Development and Results of an Implementation Plan for High-Intensity Gait Training.

BACKGROUND AND PURPOSE: High-intensity gait training is recommended in stroke rehabilitation to improve gait speed, walking distance, and balance. However, identifying effective and efficient implementation methods is a challenge for rehabilitation providers. This article describes the development of an implementation plan, presents findings of each implementation phase, and identifies the project's impact on clinicians and the health system. METHODS: Two inpatient rehabilitation facilities, including 9 physical therapists, collaborated with a knowledge translation center to implement this program. We developed an implementation plan using the Knowledge-to-Action Framework and utilized the Consolidated Framework for Implementation Research to identify barriers and select implementation strategies. Using mix-methods research, including surveys and informal discussions, we evaluated current practice, barriers, outcomes, and the sustainability of high-intensity gait training in practice. RESULTS: A multicomponent implementation plan that targeted barriers was developed. Before implementation, clinicians reported providing several balance, strength training, and gait interventions to improve walking. Barriers to using high-intensity gait training included knowledge, beliefs, adaptability of high-intensity gait training, resources, culture, and others. Twenty-six implementation strategies were selected to target the barriers. Surveys and informal discussions identified significant changes in perceived practice, adoption of high-intensity gait training, and positive impacts on the health system. The 2-year follow-up survey indicated that the new practice was sustained. DISCUSSION AND CONCLUSIONS: Using a multicomponent implementation plan that targeted barriers, we successfully implemented high-intensity gait training in clinical practice. Contributors to successful implementation may include the implementation methods, usual care interventions, and clinicians' readiness for this change.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A352.).

Implementation of High-Intensity Stepping Training During Inpatient Stroke Rehabilitation Improves Functional Outcomes.

Background and Purpose- Therapeutic strategies that capitalize on the intrinsic capacity for neurological recovery early poststroke to improve locomotion are uncertain. Emerging data suggest that task-specific stepping practice provided at higher cardiovascular intensities may be critical dosage parameters that could maximize locomotor recovery. The purpose of this investigation was to determine the comparative effectiveness of providing high-intensity training on locomotor capacity early poststroke as compared with usual care. Methods- A quasi-experimental design was used to compare changes in stepping activity (StepWatch), walking, and balance outcomes during usual care (n=56) versus high-intensity stepping intervention (n=54) in inpatient stroke patients. Primary outcomes assessed weekly included self-selected and fastest gait speed, 6-minute walk test, and the Berg Balance Scale, with secondary outcomes of Swedish Postural Assessment Scale for Stroke-Norwegian version, Functional Ambulation Category, 30-s sit-to-stand, strength (average manual muscle testing), and Barthel Index. Regression analyses identified relationships between demographics, baseline function, and training activities (steps per day; duration achieved, 70%-85% maximum heart rates) and primary outcomes at discharge. Results- Following implementation of high-intensity stepping, average steps per day (5777±2784) were significantly greater than during usual care (3917±2656; P<0.001). Statistically different and clinically meaningful changes in self-selected speed (0.39±0.28 versus 0.16±0.26 m/s) and fastest gait speed (0.47±0.41 versus 0.17±0.38 m/s; both P<0.001) were observed following high-intensity interventions versus usual care and at every assessment throughout the length of stay. Changes in Berg Balance Scale and 6-minute walk test were also statistically and clinically different between groups, while secondary measures of Functional Ambulation Category and strength were also different at discharge. Primary predictors of improved walking capacity were steps per day, baseline impairments, and age. Conclusions- Provision of high-intensity stepping training applied during inpatient rehabilitation resulted in significantly greater walking and balance outcomes. This training paradigm should be further tested in other contexts to determine the generalizability to real-world and community settings.

A novel homozygous variant in the SPG7 gene presenting with childhood optic nerve atrophy.

