Establishment of regression-based isometric strength reference values for the upper limb in persons with multiple sclerosis.

BACKGROUND: Muscle weakness is common and significantly affects persons with multiple sclerosis (PwMS), with dysfunction in upper limb (UL) muscle groups occurring in approximately 60% of PwMS. OBJECTIVE: To develop gender-specific regression-based prediction equations, with 95% confidence intervals for maximal bilateral UL isometric strength (shoulder abduction and adduction, wrist flexion and extension) and hand grip strength in PwMS. DESIGN: Cross-sectional study. SETTING: Comprehensive MS center. PARTICIPANTS: 256 PwMS. INTERVENTIONS: Not Applicable. MAIN OUTCOME MEASURES: Shoulder abduction and adduction and wrist flexion and extension isometric strength (Biodex System 4 Pro Dynamometer) and hand grip strength (Jamar handheld dynamometer) were measured. Disease characteristics (disability and disease duration) and demographics (age, height, and weight) were collected. Regression-based predictive equations were generated for the UL muscle groups for each gender and limb, using age, height, weight, disability, and disease duration as covariates. Variables were compared between genders using the Mann-Whitney U test. Maximal voluntary contraction (MVC) reference values (mean ± SD) were reported based on age (<30, 30-39, 40-49, 50-59, 60-69 years) and disability (mild, moderate, severe ambulant, and severe nonambulant) for each gender and limb. RESULTS: Regression-based equations were developed for both genders' strongest and weakest limb, accounting for age, height, weight, disability, and disease duration. MVC was higher in men than women (p < .001) in all muscle groups. Overall, MVC was significantly related to age in 14, height in 5, weight in 6, disability in 14, and disease duration in none of the 20 models. CONCLUSION: This is the first study to provide regression-based prediction equations for strongest and weakest MVC of UL muscle groups and demonstrated an inverse relationship between MVC with disability and age. Regression-based reference strength values can help clinicians understand muscular strength along a spectrum of PwMS and can aid in goal setting and education for realistic outcomes.

Patterns of prospective memory errors differ in persons with multiple sclerosis.

INTRODUCTION: Prospective memory (PM) deficits have been documented in multiple sclerosis (MS). This study aimed to explore the specific types of errors made by persons with MS (PwMS), including differences between PwMS and healthy controls (HC) and PwMS who do and do not have impairments in processing speed and/or verbal learning and memory. METHOD: PwMS (n = 111) and HC (n = 75) completed the Memory for Intentions Test (MIST), an objective measure of PM that has five types of errors that can be coded (PM failure, task substitution, loss of content, loss of time, and random errors). The number and types of PM errors were calculated for the overall MIST and six subscales, which break down performance by types of delay (2-Minute and 15-Minute), cue (Time and Event), and response (Verbal and Action). Impairment was defined as performing < 1.5 SD on either the Symbol Digit Modalities Test (SDMT) or Rey Auditory Verbal Learning Test (RAVLT). Bivariate analyses were used to examine group differences, with post-hoc pairwise comparisons with Bonferroni corrections. RESULTS: Nearly 93% of PwMS made at least one PM error, compared to 76% of HC (V = .24, p = .001). The most commonly made PM error by PwMS was loss of content errors (45.0%). PwMS made significantly more task substitution errors (26.4% vs. 7.6%, p < .001) and fewer loss of time errors (9.5% vs. 21.2%, p < .001) than HC. Impaired PwMS made more errors than non-impaired PwMS, specifically PM failures on time-based tasks. CONCLUSIONS: PM errors are common in PwMS, particularly when there are longer delays and time-based cues. Not only do PwMS make more errors than demographically similar HC, but they exhibit different cognitive process failures.

Physical Activity and Life Stress Are Associated With Illness Intrusiveness in Persons With Multiple Sclerosis.

