Gait freezing and speech disturbance in Parkinson's disease.

Gait freezing and speech disturbance are disabling axial features of Parkinson's disease (PD). However, the pathogenesis of these features remains unclear. We investigated the relation between changes in gait freezing and speech disturbance using visual and auditory cues in PD. 18 PD patients, comprising of 9 patients with freezing (PDGF) and 9 without gait freezing were studied. Patients performed a 7-m back-and-forth walk in a baseline state and with visual and auditory cues. Gait velocity, stride length and cadence were evaluated using a three-dimensional gait analysis system. For speech evaluation, patients read ten sentences in a baseline state and with visual and auditory cues. The time delay of speech initiation, speech rate and the number of repetitions per sentence were quantified. In PDGF patients, the increase in gait velocity positively correlated with the decrease in the time delay of the speech initiation. Also, the increase in the gait velocity and cadence positively correlated with the decrease in the number of repetitions per sentence. The increase in the stride length positively correlated with the increase in speech rate. Lastly, the increase in stride length positively correlated with the decrease in the number of repetitions per sentence. These findings suggest that there is a common pathomechanism of gait freezing and speech disturbance in PD.

Changes of timing variables in swallowing of boluses with different viscosities in patients with dysphagia.

OBJECTIVES: To evaluate the timing of the swallowing process and the effect of bolus viscosity on swallowing. DESIGN: Prospective observational study. SETTING: General teaching hospital, rehabilitation unit. PARTICIPANTS: We enrolled patients with dysphagia (n=82) in a videofluoroscopic swallowing study (VFSS) from January 13, 2009, to October 22, 2009. Based on VFSS results, we classified patients as "thin-fluid aspirators" (n=40) or as "nonaspirators" (n=42). INTERVENTIONS: Swallowing of a 5-mL thick bolus and a 5-mL thin bolus in all patients. MAIN OUTCOME MEASURES: Kinematic analysis of various variables during the swallowing process (pharyngeal phase), including epiglottis contact with the bolus, laryngeal elevation, pharyngeal constriction, and upper esophageal sphincter opening. RESULTS: In both groups, the thin bolus arrived at the vallecular pouch earlier than the thick bolus. During swallowing of the thick bolus, the thin-fluid aspirators had a delayed latency of upper esophageal sphincter opening, delayed laryngeal elevation to peak level, and significantly longer rise time of laryngeal elevation. CONCLUSIONS: Our results indicate clear differences in the degree of adaptation to bolus viscosity between patients classified as thin-fluid aspirators and as nonaspirators. These differences were mainly in activities of laryngeal elevators rather than pharyngeal constrictors.

Erythropoietin promotes oligodendrogenesis and myelin repair following lysolecithin-induced injury in spinal cord slice culture.

Here, we sought to delineate the effect of EPO on the remyelination processes using an in vitro model of demyelination. We report that lysolecithin-induced demyelination elevated EPO receptor (EpoR) expression in oligodendrocyte progenitor cells (OPCs), facilitating the beneficial effect of EPO on the formation of oligodendrocytes (oligodendrogenesis). In the absence of EPO, the resultant remyelination was insufficient, possibly due to a limiting number of oligodendrocytes rather than their progenitors, which proliferate in response to lysolecithin-induced injury. By EPO treatment, lysolecithin-induced proliferation of OPCs was accelerated and the number of myelinating oligodendrocytes and myelin recovery was increased. EPO also enhanced the differentiation of neural progenitor cells expressing EpoR at high level toward the oligodendrocyte-lineage cells through activation of cyclin E and Janus kinase 2 pathways. Induction of myelin-forming oligodendrocytes by high dose of EPO implies that EPO might be the key factor influencing the final differentiation of OPCs. Taken together, our data suggest that EPO treatment could be an effective way to enhance remyelination by promoting oligodendrogenesis in association with elevated EpoR expression in spinal cord slice culture after lysolecithin-induced demyelination.