PURPOSE: To describe a case of hereditary spastic ataxia (HSP) presenting with childhood optic nerve atrophy and report a novel homozygous variant in the SPG7 gene. OBSERVATIONS: A 57-year-old man suffering from progressive optic nerve atrophy since childhood eventually underwent genetic testing. A targeted whole exome gene sequencing panel for optic neuropathy identified a novel homozygous variant in the SPG7 gene, c.2T > G, p.(Met?), which likely abolished production of paraplegin, an inner mitochondrial membrane protein. Subsequent neurologic examination revealed subtle signs of spastic paraplegia and ataxia in keeping with the genetic diagnosis of SPG7. CONCLUSION AND IMPORTANCE: Spastic paraplegia 7 (SPG7) is an autosomal recessive form of the neurodegenerative disorder HSP. Pure HSP is characterized by spastic paraparesis in the lower limbs, whereas complicated HSP presents additional neurological manifestations. This case report adds to the evidence that SPG7 can present with childhood optic nerve atrophy, preceding the characteristic SPG7 manifestations. SPG7 should be considered in the workup of suspected hereditary optic neuropathy.

Successful treatment with repeated dexamethasone implant injections for recurrent macular edema after acute retinal necrosis.

BACKGROUND: The treatment of recurrent cystoid macular edema associated with acute retinal necrosis is challenging due to the concern that treatment with intravitreal steroids may reactivate the retinitis. CASE REPORT: An immunocompetent patient diagnosed with acute retinal necrosis was treated with oral valacyclovir and intravitreal injections of foscarnet. Giant tears in her retina necessitated a vitrectomy with silicone oil. She developed cystoid macular edema after the removal of the silicone oil. The edema responded to high-dose prednisolone but recurred when the dose was tapered to 20 mg daily. Under close surveillance and increased antiviral medication, she was treated with a dexamethasone implant with complete resolution of the edema. Unfortunately, the edema recurred, and the treatment had to be repeated. Over 18 months, she received five dexamethasone implants without recurrence of the viral retinitis. CONCLUSIONS: This case shows successful treatment of recurring cystoid macular edema following acute retinal necrosis with repeated intravitreal dexamethasone implants in a patient receiving valacyclovir maintenance treatment.

Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5.

The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the GEMIN5 gene among seven unrelated families with nine affected individuals presenting with spastic ataxia and cerebellar atrophy. GEMIN5, an RNA-binding protein, has been shown to regulate transcription and translation machinery. GEMIN5 is a component of small nuclear ribonucleoprotein (snRNP) complexes and helps in the assembly of the spliceosome complexes. We found that biallelic GEMIN5 variants cause structural abnormalities in the encoded protein and reduce expression of snRNP complex proteins in patient cells compared with unaffected controls. Finally, knocking out endogenous Gemin5 in mice caused early embryonic lethality, suggesting that Gemin5 expression is crucial for normal development. Our work further expands on the phenotypic spectrum associated with GEMIN5-related disease and implicates the role of GEMIN5 among patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.

Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study.

A population-based, cross-sectional study was performed in southeast Norway, between January 2002 and February 2008, to identify subjects with hereditary ataxia and hereditary spastic paraplegia, and to estimate the prevalence of these disorders. Patients were recruited through colleagues, families, searches in computerized hospital archives and the National Patients' Association for Hereditary Ataxia and Spastic Paraplegia. Strict criteria were used for inclusion of familial and isolated subjects. A project neurologist examined all index subjects and clinical and genetic data were registered. The source population on January 1, 2008 was 2.63 million and the prevalence day was set as February 1, 2008. One hundred seventy-one subjects from 87 unrelated families with hereditary ataxia and 194 subjects from 65 unrelated families with hereditary spastic paraplegia were included. The total prevalence was estimated at 13.9/100 000. Hereditary ataxia prevalence in the region was estimated at 6.5/100 000: 4.2/100 000 for autosomal-dominant and 2.3/100 000 for autosomal recessive, 0.15/100 000 for Friedreich's ataxia and 0.4/100 000 for ataxia telangiectasia. Hereditary spastic paraplegia prevalence was 7.4/100 000: 5.5/100 000 for autosomal dominant-hereditary spastic paraplegia, 0.6/100 000 for autosomal recessive-hereditary spastic paraplegia and 1.3/100 000 for isolated subjects. Marked differences were found in the frequencies of hereditary ataxia subtypes compared with other countries, while those of the most common autosomal dominant-hereditary spastic paraplegia genotypes, SPG4, SPG3 and SPG31, were similar to those previously reported. Clear variations between age groups and counties were observed, but no gender differences. Mean age on prevalence day was 48 years, mean age at onset was 24 years. We present the largest population study performed on hereditary ataxia and hereditary spastic paraplegia prevalence and report a higher prevalence than expected. Better inclusion criteria and multiple search strategies may explain the observed differences.

Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.

Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 +/- 6.6 years, the phenotype of 38 SPG11 patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.

Hereditary spastic paraplegia 3A associated with axonal neuropathy.

OBJECTIVE: To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia. DESIGN: We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4. RESULTS: In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy. CONCLUSIONS: We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.

A polymorphic Alu insertion that mediates distinct disease-associated deletions.

Large deletions that are associated with insertions of Alu-derived sequence represent a rare, but potentially unique class of alterations. Whether they form by a one-step mechanism or by a primary insertion step followed by an independent secondary deletion step is not clear. We resolved two disease-associated SPAST deletions, which involve distinct exons by long range PCR. Alu-derived sequence was observed between the breakpoints in both cases. The intronic regions that represent the targets of potentially involved Alu retrotransposition events overlapped. Microsatellite- and SNP-based haplotyping indicated that both deletions originated on one and the same founder allele. Our data suggest that the deletions are best explained by two-step insertion-deletion scenarios for which a single Alu retrotransposition event represents the shared primary step. This Alu then mediated one of the deletions by non-homologous end joining and the other by non-allelic homologous recombination. Our findings thus strongly argue for temporal separation of insertion and deletion in Alu insertion-associated deletions. They also suggest that certain Alu integrations confer a general increase in local genomic instability, and that this explains why they are usually not detected during the probably short time that precedes the rearrangements they mediate.

Efficacy of Constraint-Induced Movement Therapy in Early Stroke Rehabilitation: A Randomized Controlled Multisite Trial.

BACKGROUND: There is limited evidence for the effects of constraint-induced movement therapy (CIMT) in the early stages of stroke recovery. OBJECTIVE: To evaluate the effect of a modified CIMT within 4 weeks poststroke. METHODS: This single-blinded randomized multisite trial investigated the effects of CIMT in 47 individuals who had experienced a stroke in the preceding 26 days. Patients were allocated to a CIMT or a usual care (control) group. The CIMT program was 3 h/d over 10 consecutive working days, with mitt use on the unaffected arm for up to 90% of waking hours. The follow-up time was 6 months. The primary outcome was the Wolf Motor Function test (WMFT) score. Secondary outcomes were the Fugl-Meyer upper-extremity motor score, Nine-Hole Peg test (NHPT) score, the arm use ratio, and the Stroke Impact Scale. Analyses of covariance with adjustment for baseline values were used to assess differences between the groups. RESULTS: After treatment, the mean timed WMFT score was significantly better in the CIMT group compared with the control group. Moreover, posttreatment dexterity, as tested with the NHPT, was significantly better in the CIMT group, whereas the other test results were similar in both the groups. At the 6-month follow-up, the 2 groups showed no significant difference in arm impairment, function, or use in daily activities. CONCLUSIONS: Despite a favorable effect of CIMT on timed movement measures immediately after treatment, significant effects were not found after 6 months.

Norwegian constraint-induced therapy multisite trial: adherence to treatment protocol applied early after stroke.

