Meta-analyses of data from human studies are invaluable resources in the life sciences and the methods to conduct these are well documented. Similarly there are a number of benefits in conducting meta-analyses on data from animal studies; they can be used to inform clinical trial design, or to try and explain discrepancies between preclinical and clinical trial results. However there are inherit differences between animal and human studies and so applying the same techniques for the meta-analysis of preclinical data is not straightforward. For example preclinical studies are frequently small and there is often substantial heterogeneity between studies. This may have an impact on both the method of calculating an effect size and the method of pooling data. Here we describe a practical guide for the meta-analysis of data from animal studies including methods used to explore sources of heterogeneity.

Spinal cord injury (SCI) is a devastating condition that causes substantial morbidity and mortality and for which no treatments are available. Stem cells offer some promise in the restoration of neurological function. We used systematic review, meta-analysis, and meta-regression to study the impact of stem cell biology and experimental design on motor and sensory outcomes following stem cell treatments in animal models of SCI. One hundred and fifty-six publications using 45 different stem cell preparations met our prespecified inclusion criteria. Only one publication used autologous stem cells. Overall, allogeneic stem cell treatment appears to improve both motor (effect size, 27.2%; 95% Confidence Interval [CI], 25.0%–29.4%; 312 comparisons in 5,628 animals) and sensory (effect size, 26.3%; 95% CI, 7.9%–44.7%; 23 comparisons in 473 animals) outcome. For sensory outcome, most heterogeneity between experiments was accounted for by facets of stem cell biology. Differentiation before implantation and intravenous route of delivery favoured better outcome. Stem cell implantation did not appear to improve sensory outcome in female animals and appeared to be enhanced by isoflurane anaesthesia. Biological plausibility was supported by the presence of a dose–response relationship. For motor outcome, facets of stem cell biology had little detectable effect. Instead most heterogeneity could be explained by the experimental modelling and the outcome measure used. The location of injury, method of injury induction, and presence of immunosuppression all had an impact. Reporting of measures to reduce bias was higher than has been seen in other neuroscience domains but were still suboptimal. Motor outcomes studies that did not report the blinded assessment of outcome gave inflated estimates of efficacy. Extensive recent preclinical literature suggests that stem-cell–based therapies may offer promise, however the impact of compromised internal validity and publication bias mean that efficacy is likely to be somewhat lower than reported here. Spinal cord injury is an important cause of disability in young adults, and stem cells have been proposed as a possible treatment. Here we systematically assess the evidence in the scientific literature for the effectiveness of stem-cell–based therapies in animal models of spinal cord injury. More studies reported effects on the ability to move (“motor outcomes”) than on sensation (“sensory outcomes”). Overall, treatment improves both sensory and motor outcomes, and for sensory outcome there was a dose–response effect (which suggests an underlying biological basis). Although more measures were taken to reduce the risk of bias than in other areas of translational neuroscience, unblinded studies tended to overstate the effectiveness of the treatment. The variability observed between the studies is not explained by differences in the stem cells used, but does seem to depend on the different injury models used to emulate human spinal cord injury. This suggests that the mechanism of injury should be an important consideration in the design of future clinical trials. Furthermore, open questions arise about the use of immunosuppressive drugs, and efficacy in female animals; these should be addressed before proceeding to clinical trial.

Therapeutic hypothermia is a clinically useful neuroprotective therapy for cardiac arrest and neonatal hypoxic ischemic encephalopathy and may potentially be useful for the treatment of other neurological conditions including traumatic spinal cord injury (SCI). The pre-clinical studies evaluating the effectiveness of hypothermia in acute SCI broadly utilise either systemic hypothermia or cooling regional to the site of injury. The literature has not been uniformly positive with conflicting studies of varying quality, some performed decades previously. In this study, we systematically review and meta-analyse the literature to determine the efficacy of systemic and regional hypothermia in traumatic SCI, the experimental conditions influencing this efficacy, and the influence of study quality on outcome. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of the (i) reporting of efficacy of hypothermia on functional outcome (ii) number of animals and (iii) mean outcome and variance in each group. Systemic hypothermia improved behavioural outcomes by 24.5% (95% CI 10.2 to 38.8) and a similar magnitude of improvement was seen across a number of high quality studies. The overall behavioural improvement with regional hypothermia was 26.2%, but the variance was wide (95% CI −3.77 to 56.2). This result may reflect a preponderance of positive low quality data, although a preferential effect of hypothermia in ischaemic models of injury may explain some of the disparate data. Sufficient heterogeneity was present between studies of regional hypothermia to reveal a number of factors potentially influencing efficacy, including depth and duration of hypothermia, animal species, and neurobehavioural assessment. However, these factors could reflect the influence of earlier lower quality literature. Systemic hypothermia appears to be a promising potential method of treating acute SCI on the basis of meta-analysis of the pre-clinical literature and the results of high quality animal studies.