Subclinical gait disturbance and postoperative gait improvement in patients with degenerative cervical myelopathy.

This study aimed to evaluate the subclinical gait abnormalities and the postoperative gait improvements in patients with degenerative cervical myelopathy using three-dimensional gait analysis. We reviewed the gait analysis of 62 patients who underwent surgical treatment for degenerative cervical myelopathy. The asymptomatic gait group included 30 patients and the gait disturbance group included 32 patients who can walk on their own slowly or need assistive device on stairs. The step width (17.2 cm vs. 15.9 cm, P = 0.003), stride length (105.2 cm vs. 109.1 cm, P = 0.015), and double-limb support duration (13.4% vs. 11.7%, P = 0.027) improved only in the asymptomatic gait group. Preoperatively, the asymptomatic gait group exhibited better maximum knee flexion angle (60.5° vs. 54.8°, P = 0.001) and ankle plantarflexion angle at push-off (- 12.2° vs. - 6.5°, P = 0.001) compared to the gait disturbance group. Postoperatively, maximum knee flexion angle (62.3° vs. 58.2°, P = 0.004) and ankle plantarflexion angle at push-off (- 12.8° vs. - 8.3°, P = 0.002) were still better in the asymptomatic gait group, although both parameters improved in the gait disturbance group (P = 0.005, 0.039, respectively). Kinematic parameters could improve in patients with gait disturbance. However, temporospatial parameters improvement may be expected when the operative treatment is performed before apparent gait disturbance.

Gait analysis for evaluating the relationship between increased signal intensity on t2-weighted magnetic resonance imaging and gait function in cervical spondylotic myelopathy.

OBJECTIVE: To determine relationships between increased signal intensity (ISI) on T2-weighted cervical spine magnetic resonance imaging (MRI) and parameters of gait analysis in patients with cervical spondylotic myelopathy (CSM). DESIGN: Retrospective comparative study. SETTING: Gait analysis laboratory. PARTICIPANTS: Patients (N=36) who undertook cervical laminectomy or laminoplasty because of CSM. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Subjects were evaluated by using the modified Japanese Orthopaedic Association (JOA) scale, the Nurick scale, cervical spine MRI, and gait analysis. Two radiologists classified patients into 3 groups: intense, faint, and no ISI. RESULTS: Relative to patients without ISI, those with ISI showed significantly slower gait speed, longer step time, decreased single-limb support time, increased double-limb support time, and limited range of motion of knee and ankle (P<.05). Increased intensity tended to correlate with poor gait function including slower gait speed, longer step time, decreased single-limb support time, and increased double-limb support time. The modified JOA and Nurick scale did not correlate with ISI. CONCLUSIONS: In patients with CSM who received surgical treatment, more intense ISI on T2-weighted MRI correlated preoperatively with increased difficulties in gait function. Gait analysis may be a useful tool for evaluating gait functions in cervical myelopathy.

Neuroprotective effects of erythropoietin posttreatment against kainate-induced excitotoxicity in mixed spinal cultures.

Although the neuroprotective effects of erythropoietin (EPO) preconditioning are well known, the potential of postapplied EPO to protect neurons against excitotoxic injury has not been clearly established. Here we show that kainate (KA)-induced excitotoxicity, which plays a key role in secondary spinal cord injury, decreased neuron survival, inhibited neurite extension, and significantly reduced the expression of erythropoietin receptors (EpoR) in cultured spinal neurons. Posttreatment with EPO for 48 hr protected neurons against KA-induced injury, opposing KA-induced apoptosis and promoting regrowth of motoneuron neurites. These neuroprotective effects were paralleled by a restoration of EpoR expression. The importance of the EpoR signaling pathway was demonstrated using an EpoR blocking antibody, which neutralized the neuroprotective action of EPO posttreatment and prevented EPO-induced increases in EpoR expression. We also found that up-regulated EpoR stimulated the Janus kinase 2 (JAK2) pathway, which is known to facilitate neuronal growth and neurite regeneration. Although EPO posttreatment modestly attenuated KA-induced reactive gliosis in mixed neuron-glial cultures, blocking EpoR activity did not alter glial fibrillary acidic protein expression or astrocyte proliferation. In conclusion, 48 hr treatment with EPO following KA exposure induced EpoR-dependent protection against excitotoxic injury, demonstrating that preconditioning is not a prerequisite for neuroprotection by EPO. The neuroprotective effects of EPO posttreatment were mediated by an EpoR-dependent signaling pathway that possibly involves JAK2. The neuroprotective effect of EPO posttreatment against KA excitotoxicity appears to reflect direct effects on neurons and not indirect effects mediated by astrocytes.