OBJECTIVE: To investigate to what degree patients adhered to a modified constraint-induced movement therapy protocol, and to explore factors associated with the results. DESIGN: Prospective follow-up of the intervention arm in a randomized controlled trial. SUBJECTS: Twenty-four patients within 28 days after stroke. METHODS: The protocol specified 180 min of treatment/day for 10 days. Therapy schedules were used to calculate the time spent in shaping, task practice and transfer package, as well as movement quality, perceived exertion and treatment progression. RESULTS: The participants spent a mean of 91.3% of the intended time for treatment. Time spent practicing tasks was 30 min less than the intended 150 min, whereas slightly more time than intended was spent on the transfer package. Of the time spent in shaping, 33% was spent in pure activity. The remainder was used on feedback, task set-up, and rests. Adherence was positively associated with treatment progression (r = 0.74) and negatively associated with age (r = -0.65). Women were less likely to use the mitt (r = -0.55). CONCLUSION: Overall adherence was good; however, time spent in motor activity was only one-third of total treatment time. The parameters in the constraint-induced movement therapy protocol should be individually adjusted early after stroke.

STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.

BACKGROUND: A subset of hereditary cerebellar ataxias is inherited as autosomal recessive traits (ARCAs). Classification of recessive ataxias due to phenotypic differences in the cerebellum and cerebellar structures is constantly evolving due to new identified disease genes. Recently, reports have linked mutations in genes involved in ubiquitination (RNF216, OTUD4, STUB1) to ARCA with hypogonadism. METHODS AND RESULTS: With a combination of homozygozity mapping and exome sequencing, we identified three mutations in STUB1 in two families with ARCA and cognitive impairment; a homozygous missense variant (c.194A > G, p.Asn65Ser) that segregated in three affected siblings, and a missense change (c.82G > A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A > T, p.Lys144Ter) in another patient. STUB1 encodes CHIP (C-terminus of Heat shock protein 70 - Interacting Protein), a dual function protein with a role in ubiquitination as a co-chaperone with heat shock proteins, and as an E3 ligase. We show that the p.Asn65Ser substitution impairs CHIP's ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate. These results are consistent with previous studies highlighting this as a critical residue for the interaction between CHIP and its co-chaperones. Furthermore, we show that the levels of CHIP are strongly reduced in vivo in patients' fibroblasts compared to controls. CONCLUSIONS: These results suggest that STUB1 mutations might cause disease by impacting not only the E3 ligase function, but also its protein interaction properties and protein amount. Whether the clinical heterogeneity seen in STUB1 ARCA can be related to the location of the mutations remains to be understood, but interestingly, all siblings with the p.Asn65Ser substitution showed a marked appearance of accelerated aging not previously described in STUB1 related ARCA, none display hormonal aberrations/clinical hypogonadism while some affected family members had diabetes, alopecia, uveitis and ulcerative colitis, further refining the spectrum of STUB1 related disease.

A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42).

The most frequent causes of autosomal dominant (AD) hereditary spastic paraplegias (HSP) (ADHSP) are mutations in the SPAST gene (SPG4 locus). However, roughly 60% of patients are negative for SPAST mutations, despite their family history being compatible with AD inheritance. A mutation in the gene for an acetyl-CoA transporter (SLC33A1) has recently been reported in one Chinese family to cause ADHSP-type SPG42. In this study, we screened 220 independent SPAST mutation-negative ADHSP samples for mutations in the SLC33A1 gene by high-resolution melting curve analysis. Conspicuous samples were validated by direct sequencing. Moreover, copy number variations affecting SLC33A1 were screened by multiplex ligation-dependent probe amplification assay. We could not identify potentially disease-causing mutations in our patients either by mutation scanning or by gene dosage analysis, as for the latter specific positive controls are not available to date. As our sample represents ADHSP patients for whom SPAST mutations and almost in all cases ATL1 and REEP1 mutations had been excluded, we consider SLC33A1 gene mutations as being very rare in a European ADHSP cohort, if present at all. To date, as SPG42 has still not been identified in a second, unrelated family, systematic genetic testing for SLC33A1 mutations is not recommended.