-
Journal of Clinical Neuroscience :... Sep 2023Stroke presenting with a reduced level of consciousness (RLOC) may result in diagnostic error and/or delay. Missed or delayed diagnosis of acute ischaemic stroke may... (Review)
Review
INTRODUCTION
Stroke presenting with a reduced level of consciousness (RLOC) may result in diagnostic error and/or delay. Missed or delayed diagnosis of acute ischaemic stroke may preclude otherwise applicable hyperacute stroke interventions. The frequency, reasons for, and consequences of diagnostic error and delay due to RLOC are uncertain.
METHOD
The databases PubMed, EMBASE, and Cochrane library were searched in adherence with the PRISMA guidelines. The systematic review was prospectively registered on PROSPERO.
RESULTS
Initial searches returned 1162 results, of which 6 fulfilled inclusion criteria. The majority of identified studies show that ischaemic stroke presenting with RLOC is at increased risk of missed or delayed diagnosis. Hyperacute stroke interventions may also be delayed. There is limited evidence regarding the reason for these delays; however, the delays may result from neuroimaging delay associated with diagnostic uncertainty. There is also limited evidence regarding the outcomes of patients with stroke and RLOC who experience diagnostic delay; however, the available literature suggests that outcomes may be poor, including motor and cognitive impairment, as well as long-term impaired consciousness. The included studies did not evaluate, but have suggested urgent MRI access, educational interventions, and protocolisation of the evaluation of RLOC as means to reduce poor outcomes.
CONCLUSIONS
Ischaemic stroke patients with RLOC are at risk of diagnostic delay and error. These patients may have poor outcomes. Additional research is required to identify the contributing factors more clearly and to provide amelioration strategies.
Topics: Humans; Stroke; Brain Ischemia; Consciousness; Delayed Diagnosis; Ischemic Stroke
PubMed: 37454440
DOI: 10.1016/j.jocn.2023.07.009 -
Neurobiology of Disease Jul 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial... (Meta-Analysis)
Meta-Analysis
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen's d' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.
Topics: Humans; Autism Spectrum Disorder; Biomarkers; DNA, Mitochondrial; Mitochondria; Mitochondrial Diseases
PubMed: 38703861
DOI: 10.1016/j.nbd.2024.106520 -
Journal of Neuromuscular Diseases 2024The objective of this study was to describe predictors of loss of ambulation in Duchenne muscular dystrophy (DMD). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The objective of this study was to describe predictors of loss of ambulation in Duchenne muscular dystrophy (DMD).
METHODS
This systematic review and meta-analysis included searches of MEDLINE ALL, Embase, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of loss of ambulation in DMD. Search terms included "Duchenne muscular dystrophy" as a Medical Subject Heading or free text term, in combination with variations of the term "predictor". Risk of bias was assessed using the Newcastle-Ottawa Scale. We performed meta-analysis pooling of hazard ratios of the effects of glucocorticoids (vs. no glucocorticoid therapy) by fitting a common-effect inverse-variance model.
RESULTS
The bibliographic searches resulted in the inclusion of 45 studies of children and adults with DMD from 17 countries across Europe, Asia, and North America. Glucocorticoid therapy was associated with delayed loss of ambulation (overall meta-analysis HR deflazacort/prednisone/prednisolone: 0.44 [95% CI: 0.40-0.48]) (n = 25 studies). Earlier onset of first signs or symptoms, earlier loss of developmental milestones, lower baseline 6MWT (i.e.,<350 vs. ≥350 metres and <330 vs. ≥330 metres), and lower baseline NSAA were associated with earlier loss of ambulation (n = 5 studies). Deletion of exons 3-7, proximal mutations (upstream intron 44), single exon 45 deletions, and mutations amenable of skipping exon 8, exon 44, and exon 53, were associated with prolonged ambulation; distal mutations (intron 44 and downstream), deletion of exons 49-50, and mutations amenable of skipping exon 45, and exon 51 were associated with earlier loss of ambulation (n = 13 studies). Specific single-nucleotide polymorphisms in CD40 gene rs1883832, LTBP4 gene rs10880, SPP1 gene rs2835709 and rs11730582, and TCTEX1D1 gene rs1060575 (n = 7 studies), as well as race/ethnicity and level of family/patient deprivation (n = 3 studies), were associated with loss of ambulation. Treatment with ataluren (n = 2 studies) and eteplirsen (n = 3 studies) were associated with prolonged ambulation. Magnetic resonance biomarkers (MRI and MRS) were identified as significant predictors of loss of ambulation (n = 6 studies). In total, 33% of studies exhibited some risk of bias.
