

Combining Growth Factor and Bone Marrow Cell Therapy Induces Bleeding and Alters Immune Response After Stroke in Mice.

BACKGROUND AND PURPOSE: Bone marrow cell (BMC)-based therapies, either the transplantation of exogenous cells or stimulation of endogenous cells by growth factors like the granulocyte colony-stimulating factor (G-CSF), are considered a promising means of treating stroke. In contrast to large preclinical evidence, however, a recent clinical stroke trial on G-CSF was neutral. We, therefore, aimed to investigate possible synergistic effects of co-administration of G-CSF and BMCs after experimental stroke in mice to enhance the efficacy compared with single treatments. METHODS: We used an animal model for experimental stroke as paradigm to study possible synergistic effects of co-administration of G-CSF and BMCs on the functional outcome and the pathophysiological mechanism. RESULTS: G-CSF treatment alone led to an improved functional outcome, a reduced infarct volume, increased blood vessel stabilization, and decreased overall inflammation. Surprisingly, the combination of G-CSF and BMCs abrogated G-CSFs' beneficial effects and resulted in increased hemorrhagic infarct transformation, altered blood-brain barrier, excessive astrogliosis, and altered immune cell polarization. These increased rates of infarct bleeding were mainly mediated by elevated matrix metalloproteinase-9-mediated blood-brain barrier breakdown in G-CSF- and BMCs-treated animals combined with an increased number of dilated and thus likely more fragile vessels in the subacute phase after cerebral ischemia. CONCLUSIONS: Our results provide new insights into both BMC-based therapies and immune cell biology and help to understand potential adverse and unexpected side effects.

Case report of bilateral relapsing-remitting sciatic nerve palsy during two pregnancies.

BACKGROUND: Unlike puerperal peripheral nerve lesions, mononeuropathy during pregnancy is rarely encountered. We report a case of bilateral relapsing-remitting sciatic nerve palsy during two pregnancies. An extensive literature search in PubMed brought no similar cases. CASE PRESENTATION: A healthy young woman presented with initially unilateral sciatic nerve palsy, which manifested and worsened during the early phases of two successive pregnancies. Electrophysiology revealed axonal lesion of the sciatic nerve with predominant affection of the peroneal part. Extensive laboratory examination including cerebrospinal fluid examination was unremarkable. MR imaging was compatible with bilateral intraneural perineurioma. Recurrent occurrence during two pregnancies and an anamnestic relationship between intermediate worsening of the paresis and the menstrual cycle suggested hormone-dependency of the tumor. However, response to repeated intravenous immunoglobuline (IVIG) therapy during pregnancy and shortly after childbirth resulted in partial reversion of foot drop. This was also indicative of an immunoneuropathy. Nerve biopsy was not performed because of clinical improvement. The precise underlying neuropathological mechanism remained unclear. CONCLUSION: To increase knowledge and awareness of this rare entity, potential etiologies of mononeuropathies during pregnancy are discussed in the context of this case report. In the rare occasion of peripheral nerve mononeuropathy during pregnancy, in which therapeutic opportunities are limited, IVIG therapy may be an option when the etiology cannot clearly be determined after thorough medical investigation.

Feasibility platform for stroke studies: an online tool to improve eligibility criteria for clinical trials.

BACKGROUND AND PURPOSE: Eligibility criteria are a key factor for the feasibility and validity of clinical trials. We aimed to develop an online tool to assess the potential effect of inclusion and exclusion criteria on the proportion of patients eligible for an acute stroke trial. METHODS: We identified relevant inclusion and exclusion criteria of acute stroke trials. Based on these criteria and using a cohort of 1537 consecutive patients with acute ischemic stroke from 3 stroke centers, we developed a web portal feasibility platform for stroke studies (FePASS) to estimate proportions of eligible patients for acute stroke trials. We applied the FePASS resource to calculate the proportion of patients eligible for 4 recent stroke studies. RESULTS: Sixty-one eligibility criteria were derived from 30 trials on acute ischemic stroke. FePASS, publicly available at http://fepass.uni-muenster.de, displays the proportion of patients in percent to assess the effect of varying values of relevant eligibility criteria, for example, age, symptom onset time, National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale, on this proportion. The proportion of eligible patients for 4 recent stroke studies ranged from 2.1% to 11.3%. Slight variations of the inclusion criteria could substantially increase the proportion of eligible patients. CONCLUSIONS: FePASS is an open access online resource to assess the effect of inclusion and exclusion criteria on the proportion of eligible patients for a stroke trial. FePASS can help to design stroke studies, optimize eligibility criteria, and to estimate the potential recruitment rate.

