Longitudinal assessment of hand function in individuals with multiple sclerosis.

OBJECTIVE: Little is known about the frequency and severity of hand dysfunction in individuals with multiple sclerosis (MS). Hence, we sought to determine the extent that quantitative tests of hand function detect changes over time, evaluate their relationship to global disability measures, and identify predictors of hand function. METHODS: One-hundred and forty-seven individuals with MS were included (96 women, 84 relapsing-remitting MS [RRMS]) along with 35 age-and-sex matched controls. Quantitative tests of hand function (grip strength, pinch strength, 9 hole peg test [9HPT], finger tapping) and leg strength were acquired and normalized to age and sex. Expanded Disability Status Scale (EDSS) and timed 25 foot walk were also obtained. Spearman correlations, multivariate regression models and mixed effects linear regression were used for analysis. RESULTS: Our cohort had an EDSS of 3.6 ±â€¯2.2 (median ± SD) and age 44.6 ±â€¯11.9 years. Follow up time was up to 5 years. At baseline, 14/63 individuals with progressive MS (PMS) required more than twice as much time to complete the 9HPT using their dominant hand, compared to controls. Similarly, 11 individuals with PMS had less than 50% of grip strength and 6 had less than 50% of pinch strength, compared to controls. Additionally, 7 individuals with PMS were found to be at least 50% slower than controls in finger tapping. Over two years, 27/85 individuals with MS had more than 20% worsening in their 9HPT results from baseline (17 RRMS, 10 PMS) and 37/74 (20 RRMS, 17 PMS) had more than 20% worsening in their grip strength compared to baseline. CONCLUSIONS: Hand function is commonly impaired in individuals with MS. Assessing hand dysfunction with dynamometry and the 9HPT could help improve the precision of detecting changes in hand function over time in MS, and may be more sensitive in detecting changes in PMS. These quantitative tests may be useful as outcome measures in clinical trials using neuroprotective or reparative therapies and rehabilitative interventions.

Longitudinal relationships among posturography and gait measures in multiple sclerosis.

OBJECTIVE: Gait and balance dysfunction frequently occurs early in the multiple sclerosis (MS) disease course. Hence, we sought to determine the longitudinal relationships among quantitative measures of gait and balance in individuals with MS. METHODS: Fifty-seven ambulatory individuals with MS (28 relapsing-remitting, 29 progressive) were evaluated using posturography, quantitative sensorimotor and gait measures, and overall MS disability with the Expanded Disability Status Scale at each session. RESULTS: Our cohort's age was 45.8 ± 10.4 years (mean ± SD), follow-up time 32.8 ± 15.4 months, median Expanded Disability Status Scale score 3.5, and 56% were women. Poorer performance on balance measures was related to slower walking velocity. Two posturography measures, the anterior-posterior sway and sway during static eyes open, feet apart conditions, were significant contributors to walk velocity over time (approximate R(2) = 0.95), such that poorer performance on the posturography measures was related to slower walking velocity. Similarly, the anterior-posterior sway and sway during static eyes closed, feet together conditions were also significant contributors to the Timed 25-Foot Walk performance over time (approximate R(2) = 0.83). CONCLUSIONS: This longitudinal cohort study establishes a strong relationship between clinical gait measures and posturography. The data show that increases in static posturography and reductions in dynamic posturography are associated with a decline in walk velocity and Timed 25-Foot Walk performance over time. Furthermore, longitudinal balance measures predict future walking performance. Quantitative walking and balance measures are important additions to clinical testing to explore longitudinal change and understand fall risk in this progressive disease population.

The impact of dynamic balance measures on walking performance in multiple sclerosis.