CONCLUSION
Our synthesis of predictors of loss of ambulation in DMD contributes to the understanding the natural history of disease and informs the design of new trials of novel therapies targeting this heavily burdened patient population.
Topics: Muscular Dystrophy, Duchenne; Humans; Glucocorticoids; Walking; Pregnenediones; Latent TGF-beta Binding Proteins
PubMed: 38669554
DOI: 10.3233/JND-230220 -
Frontiers in Psychiatry 2024There is a lack of robust research investigating the association between neurocognitive impairments and chronic tobacco smoking in adolescents/young adults. Therefore, a...
There is a lack of robust research investigating the association between neurocognitive impairments and chronic tobacco smoking in adolescents/young adults. Therefore, a systematic review and meta-analysis were conducted to examine this association by pooling cross-sectional studies published from 1980 to 2023. The systematic review assessed the neurocognitive performances between chronic tobacco smokers and non-smokers in each study. The meta-analysis included six studies that compared chronic tobacco smokers against non-smokers using neuropsychological tests covering three neurocognitive domains. The results showed a cross-sectional association between impairpments in across two aspects: and , with the effect size being (SDM = 0.615, p = 0.000) and (SDM = 0.593, p = 0.000) respectively. However, no significant associations were found for (SDM = 0.221, p = 0.425) or (SDM = 0.150, p = 0.581). This study highlights the need for further research to explore a greater number of neurocognitive domains in the context of chronic smoking in adolescents/young adults, particularly motor impulsivity, intelligence and working memory, as well as the socioeconomic factors involved. There is also a need to further study the effects of emerging alternative nicotine administration methods in this age group.
PubMed: 38716120
DOI: 10.3389/fpsyt.2024.1384408 -
Biomolecules Feb 2024Developmental and epileptic encephalopathies (DEE) encompass a group of rare diseases with hereditary and genetic causes as well as acquired causes such as brain... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Developmental and epileptic encephalopathies (DEE) encompass a group of rare diseases with hereditary and genetic causes as well as acquired causes such as brain injuries or metabolic abnormalities. The phosphofurin acidic cluster sorting protein 2 (PACS2) is a multifunctional protein with nuclear gene expression. The first cases of the recurrent c.625G>A pathogenic variant of gene were reported in 2018 by Olson et al. Since then, several case reports and case series have been published.
METHODS
We performed a systematic review of the PUBMED and SCOPUS databases using Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Our search parameters included DEE66 with a pathogenic gene p.Glu209Lys mutation published cases to which we added our own clinical experience regarding this pathology.
RESULTS
A total of 11 articles and 29 patients were included in this review, to which we added our own experience for a total of 30 patients. There was not a significant difference between sexes regarding the incidence of this pathology (M/F: 16/14). The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait. Facial dysmorphism and other organs' involvement were also frequently reported. Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement. Genetic testing is more frequent in children. Only 4 cases have been reported in adults to date.
CONCLUSIONS
It is important to maintain a high suspicion of new pathogenic gene variants in adult patients presenting with a characteristic clinical picture correlated with radiologic changes. The neurologist must gradually recognize the distinct evolving phenotype of DEE66 in adult patients, and genetic testing must become a scenario with which the neurologist attending adult patients should be familiar. Accurate diagnosis is required for adequate treatment, genetic counseling, and an improved long-term prognosis.
Topics: Child; Adult; Humans; Epilepsy; Mutation; Cerebellum; Phenotype; Brain Injuries; Vesicular Transport Proteins
PubMed: 38540691
DOI: 10.3390/biom14030270 -
Neuropsychiatric Disease and Treatment 2023The gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations....
INTRODUCTION
The gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life.
METHODS
We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials.
RESULTS
We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints.
DISCUSSION
We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.