Therapeutic effects of strengthening exercise on gait function of cerebral palsy.

PURPOSE: To assess the effectiveness of strengthening exercises of the lower limbs on improvement of muscle strength and gait function. METHOD: Those included were diagnosed as spastic diplegic or hemiplegic type of cerebral palsy (CP) and verified as grade 2 or 3 of the Gross Motor Function Classification System (GMFCS). Participants were divided into an experimental group (n = 9) or a control group (n = 8). The experimental group completed a 5-week strengthening program and the control group took part in conventional physical therapy. Muscle tone and strength of lower limb, Gross Motor Function Measure, lateral step up, squat to stand, and three dimensional gait analysis were tested at pre-training, post-training, and 6 week follow up. RESULTS: Maximal hip extensor strength, and number of squat to stand were significantly increased at post-training and 6 weeks follow up in the experimental group compared with the control group. GMFM score D and E significantly improved in the experimental group at post-training. The experimental group demonstrated significant increase of gait speed and stride length and decrease of double support phase at post-training and 6 weeks follow up. CONCLUSIONS: Strengthening exercises could be a useful method to improve gait function of patients with spastic CP.

Therapeutic time window for the effects of erythropoietin on astrogliosis and neurite outgrowth in an in vitro model of spinal cord injury.

BACKGROUND: The objective of this study was to investigate the underlying molecular mechanisms and the therapeutic time window for preventing astrogliosis with erythropoietin (EPO) treatment after in vitro modeled spinal cord injury (SCI). METHODS: Cultured rat spinal cord astrocytes were treated with kainate and scratching to generate an in vitro model of SCI. EPO (100U/mL or 300U/mL) was added immediately or 2, 4, or 8 hours after injury. Some cultures were also treated with AG490, an inhibitor of the EPO-EPO receptor (EpoR) pathway mediator Janus kinase 2 (JAK2). To evaluate neurite extension, rat embryonic spinal cord neurons were seeded onto astrocyte cultures and treated with EPO immediately after injury in the presence or absence of anti-EpoR antibody. RESULTS: EPO treatment at up to 8 hours after injury reduced the expression of axonal growth inhibiting molecules (glial fibrillary acidic protein, vimentin, and chondroitin sulfate proteoglycan), cytoskeletal regulatory proteins (Rho-associated protein kinase and ephephrin A4), and proinflammatory cytokines (tumor necrosis factor-alpha, transforming growth factor-beta, and phosphorylated-Smad3) in a dosedependent manner (P < .001). Most effects peaked with EPO treatment 2-4hours after injury. Additionally, EPO treatment up to 4 hours after injury promoted expression of the EpoR (>2-fold) and JAK2 (>3-fold) in a dose-dependent manner (P < .001), whereas co-treatment with AG490 precluded these effects (P < .001). EPO treatment up to 4hours after injury also enhanced axonal b-III tubulin-immunoreactivity (>12-fold), and this effect was precluded by co-treatment with an anti-EpoR antibody (P < .001). CONCLUSIONS: EPO treatment within 8 hours after injury reduced astrogliosis, and EPO treatment within 4 hours promoted neurite outgrowth. EPO therapy immediately after spinal cord injury may regulate glia to generate an environment permissive of axonal regeneration.