Vitamin B status in patients with type 2 diabetes mellitus with and without incipient nephropathy.

AIM: To investigate the vitamin B status, with particular focus on vitamin B6, in adults with and without incipient nephropathy secondary to type 2 diabetes mellitus. METHODS: Plasma and/or urine concentrations of vitamins B6, B1, B12, related vitamers and biomarkers (including total homocysteine, methylmalonic acid) were measured in 120 adults with type 2 diabetes (including 46 patients with microalbuminuria) and 52 non-diabetic control subjects. RESULTS: Plasma concentrations of pyridoxal 5'-phosphate (PLP) were significantly lower in patients with type 2 diabetes than in control subjects (median: 22.7 nmol/L, diabetes with microalbuminuria; 26.8 nmol/L, diabetes without microalbuminuria; 39.5 nmol/L, non-diabetic control; p<0.0001). The prevalence of low PLP (<30 nmol/L) was 63%, 58%, and 25% in the diabetes groups with and without microalbuminuria and the control group, respectively. Plasma levels of pyridoxine and pyridoxal were also lower (p<0.0001), but levels of pyridoxamine, pyridoxamine 5'-phosphate, and pyridoxic acid were higher in both groups with diabetes compared to the control group (p<0.001). Thiamine deficiency was highly prevalent in all groups, whereas low vitamin B12 and elevated methylmalonic acid were rare. Increased levels of C-reactive protein and soluble vascular cell adhesion molecule-1 were observed in the groups with diabetes (p<0.05, versus healthy control). CONCLUSIONS: Deficiency of vitamin B6 (PLP, pyridoxine, pyridoxal) and vitamin B1 (thiamine) was prevalent in type 2 diabetes. Incipient nephropathy was associated with more pronounced alterations in vitamin B6 metabolism and stronger indications of endothelial dysfunction and inflammation.

The temporo-spatial localization of polymorphonuclear cells related to the neurovascular unit after transient focal cerebral ischemia.

Inflammatory responses after cerebral ischemia are important for the development of final infarct size but the role of polymorphonuclear cells (PMN) is still a matter of debate, since previously used antibodies were recently declared as non-specific. In the present study, we investigated the temporo-spatial localization of PMN related to the neurovascular unit using specific antibodies, 7/4 and Ly6G, and application of G-CSF to induce proliferation and mobilization of PMN precursors after transient focal cerebral ischemia in mice. Infarct volumes, sensorimotor function, neurological outcome and immunohistochemical analysis of PMN were performed after G-CSF administration or placebo treatment. G-CSF-treated mice showed reduced infarct size (51.15±15.68 mm(2) vs. 39.31±16.13 mm(2) at day 1; 50.11±16.68 mm(2) vs. 33.16±4.86 mm(2) at day 4; p<0.05). They showed improved motor-function recovery and had a significantly better outcome compared to placebo-treated animals. Comparison of the two PMN detecting antibodies showed no difference in saturation plots or cell quantification. Studying the basement membrane-associated localization revealed ca. 60% extravascular PMN, independent of G-CSF administration. Extravascular PMNs were without any connection to laminin, but all near to the vessels. We conclude that 7/4 is a suitable marker to investigate PMN compared to Ly6G, which confirms results from former studies using the 7/4-antibody. Furthermore we report the observation that PMN were detected outside the laminin barrier but almost exclusively in close vicinity to the neurovascular unit.

Analysis of early phase and subsequent phase III stroke studies of neuroprotectants: outcomes and predictors for success.