Posttraumatic epilepsy (PTE) is a well‐known chronic complication following traumatic brain injury (TBI). Despite some evidence that age at the time of injury may influence the likelihood of PTE, the incidence of PTE in pediatric populations remains unclear. We therefore conducted a systematic review to determine the overall reported incidence of PTE, and explore potential risk factors associated with PTE after pediatric TBI. A comprehensive literature search of the PubMed, Embase, and Web of Science databases was conducted, including randomized controlled trials and cohort studies assessing the incidence of PTE in TBI pediatric patients. We excluded studies with a sample size of <10 patients and those in which a pediatric cohort was not clearly discernable. The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines. We found that the overall incidence of PTE following pediatric TBI was 10% (95% confidence interval [CI] = 5.9%–15%). Subgroup analysis of a small number of studies demonstrated that the occurrence of early seizures (cumulative incidence ratio [CIR] = 7.28, 95% CI = 1.09–48.4, p = .040), severe TBI (CIR = 1.81, 95% CI = 1.23–2.67, p < .001), and intracranial hemorrhage (CIR = 1.60, 95% CI = 1.06–2.40, p = .024) increased the risk of PTE in this population. Other factors, including male sex and neurosurgical intervention, were nonsignificantly associated with a higher incidence of PTE. In conclusion, PTE is a significant chronic complication following childhood TBI, similar to in the adult population. Further standardized investigation into clinical risk factors and management guidelines is warranted. PROSPERO ID# CRD42021245802.

Although commonly used in the evaluation of patients for epilepsy surgery, the association between the detection of localizing ¹⁸fluorine fluorodeoxyglucose PET (¹⁸F-FDG-PET) hypometabolism and epilepsy surgery outcome is uncertain. We conducted a systematic review and meta-analysis to determine whether localizing ¹⁸F-FDG-PET hypometabolism is associated with favorable outcome after epilepsy surgery. A systematic literature search was undertaken. Eligible publications included evaluation with ¹⁸F-FDG-PET before epilepsy surgery, with ≥10 participants, and those that reported surgical outcome at ≥12 months. Random-effects meta-analysis was used to calculate the odds of achieving a favorable outcome, defined as Engel class I, International League Against Epilepsy class 1-2, or seizure-free, with localizing ¹⁸F-FDG-PET hypometabolism, defined as concordant with the epilepsy surgery resection zone. Meta-regression was used to characterize sources of heterogeneity. The database search identified 8,916 studies, of which 98 were included (total patients n = 4,104). Localizing ¹⁸F-FDG-PET hypometabolism was associated with favorable outcome after epilepsy surgery for all patients with odds ratio (OR) 2.68 (95% CI 2.08-3.45). Subgroup analysis yielded similar findings for those with (OR 2.64, 95% CI 1.54-4.52) and without epileptogenic lesion detected on MRI (OR 2.49, 95% CI 1.80-3.44). Concordance with EEG (OR 2.34, 95% CI 1.43-3.83), MRI (OR 1.69, 95% CI 1.19-2.40), and triple concordance with both (OR 2.20, 95% CI 1.32-3.64) was associated with higher odds of favorable outcome. By contrast, diffuse ¹⁸F-FDG-PET hypometabolism was associated with worse outcomes compared with focal hypometabolism (OR 0.34, 95% CI 0.22-0.54). Localizing ¹⁸F-FDG-PET hypometabolism is associated with favorable outcome after epilepsy surgery, irrespective of the presence of an epileptogenic lesion on MRI. The extent of ¹⁸F-FDG-PET hypometabolism provides additional information, with diffuse hypometabolism associated with worse surgical outcome than focal ¹⁸F-FDG-PET hypometabolism. These findings support the incorporation of ¹⁸F-FDG-PET into routine noninvasive investigations for patients being evaluated for epilepsy surgery to improve epileptogenic zone localization and to aid patient selection for surgery.