PubMed: 37881807
DOI: 10.2147/NDT.S379703 -
Current Issues in Molecular Biology Apr 2024Gut microbiome-targeted interventions such as fecal transplant, prebiotics, probiotics, synbiotics, and antibiotic gut depletion are speculated to be of potential use in... (Review)
Review
Gut microbiome-targeted interventions such as fecal transplant, prebiotics, probiotics, synbiotics, and antibiotic gut depletion are speculated to be of potential use in delaying the onset and progression of Parkinson's disease by rebalancing the gut microbiome in the context of the gut-brain axis. Our study aims to organize recent findings regarding these interventions in Parkinson's disease animal models to identify how they affect neuroinflammation and motor outcomes. A systematic literature search was applied in PubMed, Web of Science, Embase, and SCOPUS for gut microbiome-targeted non-dietary interventions. Studies that investigated gut-targeted interventions by using in vivo murine PD models to follow dopaminergic cell loss, motor tests, and neuroinflammatory markers as outcomes were considered to be eligible. A total of 1335 studies were identified in the databases, out of which 29 were found to be eligible. A narrative systematization of the resulting data was performed, and the effect direction for the outcomes was represented. Quality assessment using the SYRCLE risk of bias tool was also performed. Out of the 29 eligible studies, we found that a significant majority report that the intervention reduced the dopaminergic cell loss (82.76%, 95% CI [64.23%, 94.15%]) produced by the induction of the disease model. Also, most studies reported a reduction in microglial (87.5%, 95% CI [61.65%, 98.45%]) and astrocytic activation (84,62%, 95% CI [54.55%, 98.08%]) caused by the induction of the disease model. These results were also mirrored in the majority (96.4% 95% CI [81.65%, 99.91%]) of the studies reporting an increase in performance in behavioral motor tests. A significant limitation of the study was that insufficient information was found in the studies to assess specific causes of the risk of bias. These results show that non-dietary gut microbiome-targeted interventions can improve neuroinflammatory and motor outcomes in acute Parkinson's disease animal models. Further studies are needed to clarify if these benefits transfer to the long-term pathogenesis of the disease, which is not yet fully understood. The study had no funding source, and the protocol was registered in the PROSPERO database with the ID number CRD42023461495.
PubMed: 38785512
DOI: 10.3390/cimb46050244 -
Emergency Radiology Apr 2024Trauma is a significant cause of mortality and morbidity. It is crucial to diagnose trauma patients quickly to provide effective treatment interventions in such... (Meta-Analysis)
Meta-Analysis Review
Trauma is a significant cause of mortality and morbidity. It is crucial to diagnose trauma patients quickly to provide effective treatment interventions in such conditions. Whole-body computed tomography (WBCT)/pan-scan is an imaging technique that enables a faster and more efficient diagnosis for polytrauma patients. The purpose of this systematic review and meta-analysis is to evaluate the efficacy of WBCT in diagnosing injuries in polytrauma patients. We will also assess its impact on the mortality rate and length of hospital stay among trauma centers between patients who underwent WBCT and those who did not (non-WBCT). Twenty-seven studies meeting our inclusion criteria were selected among PubMed, Scopus, Web of Science, and Google Scholar. The criteria were centered on the significance of WBCT/pan-scan application in trauma patients. Stata version 15 was used to perform statistical analysis on the data. The authors have also used I statistics to evaluate heterogeneity. Egger and Begg's tests were performed to rule out any publication bias. Total of twenty-seven studies including 68,838 trauma patients with a mean age of 45.0 ± 24.7 years were selected. Motor vehicle collisions were the most common cause of blunt injuries (80.0%). Head, neck, and face injuries were diagnosed in 44% (95% CI, 0.28-0.60; I = 99.8%), 6% (95% CI, 0.02-0.09; I = 97.2%), and 9% (95% CI, 0.05-0.13; I = 97.1%), respectively. Chest injuries were diagnosed by WBCT in 39% (95% CI, 0.28-0.51; I = 99.8%), abdominal injuries in 23% (95% CI, 0.03-0.43; I = 99.9%) of cases, spinal injuries 19% (95% CI, 0.11-0.27; I = 99.4%), extremity injuries 33% (95% CI, 0.23-0.43; I = 99.2%), and pelvic injuries 11% (95% CI, 0.04-0.18; I = 97.4%). A mortality odd ratio of 0.94 (95% CI, 0.83-1.06; I = 40.1%) was calculated while comparing WBCT and non-WBCT groups. This systematic review and meta-analysis provide insight into the possible safety, efficacy, and efficiency of WBCT/pan-scan as a diagnostic tool for trauma patients with serious injuries, regardless of their hemodynamic status. In patients with serious injuries from trauma, whether or not there are indicators of hemodynamic instability, our recommended approach is to, wherever possible, perform a WBCT without stopping the hemostatic resuscitation. By using this technology, the optimal surgical strategy for these patients can be decided upon without causing any delays in their final care or greatly raising their radiation dose.
