Cerebral Palsy:Early Markers of Clinical Phenotype and Functional Outcome

The Prechtl General Movement Assessment (GMA) has become a cornerstone assessment in early identification of cerebral palsy (CP), particularly during the fidgety movement period at 3-5 months of age. Additionally, assessment of motor repertoire, such as antigravity movements and postural patterns, which form the Motor Optimality Score (MOS), may provide insight into an infant's later motor function. This study aimed to identify early specific markers for ambulation, gross motor function (using the Gross Motor Function Classification System, GMFCS), topography (unilateral, bilateral), and type (spastic, dyskinetic, ataxic, and hypotonic) of CP in a large worldwide cohort of 468 infants. We found that 95% of children with CP did not have fidgety movements, with 100% having non-optimal MOS. GMFCS level was strongly correlated to MOS. An MOS > 14 was most likely associated with GMFCS outcomes I or II, whereas GMFCS outcomes IV or V were hardly ever associated with an MOS > 8. A number of different movement patterns were associated with more severe functional impairment (GMFCS III-V), including atypical arching and persistent cramped-synchronized movements. Asymmetrical segmental movements were strongly associated with unilateral CP. Circular arm movements were associated with dyskinetic CP. This study demonstrated that use of the MOS contributes to understanding later CP prognosis, including early markers for type and severity

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Reliability of the Motor Optimality Score‐Revised: A study of infants at elevated likelihood for adverse neurological outcomes

AimTo assess the inter-assessor reliability of the Motor Optimality Score-Revised (MOS-R) when used in infants at elevated likelihood for adverse neurological outcome.MethodsMOS-R were assessed in three groups of infants by two assessors/cohort. Infants were recruited from longitudinal projects in Sweden (infants born extremely preterm), India (infants born in low-resource communities) and the USA (infants prenatally exposed to SARS-CoV-2). Intraclass correlation coefficients (ICC) and kappa (κw) were applied. ICC of MOS-R subcategories and total scores were presented for cohorts together and separately and for age-spans: 9-12, 13-16 and 17-25-weeks post-term age.Results252 infants were included (born extremely preterm n = 97, born in low-resource communities n = 97, prenatally SARS-CoV-2 exposed n = 58). Reliability of the total MOS-R was almost perfect (ICC: 0.98-0.99) for all cohorts, together and separately. Similar result was found for age-spans (ICC: 0.98-0.99). Substantial to perfect reliability was shown for the MOS-R subcategories (κw: 0.67-1.00), with postural patterns showing the lowest value 0.67.ConclusionThe MOS-R can be used in high-risk populations with substantial to perfect reliability, both in regards of total/subcategory scores as well as in different age groups. However, the subcategory postural patterns as well as the clinical applicability of the MOS-R needs further study

Reliability of the Motor Optimality Score- Revised: A study of infants at elevated likelihood for adverse neurological outcomes

Aim: To assess the inter--assessor reliability of the Motor Optimality Score-Revised (MOS-R) when used in infants at elevated likelihood for adverse neurological outcome. Methods: MOS-R were assessed in three groups of infants by two assessors/cohort. Infants were recruited from longitudinal projects in Sweden (infants born extremely preterm), India (infants born in low-resource communities) and the USA (infants prenatally exposed to SARS-CoV-2). Intraclass correlation coefficients (ICC) and kappa (.w) were applied. ICC of MOS- -R subcategories and total scores were presented for cohorts together and separately and for age-spans: 9-12, 13--16 and 17-25-weeks post--term age. Results: 252 infants were included (born extremely preterm n = 97, born in low-resource communities n = 97, prenatally SARS-CoV-2 exposed n = 58). Reliability of the total MOS-R was almost perfect (ICC: 0.98-0.99) for all cohorts, together and separately. Similar result was found for age-spans (ICC: 0.98-0.99). Substantial to perfect reliability was shown for the MO-R subcategories (.w: 0.67--1.00), with postural patterns showing the lowest value 0.67. Conclusion: The MOS-R can be used in high-risk populations with substantial to perfect reliability, both in regards of total/subcategory scores as well as in different age groups. However, the subcategory postural patterns as well as the clinical applicability of the MOS-R needs further study.Funding Agencies|Jerring foundation; Kronprinsessan Lovisas foerening foer barnasjukvard/Stiftelsen Axel Tielmans minnesfond; Promobilia Foundation Sweden; Region Stockholm (clinical research appointment); Saellskapet Barnavard; Swedish governmental funding of clinical research; Swedish Medical Research Council; Austrian Science Fund [FWF -KLI811]; DFG -SFB [1528 (C03)]; BMBF (CP-Diadem project); Cocozza foundation; Laerdal Foundation; Leibniz Foundation (LSC Audacity Award); Philipson Foundation; Simons Foundation SFARI program; Swedish Brain Foundation; Swedish Medical Society; Swedish Order of Freemasons in Stockholm; Volkswagenfoundation</p

Enhancing early detection of neurological and developmental disorders and provision of intervention in low-resource settings in Uttar Pradesh, India: study protocol of the G.A.N.E.S.H. programme

Introduction Around 9% of India’s children under six are diagnosed with neurodevelopmental disorders. Low-resource, rural communities often lack programmes for early identification and intervention. The Prechtl General Movement Assessment (GMA) is regarded as the best clinical tool to predict cerebral palsy in infants &lt;5 months. In addition, children with developmental delay, intellectual disabilities, late detected genetic disorders or autism spectrum disorder show abnormal general movements (GMs) during infancy. General Movement Assessment in Neonates for Early Identification and Intervention, Social Support and Health Awareness (G.A.N.E.S.H.) aims to (1) provide evidence as to whether community health workers can support the identification of infants at high-risk for neurological and developmental disorders and disabilities, (2) monitor further development in those infants and (3) initiate early and targeted intervention procedures.Methods This 3-year observational cohort study will comprise at least 2000 infants born across four districts of Uttar Pradesh, India. Community health workers, certified for GMA, video record and assess the infants’ GMs twice, that is, within 2 months after birth and at 3–5 months. In case of abnormal GMs and/or reduced MOSs, infants are further examined by a paediatrician and a neurologist. If necessary, early intervention strategies (treatment as usual) are introduced. After paediatric and neurodevelopmental assessments at 12–24 months, outcomes are categorised as normal or neurological/developmental disorders. Research objective (1): to relate the GMA to the outcome at 12–24 months. Research objective (2): to investigate the impact of predefined exposures. Research objective (3): to evaluate the interscorer agreement of GMA.Ethics and dissemination G.A.N.E.S.H. received ethics approval from the Indian Government Chief Medical Officers of Varanasi and Mirzapur and from the Ramakrishna Mission Home of Service in Varanasi. GMA is a worldwide used diagnostic tool, approved by the Ethics Committee of the Medical University of Graz, Austria (27-388 ex 14/15). Apart from peer-reviewed publications, we are planning to deploy G.A.N.E.S.H. in other vulnerable settings