BACKGROUND: Static posture imbalance and gait dysfunction are common in individuals with multiple sclerosis (MS). Although the impact of strength and static balance on walking has been examined, the impact of dynamic standing balance on walking in MS remains unclear. OBJECTIVE: To determine the impact of dynamic balance, static balance, sensation, and strength measures on walking in individuals with MS. METHODS: Fifty-two individuals with MS (27 women; 26 relapsing-remitting; mean age = 45.6 ± 10.3 years; median Expanded Disability Status Scale score = 3.5) participated in posturography testing (Kistler-9281 force plate), hip flexion, hip extension, ankle dorsiflexion strength (Microfet2 hand-held dynamometer), sensation (Vibratron II), and walk velocity (Optotrak Motion Analysis System). Analyses included, Mann-Whitney, Spearman correlation coefficients, and multiple regression. RESULTS: All measures were abnormal in individuals with MS when compared with norms (P < .05). Static balance (eyes open, feet together [EOFT]), anterior-posterior (AP) dynamic sway, and hip extension strength were strongly correlated with walking velocity (AP sway r = 0.68; hip extension strength r = 0.73; EOFT r = -0.40). Together, AP dynamic sway (ρr = 0.71; P < .001), hip extension strength (ρr = 0.54; P < .001), and EOFT static balance (ρr = -0.41; P = .01) explained more than 70% of the variance in walking velocity (P < .001). CONCLUSIONS: AP dynamic sway affects walking performance in MS. A combined evaluation of dynamic balance, static balance, and strength may lead to a better understanding of walking mechanisms and the development of strategies to improve walking.

Prevalence of ataxia in children: a systematic review.

OBJECTIVE: To estimate the prevalence of childhood ataxia resulting from both genetic and acquired causes. METHODS: A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. Five databases were searched for articles reporting a frequency measure (e.g., prevalence, incidence) of ataxia in children. Included articles were first grouped according to the World Health Organization (WHO) regions and subsequently classified according to etiology (genetic, acquired, or mixed). Each article was assessed for its risk of bias on the domains of sampling, measurement, and analysis. Incidence values were converted to prevalence estimates whenever possible. European prevalence estimates for different etiologies of ataxia were summed to gauge the overall prevalence of childhood ataxia. RESULTS: One hundred fifteen articles were included in the review. More than 50% of the data originated from the Europe WHO region. Data from this region also showed the least susceptibility to bias. Little data were available for Africa and Southeast Asia. The prevalence of acquired ataxias was found to vary more greatly across regions than the genetic ataxias. Ataxic cerebral palsy was found to be a significant contributor to the overall prevalence of childhood ataxia across WHO regions. The prevalence of childhood ataxias in Europe was estimated to be ∼26/100,000 children and likely reflects a minimum prevalence worldwide. CONCLUSIONS: The findings show that ataxia is a common childhood motor disorder with a higher prevalence than previously assumed. More research concerning the epidemiology, assessment, and treatment of childhood ataxia is warranted.

Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis.

BACKGROUND: The mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in CF. The most common mutation, ΔF508-CFTR, is a temperature-sensitive, trafficking mutant with reduced chloride transport and exaggerated immune response. The ΔF508-CFTR is misfolded, ubiquitinated, and prematurely degraded by proteasome mediated- degradation. We recently demonstrated that selective inhibition of proteasomal pathway by the FDA approved drug PS-341 (pyrazylcarbonyl-Phe-Leuboronate, a.k.a. Velcade or bortezomib) ameliorates the inflammatory pathophysiology of CF cells. This proteasomal drug is an extremely potent, stable, reversible and selective inhibitor of chymotryptic threonine protease-activity. The apprehension in considering the proteasome as a therapeutic target is that proteasome inhibitors may affect proteostasis and consecutive processes. The affect on multiple processes can be mitigated by nanoparticle mediated PS-341 lung-delivery resulting in favorable outcome observed in this study. RESULTS: To overcome this challenge, we developed a nano-based approach that uses drug loaded biodegradable nanoparticle (PLGA-PEGPS-341) to provide controlled and sustained drug delivery. The in vitro release kinetics of drug from nanoparticle was quantified by proteasomal activity assay from days 1-7 that showed slow drug release from day 2-7 with maximum inhibition at day 7. For in vivo release kinetics and biodistribution, these drug-loaded nanoparticles were fluorescently labeled, and administered to C57BL6 mice by intranasal route. Whole-body optical imaging of the treated live animals demonstrates efficient delivery of particles to murine lungs, 24 hrs post treatment, followed by biodegradation and release over time, day 1-11. The efficacy of drug release in CF mice (Cftr-/-) lungs was determined by quantifying the changes in proteasomal activity (~2 fold decrease) and ability to rescue the Pseudomonas aeruginosa LPS (Pa-LPS) induced inflammation, which demonstrates the rescue of CF lung disease in murine model. CONCLUSION: We have developed a novel drug delivery system to provide sustained delivery of CF "correctors" and "anti-inflammatories" to the lungs. Moreover, we demonstrate here the therapeutic efficacy of nano-based proteostasis-modulator to rescue Pa-LPS induced CF lung disease.