OBJECTIVES: To explore which modifiable lifestyle behaviors contribute to illness intrusiveness in persons with multiple sclerosis (MS). DESIGN: Cohort study. SETTING: Community-based comprehensive MS center. PARTICIPANTS: Adults with MS (N=154) who completed an online battery of self-report questionnaires. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Illness intrusiveness was measured with the 13-item Illness Intrusiveness Ratings Scale. Lifestyle behaviors were measured using the respective components of the Simple Lifestyle Indicator Questionnaire (ie, Diet, Physical Activity, Alcohol, Smoking, and Life Stress) and self-reported body mass index (BMI). RESULTS: After controlling for age, race, sex, disease duration, and level of physical disability ("disability"), life stress was associated with greater illness intrusiveness (b=4.65, P<.001), and physical activity was associated with less illness intrusiveness (b=-0.67, P=.009). Exploratory mediation analyses revealed physical activity had an indirect effect on illness intrusiveness through disability (b=-0.39, 95% CI: -0.68, -0.16). Conversely, disability also displayed an indirect effect on illness intrusiveness through physical activity (b=0.57, 95% CI: 0.12, 1.16). CONCLUSIONS: Life stress and physical activity are 2 modifiable lifestyle behaviors that contribute to illness intrusiveness, with the latter also having an indirect effect through disability. These findings may help inform future behavioral interventions for improving health-related quality of life in persons with MS.

Cardiac surgical outcomes of patients with heterotaxy syndrome.

Objectives: The study objectives were to analyze the outcomes of pediatric patients with heterotaxy syndrome undergoing cardiovascular surgery and to determine the predictors of mortality. Methods: A retrospective analysis of 82 patients diagnosed with heterotaxy syndrome who underwent cardiovascular surgery between January 2008 and December 2017 was performed. Univariate and multivariable Cox regression analyses to determine risk factors for mortality and Kaplan-Meier analysis for survival were performed. Results: Patient mortality in the cohort was 34% (28/82), including 36% (20/55) for single ventricle palliation and 30% (8/27) for biventricular repair. At 5 years, the probability of survival did not differ between the groups by log-rank testing (P = .829). Multivariable analysis found extracorporeal membrane oxygenation support (hazard ratio, 10.4; 95% confidence interval, 4.3-25.4; P < .001), total anomalous pulmonary venous return (hazard ratio, 4.3; 95% confidence interval, 1.7-10.8; P = .002), and birth weight 2.5 kg or less (hazard ratio, 2.4; 95% confidence interval, 1.0-5.4; P = .041) to be independent risk factors for mortality in all-comers. Pulmonary vein stenosis was a univariate predictor of mortality among all patients with heterotaxy (hazard ratio, 3.0; 95% confidence interval, 1.4-6.4; P = .005) and in the subgroup of patients with single ventricles (hazard ratio, 4.0; 95% confidence interval, 1.7-9.7; P = .002). Overall survival was 66% (54/82) at a median follow-up time of 2.2 years (0.4-4.1) from the initial surgery. Conclusions: Outcomes of children with heterotaxy syndrome, irrespective of the operative pathway, remain suboptimal in the current era. Risk factors for mortality in this population include birth weight 2.5 kg or less, extracorporeal membrane oxygenation, pulmonary vein stenosis, and total anomalous pulmonary venous return, which may help to further optimize surgical decision making. Multiorgan system involvment is frequently encountered in these patients.

Impact of Cardiopulmonary Bypass on Neurogenesis and Cortical Maturation.

