This case report describes the use of "Pediatric Constraint-Induced Therapy (Pediatric CI Therapy)" given on 2 separate occasions for a young child with quadriparetic cerebral palsy.
The child was 15 ...months of age at the beginning of the first episode of care. She had previously received weekly physical therapy and occupational therapy for 11 months, but she had no functional use of her right upper extremity (UE), independently or in an assistive manner. She scored from 5 to 7 months below her chronological age on developmental assessments in gross motor, fine motor, and self-help skills.
Pediatric CI Therapy involved placement of a full-arm, bivalved cast on the child's less affected UE while providing 3 weeks of intensive intervention (6 hours a day) for the child's more affected UE (intervention 1). Therapy included activities that were goal oriented but broken down into progressively more challenging step-by-step tasks. Pediatric CI Therapy was administered again 5 months later to promote UE skills and independence (intervention 2).
The child developed new behaviors throughout both interventions. During intervention 1, the child developed independent reach, grasp, release, weight bearing (positioned prone on elbows) of both UEs, gestures, self-feeding, sitting, and increased interactive play using both UEs. During intervention 2, she had increased independence and improved quality of UE movement, as supported by blinded clinical evaluations and parent ratings.
Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal ...cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is ‘burnt out’ and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.
The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a ...common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies.
Antifreeze proteins (AFPs) have the unique ability to adsorb to ice and inhibit its growth. Many organisms ranging from fish to bacteria use AFPs to retard freezing or lessen the damage incurred upon ...freezing and thawing. The ice-binding mechanism of the long linear alpha-helical type I AFPs has been attributed to their regularly spaced polar residues matching the ice lattice along a pyramidal plane. In contrast, it is not known how globular antifreeze proteins such as type III AFP that lack repeating ice-binding residues bind to ice. Here we report the 1.25 A crystal structure of recombinant type III AFP (QAE isoform) from eel pout (Macrozoarces americanus), which reveals a remarkably flat amphipathic ice-binding site where five hydrogen-bonding atoms match two ranks of oxygens on the 1010 ice prism plane in the direction, giving high ice-binding affinity and specificity. This binding site, substantiated by the structures and properties of several ice-binding site mutants, suggests that the AFP occupies a niche in the ice surface in which it covers the basal plane while binding to the prism face.
Abstract Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS), the clinical course of which varies considerably between patients. Genetic complexity and ...interactions with as yet unknown environmental factors have hindered researchers from fully elucidating the aetiology of the disease. In addition to influencing disease susceptibility, epidemiological evidence suggests that genetic factors may affect phenotypic expression of the disease. Genes that affect clinical outcome may be more effective therapeutic targets than those which determine susceptibility. We present in this review a comprehensive survey of the genes (both MHC- and non-MHC-related) that have been investigated for their role in disease outcome in MS. Recent studies implicating the role of the genotype and epistatic interactions in the MHC in determining outcome are highlighted.
Pediatric constraint-induced movement therapy (CIMT) is an evidence-based treatment that has a long history of demonstrating efficacy for children with hemiparesis. The purpose of this study is to ...determine the effectiveness of a culturally responsive CIMT program for children with hemiplegic cerebral palsy (CP) developed for the Vietnam healthcare system.
Thirty children with hemiplegic CP (mean age = 2.88 years, age range: 1 to 8 yrs, 60% male) were recruited to a CIMT program (7.5 h/week, 4 weeks) developed for the cultural context of Vietnam. Motor abilities of the affected arm and participation in daily activities were evaluated at 3 time points (one-week prior to CIMT (baseline), one-week before (pre) and after (post) CIMT) using the Quality of Upper Extremity Skill Test (QUEST) and Pediatric Motor Activity Log-Revised (PMAL-R). Individual goals were measured using the Goal Attainment Scale (GAS).
There were significant increases in the "How often scale" and "How Well" scales of the PMAL-R (0.75 and 0.75,
< 0.00)). Score of Grasp and Dissociated Movement items on the QUEST increased significantly (6.47 and 7.63,
< 0.001). Group GAS T-Scores were 52.19 indicating that children met individual goals.
A model of CIMT was successfully developed and delivered within the Vietnamese healthcare system. Future studies should explore the optimal model for CIMT in various regions of world where the delivery of rehabilitation services may vary.
We assessed the hypotheses that non-major histocompatibility complex multiple sclerosis (MS) susceptibility loci would be common to sporadic cases and multiplex families, that they would have larger ...effects in multiplex families, and that the aggregation of susceptibility loci contributes to the increased prevalence of MS in such families.
A set of 43 multiplex families comprising 732 individuals and 211 affected subjects was genotyped for 13 MS candidate genes identified by genome-wide association. A control data set of 182 healthy individuals was also genotyped to perform a case-control analysis alongside the family-based pedigree disequilibrium association test, although this may have been underpowered.
An effect of the IL2RA and CD58 loci was shown in multiplex families as in sporadic MS. The aggregate of the IL2RA, IL7R, EVI5, KIAA0350, and CD58 risk genotypes in affected individuals from multiplex families was found to be notably different from controls (chi(2) = 112, p = 1 x 10(-22)).
Although differences between individual families can only be suggested, the aggregate results in multiplex families demonstrate effect sizes that are increased as compared with those reported in previous studies for sporadic cases. In addition, they imply that concentrations of susceptibility alleles at IL2RA, IL7R, EVI5, KIAA0350, and CD58 are partly responsible for the heightened prevalence of multiple sclerosis within multiplex families.
The concurrence of multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) is exceedingly rare and the pathological features have not been examined extensively. Here we describe the key ...pathological features of a 40 year old man with pathologically confirmed concurrent MS and ALS.This is the most pathologically illustrative case of coincident MS and ALS demonstrating inflammatory and neurodegenerative features characteristic of each disease, and is the first to exhibit the presence of TDP-43 inclusions in this clinical entity. The intricate relationship between neuroinflammation and neurodegeneration in these diseases is discussed.
To investigate the relationship among attacks in the first 2 years (early relapses), secondary progression (SP), and late disability in multiple sclerosis (MS).
Cohort study with follow-up of 28 ...years.
Referral MS center.
Patients (N=730) with relapsing-remitting MS diagnosed according to Poser criteria, from the database of the London Multiple Sclerosis Clinic, London, Ontario, Canada.
Long-term evolution of patients with high (≥ 3 attacks) and early (within the first 2 years of the disease) frequency of relapses. In the total SP population and in patients grouped by numbers of early relapses, we assessed the predictive effect of latency to progression (time to SP) on times to attain cane requirement (Disability Status Scale score of 6 DSS 6) and bedridden status (DSS 8).
Among the group with frequent early relapses (n=158), outcomes were variable. Although 103 (65.2%) experienced rapid conversion to SP MS (median duration, 5 years) and rapidly attained DSS 6 and DSS 8 scores (7 and 17 years, respectively), the remainder (n=55) did not enter the SP phase, despite adverse early relapse features. Among the total SP population, longer latency to progression was associated with lower probability of attaining DSS 6 (odds ratio, 0.76 95% CI, 0.69-0.84 and 0.44 95% CI, 0.37-0.52 for 5- and 15-year latency, respectively) and longer times to severe disability. The same association between time to onset of SP and late outcomes was observed even in patients matched by number of early attacks. However, duration of the relapsing-remitting phase did not influence the times from SP onset to DSS levels.
Our results indicate dissociation between early inflammatory attacks and onset of the SP phase and further question the validity of relapse frequency as a surrogate marker for late disability. Among the group with frequent early relapses, we observed a large variability of outcomes, ranging from one extreme to the opposite.
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