BACKGROUND: Efficacy of neuroprotective treatments for ischemic stroke was not convincingly demonstrated in clinical phase III trials so far, whereas some preceding early phase studies found neuroprotection to be beneficial. We aimed to determine the frequency with which phase III studies are preceded by positive early phase studies, and to identify characteristics of early phase studies that are associated with correct prediction of phase III studies. METHODS: We identified phase III studies and corresponding early phase studies of neuroprotective treatments for stroke. Data on study characteristics of early phase trials were extracted and compared between studies that were classified according to their results as "false positive" and "true neutral" using logistic regression analysis. RESULTS: Forty-six phase III studies and 59 corresponding early phase studies were identified. Only one phase III study was positive and this study was followed by a larger negative study. Twenty-two (37.3%) early phase studies were considered to be false positive and 37 (62.7%) to be true neutral. None of the early phase study characteristics were significantly associated with correct prediction of phase III studies. CONCLUSIONS: More than one third of early phase studies on neuroprotective stroke treatments are false positive. Neither the results nor specific study design characteristics of early phase stroke studies reliably predict success in phase III trials. Further efforts are needed to improve early phase studies regarding its predictability and to identify those early studies that should be advanced to phase III trials.

Bone marrow-derived mononuclear cells do not exert acute neuroprotection after stroke in spontaneously hypertensive rats.

Bone marrow-derived mononuclear cells (BM-MNCs) were shown to improve the outcome in animal stroke models and clinical pilot studies on BM-MNCs for stroke patients were already conducted. However, relevant aspects of pre-clinical evaluation, such as the use of animals with comorbidities and dose-response studies, were not thoroughly addressed so far. We therefore investigated different BM-MNC doses in the clinical meaningful stroke model of spontaneously hypertensive (SH) rats. Three hours after the onset of transient middle cerebral artery occlusion (MCAO) animals received either one of three syngeneic BM-MNC doses or placebo intravenously. The primary endpoint was the infarct size. Secondary endpoints included functional outcome, mortality, inflammatory processes, and the dose-response relationship. In contrast to previous studies which used healthy animals no beneficial effect of BM-MNCs was found. Infarct volumes, mortality, behavioral outcomes, and the extent of the inflammatory response to cerebral ischemia were comparable in all groups. In conclusion, we could not demonstrate that early BM-MNC treatment improves the outcome after stroke in SH rats. Whether BM-MNCs improve neurological recovery after delayed treatment initiation was not investigated in the present study, but our data indicates that this should be determined in co-morbid animal stroke models before moving to large-scale clinical studies. Future preclinical stroke studies on co-morbid animals should also include groups of healthy animals in order to determine whether negative results can be attributed to the comorbid condition.

Meta-analysis of the efficacy of different training strategies in animal models of ischemic stroke.

BACKGROUND AND PURPOSE: Although several studies have shown beneficial effects of training in animal stroke models, the most effective training strategy and the optimal time to initiate training have not been identified. The present meta-analysis was performed to compare the efficacy of different training strategies and to determine the optimal time window for training in animal stroke models. METHODS: We searched the literature for studies analyzing the efficacy of training in animal models of ischemic stroke. Training was categorized into forced physical training, voluntary physical training, constraint-induced movement therapy, and skilled reaching training. Two reviewers independently extracted data on study quality, infarct size, and neurological outcome. Data were pooled by means of a meta-analysis. RESULTS: Thirty-five studies with >880 animals were included. A meta-analysis of all treatments showed that training reduced the infarct volume by 14% (95% confidence interval, 2%-25%) and improved the cognitive function by 33% (95% confidence interval, 8%-50%), the neuroscore by 13.4% (95% confidence interval, 1.5%-25.3%), and the running function by 6.6% (95% confidence interval, 1.4%-11.9%). Forced physical training reduced the infarct volume and enhanced the running function most effectively, whereas skilled reaching training improved the limb function most effectively. A meta-regression illustrated that training was particularly efficacious when initiated between 1 and 5 days after stroke onset. CONCLUSIONS: Our meta-analysis confirms that training reduces the infarct volume and improves the functional recovery in animal stroke models. Forced physical training and skilled reaching training were identified as particularly effective training strategies. The efficacy of training is time dependent.