OBJECTIVE: Neurodevelopmental delays and frontal lobe cortical dysmaturation are widespread among children with congenital heart disease (CHD). The subventricular zone (SVZ) is the largest pool of neural stem/progenitor cells in the postnatal brain. Our aim is to determine the effects of cardiopulmonary bypass (CPB) on neurogenesis and cortical maturation in piglets whose SVZ development is similar to human infants. METHODS: Three-week-old piglets (n = 29) were randomly assigned to control (no surgery), mild-CPB (34°C full flow for 60 minutes) and severe-CPB groups (25°C circulatory-arrest for 60 minutes). The SVZ and frontal lobe were analyzed with immunohistochemistry 3 days and 4 weeks postoperatively. MRI of the frontal lobe was used to assess cortical development. RESULTS: SVZ neurogenic activity was reduced up to 4 weeks after both mild and severe CPB-induced insults. CPB also induced decreased migration of young neurons to the frontal lobe, demonstrating that CPB impairs postnatal neurogenesis. MRI 4 weeks after CPB displayed a decrease in gyrification index and cortical volume of the frontal lobe. Cortical fractional anisotropy was increased after severe CPB injury, indicating a prolonged deleterious impact of CPB on cortical maturation. Both CPB-induced insults displayed a significant change in densities of three major inhibitory neurons, suggesting excitatory-inhibitory imbalance in the frontal cortex. In addition, different CPB insults altered different subpopulations of inhibitory neurons. INTERPRETATION: Our results provide novel insights into cellular mechanisms contributing to CHD-induced neurological impairments. Further refinement of CPB hardware and techniques is necessary to improve long-term frontal cortical dysmaturation observed in children with CHD. ANN NEUROL 2021;90:913-926.

Chronic perinatal hypoxia delays cardiac maturation in a mouse model for cyanotic congenital heart disease.

Compared with acyanotic congenital heart disease (CHD), cyanotic CHD has an increased risk of lifelong mortality and morbidity. These adverse outcomes may be attributed to delayed cardiomyocyte maturation, since the transition from a hypoxic fetal milieu to oxygen-rich postnatal environment is disrupted. We established a rodent model to replicate hypoxic myocardial conditions spanning perinatal development, and tested the hypothesis that chronic hypoxia impairs cardiac development. Pregnant mice were housed in hypoxia beginning at embryonic day 16. Pups stayed in hypoxia until postnatal day (P)8 when cardiac development is nearly complete. Global gene expression was quantified at P8 and at P30, after recovering in normoxia. Phenotypic testing included electrocardiogram, echocardiogram, and ex vivo electrophysiology study. Hypoxic P8 animals were 47% smaller than controls with preserved heart size. Gene expression was grossly altered by hypoxia at P8 (1,427 genes affected), but normalized after recovery (P30). Electrocardiograms revealed bradycardia and slowed conduction velocity in hypoxic animals at P8, with noticeable resolution after recovery (P30). Notable differences that persisted after recovery (P30) included a 65% prolongation in ventricular effective refractory period, sinus node dysfunction, 23% reduction in ejection fraction, and 16% reduction in fractional shortening in animals exposed to hypoxia. We investigated the impact of chronic hypoxia on the developing heart. Perinatal hypoxia was associated with changes in gene expression and cardiac function. Persistent changes to the electrophysiological substrate and contractile function warrant further investigation and may contribute to adverse outcomes observed in the cyanotic CHD population.NEW & NOTEWORTHY We utilized a new mouse model of chronic perinatal hypoxia to simulate the hypoxic myocardial conditions present in cyanotic congenital heart disease. Hypoxia caused numerous abnormalities in cardiomyocyte gene expression, the electrophysiologic substrate of the heart, and contractile function. Taken together, alterations observed in the neonatal period suggest delayed cardiac development immediately following hypoxia.

Identifying Early Neuropsychological Indicators of Cognitive Involvement in Multiple Sclerosis.

Multiple sclerosis (MS) is a debilitating disease of the central nervous system that is most commonly seen in early to middle adulthood, although it can be diagnosed during childhood or later in life. While cognitive impairment can become more prevalent and severe as the disease progresses, signs of cognitive involvement can be apparent in the early stages of the disease. In this review, we discuss the prevalence and types of cognitive impairment seen in early MS, including the specific measures used to identify them, as well as the challenges in characterizing their frequency and progression. In addition to examining the progression of early cognitive involvement over time, we explore the clinical factors associated with early cognitive involvement, including demographics, level of physical disability, disease modifying therapy use, vocational status, and psychological and physical symptoms. Given the prevalence and functional impact these impairments can have for persons with MS, considerations for clinicians are provided, such as the role of early cognitive screenings and the importance of comprehensive neuropsychological assessments.