Topics: Humans; Young Adult; Adult; Middle Aged; Aged; Multiple Trauma; Tomography, X-Ray Computed; Thoracic Injuries; Trauma Centers; Wounds, Nonpenetrating; Whole Body Imaging; Retrospective Studies
PubMed: 38396199
DOI: 10.1007/s10140-024-02213-5 -
European Journal of Medical Research Mar 2024Metachromatic leukodystrophy (MLD; OMIM 250100 and 249900) is a rare lysosomal storage disease caused by deficient arylsulfatase A activity, leading to accumulation of... (Review)
Review
BACKGROUND
Metachromatic leukodystrophy (MLD; OMIM 250100 and 249900) is a rare lysosomal storage disease caused by deficient arylsulfatase A activity, leading to accumulation of sulfatides in the nervous system. This systematic literature review aimed to explore the effect of MLD on the lives of patients.
METHODS
The Ovid platform was used to search Embase, MEDLINE, and the Cochrane Library for articles related to the natural history, clinical outcomes, and burden of illness of MLD; congress and hand searches were performed using 'metachromatic leukodystrophy' as a keyword. Of the 531 publications identified, 120 were included for data extraction following screening. A subset of findings from studies relating to MLD natural history and burden of illness (n = 108) are presented here.
RESULTS
The mean age at symptom onset was generally 16-18 months for late-infantile MLD and 6-10 years for juvenile MLD. Age at diagnosis and time to diagnosis varied widely. Typically, patients with late-infantile MLD presented predominantly with motor symptoms and developmental delay; patients with juvenile MLD presented with motor, cognitive, and behavioral symptoms; and patients with adult MLD presented with cognitive symptoms and psychiatric and mood disorders. Patients with late-infantile MLD had more rapid decline of motor function over time and lower survival than patients with juvenile MLD. Commonly reported comorbidities/complications included ataxia, epilepsy, gallbladder abnormalities, incontinence, neuropathy, and seizures.
CONCLUSIONS
Epidemiology of MLD by geographic regions, quantitative cognitive data, data on the differences between early- and late-juvenile MLD, and humanistic or economic outcomes were limited. Further studies on clinical, humanistic (i.e., quality of life), and economic outcomes are needed to help inform healthcare decisions for patients with MLD.
Topics: Adult; Humans; Leukodystrophy, Metachromatic; Quality of Life; Cost of Illness
PubMed: 38494502
DOI: 10.1186/s40001-024-01771-1 -
Neurorehabilitation and Neural Repair Oct 2023We aimed to identify key aspects of the learning dynamics of proprioception training including: 1) specificity to the training type, 2) acquisition of proprioceptive... (Review)
Review
OBJECTIVE
We aimed to identify key aspects of the learning dynamics of proprioception training including: 1) specificity to the training type, 2) acquisition of proprioceptive skills, 3) retention of learning effects, and 4) transfer to different proprioceptive skills.
METHODS
We performed a systematic literature search using the database (MEDLINE, EMBASE, Cochrane Library, and PEDro). The inclusion criteria required adult participants who underwent any training program that could enhance proprioceptive function, and at least 1 quantitative assessment of proprioception before and after the intervention. We analyzed within-group changes to quantify the effectiveness of an intervention.
RESULTS
In total, 106 studies with 343 participant-outcome groups were included. Proprioception-specific training resulted in large effect sizes with a mean improvement of 23.4 to 42.6%, nonspecific training resulted in medium effect sizes with 12.3 to 22% improvement, and no training resulted in small effect sizes with 5.0 to 8.9% improvement. Single-session training exhibited significant proprioceptive improvement immediately (10 studies). For training interventions with a midway evaluation (4 studies), trained groups improved by approximately 70% of their final value at the midway point. Proprioceptive improvements were largely maintained at a delayed follow-up of at least 1 week (12 studies). Finally, improvements in 1 assessment were significantly correlated with improvements in another assessment (10 studies).
CONCLUSIONS
Proprioceptive learning appears to exhibit several features similar to motor learning, including specificity to the training type, 2 time constant learning curves, good retention, and improvements that are correlated between different assessments, suggesting a possible, common mechanism for the transfer of training.
Topics: Adult; Humans; Proprioception; Learning
PubMed: 37864458
DOI: 10.1177/15459683231207354