Impact of Mesenchymal Stromal Cell Delivery Through Cardiopulmonary Bypass on Postnatal Neurogenesis.

BACKGROUND: Neurodevelopmental impairment is an important challenge for survivors after neonatal surgery with cardiopulmonary bypass (CPB). The subventricular zone, where most neural stem/progenitors originate, plays a critical role in cortical maturation of the frontal lobe. Promoting neurogenesis in the subventricular zone is therefore a potential therapeutic target for preserving cortical growth. Mesenchymal stromal cells (MSCs) promote endogenous regeneration in the rodent brain. We investigated the impact of MSC delivery through CPB on neural stem/progenitor cells and neuroblasts (ie, young neurons) in the piglet subventricular zone. METHODS: Two-week-old piglets (n = 12) were randomly assigned to one of three groups: (1) control, (2) deep hypothermic circulatory arrest, and (3) circulatory arrest, followed by MSC administration. MSCs (10 × 106 per kg) were delivered through CPB during the rewarming period. Neural stem/progenitors, proliferating cells, and neuroblasts were identified with immunohistochemistry at 3 hours after CPB. RESULTS: CPB-induced insults caused an increased proliferation of neural stem/progenitors (P < .05). MSC delivery reduced the acute proliferation. MSC treatment increased the number of neuroblasts in the outer region of the subventricular zone (P < .05) where they form migrating chains toward the frontal lobe. Conversely, the thickness of the neuroblast-dense band along the lateral ventricle was reduced after treatment (P < .05). These findings suggest that MSC treatment changes neuroblast distribution within the subventricular zone. CONCLUSIONS: MSC delivery through CPB has the potential to mitigate effects of CPB on neural stem/progenitor cells and to promote migration of neuroblasts. Further investigation is necessary to determine the long-term effect of MSC treatment during CPB on postnatal neurogenesis.

Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease.

Background Reduced oxygen delivery in congenital heart disease causes delayed brain maturation and white matter abnormalities in utero. No treatment currently exists. Tetrahydrobiopterin (BH4) is a cofactor for neuronal nitric oxide synthase. BH4 availability is reduced upon NOS activation, such as during hypoxic conditions, and leads to toxin production. We hypothesize that BH4 levels are depleted in the hypoxic brain and that BH4 replacement therapy mitigates the toxic effects of hypoxia on white matter. Methods and Results Transgenic mice were used to visualize oligodendrocytes. Hypoxia was introduced during a period of white matter development equivalent to the human third trimester. BH4 was administered during hypoxia. BH4 levels were depleted in the hypoxic brain by direct quantification (n=7-12). The proliferation (n=3-6), apoptosis (n=3-6), and developmental stage (n=5-8) of oligodendrocytes were determined immunohistologically. Total oligodendrocytes increased after hypoxia, consistent with hypoxia-induced proliferation seen previously; however, mature oligodendrocytes were less prevalent in hypoxia, and there was accumulation of immature oligodendrocytes. BH4 treatment improved the mature oligodendrocyte number such that it did not differ from normoxia, and accumulation of immature oligodendrocytes was not observed. These results persisted beyond the initial period of hypoxia (n=3-4). Apoptosis increased with hypoxia but decreased with BH4 treatment to normoxic levels. White matter myelin levels decreased following hypoxia by western blot. BH4 treatment normalized myelination (n=6-10). Hypoxia worsened sensory-motor coordination on balance beam tasks, and BH4 therapy normalized performance (n=5-9). Conclusions Suboptimal BH4 levels influence hypoxic white matter abnormalities. Repurposing BH4 for use during fetal brain development may limit white matter dysmaturation in congenital heart disease.