Erythropoietin is neuroprotective on GABAergic neurons against kainic acid-excitotoxicity in the rat spinal cell cultures.

The aim of this study was to investigate whether erythropoietin (EPO) protect the spinal GABAergic neurons against kainic acid (KA)-excitotoxic damage in rat spinal cord cell cultures. We performed immunohistochemical staining and Western blotting of glutamate decarboxylase 67 (GAD67), one isoform of GABA-producing enzyme, which was considered to have involved in nonsynaptic functions, such as energy metabolism or trophic support. T exposure to KA significantly reduced the intensity of GAD67 expression in the GABAergic neurons and whole cell lysate, indicating that the excitotoxic damage on the GABAergic neurons may lead to reduction of the GAD67 production following KA-exposure. We found that post-treatment of EPO for 48 h after KA-injury remarkably enhanced the expression level of GAD67 and erythropoietin receptors (EpoR), which were deteriorated by KA. Our confocal images clearly demonstrated a remarkably enhanced expression of EpoR on the surface of the GABAergic neurons by post-treated EPO after KA-damage. This result suggests that the neuroprotective effect of post-treated EPO on the GABAergic neurons can be related to the EPO-mediated EpoR upregulation following KA-excitotoxicity. We observed that the post-applied EPO clearly increased expression of tyrosine Janus kinase 2 (JAK2), which is known to be the first step of EpoR-stimulation. In conclusion, the post-treated EPO is a potent protector of the spinal GABAergic neurons against KA-excitotoxicity and regulates production of GAD67 for the multiple trophic roles after KA-induced disturbance. We suggested that the protective effect of post-treated EPO on the GABAergic neurons is mediated by signal transduction involving EpoR-dependent JAK2 pathway.

A Model of Glial Scarring Analogous to the Environment of a Traumatically Injured Spinal Cord Using Kainate.

OBJECTIVE: To develop an in vitro model analogous to the environment of traumatic spinal cord injury (SCI), the authors evaluated change of astrogliosis following treatments with kainate and/or scratch, and degree of neurite outgrowth after treatment with a kainate inhibitor. METHODS: Astrocytes were obtained from the rat spinal cord. Then, 99% of the cells were confirmed to be GFAP-positive astrocytes. For chemical injury, the cells were treated with kainate at different concentrations (10, 50 or 100 µM). For mechanical injury, two kinds of uniform scratches were made using a plastic pipette tip by removing strips of cells. For combined injury (S/K), scratch and kainate were provided. Cord neurons from rat embryos were plated onto culture plates immediately after the three kinds of injuries and some cultures were treated with a kainate inhibitor. RESULTS: Astro-gliosis (glial fibrillary acidic protein [GFAP], vimentin, chondroitin sulfate proteoglycan [CSPG], rho-associated protein kinase [ROCK], and ephrin type-A receptor 4 [EphA4]) was most prominent after treatment with 50 µM kainate and extensive scratch injury in terms of single arm (p<0.001) and in the S/K-induced injury model in view of single or combination (p<0.001). Neurite outgrowth in the seeded spinal cord (ß-III tubulin) was the least in the S/K-induced injury model (p<0.001) and this inhibition was reversed by the kainate inhibitor (p<0.001). CONCLUSION: The current in vitro model combining scratch and kainate induced glial scarring and inhibitory molecules and restricted neurite outgrowth very strongly than either the mechanically or chemically-induced injury model; hence, it may be a useful tool for research on SCI.

A Phase III Clinical Trial Showing Limited Efficacy of Autologous Mesenchymal Stem Cell Therapy for Spinal Cord Injury.

BACKGROUND: In our previous report, 3 of 10 patients with spinal cord injury who were injected with autologous mesenchymal stem cells (MSCs) showed motor improvement in the upper extremities and in activities of daily living. OBJECTIVE: To report on the results of a phase III clinical trial of autologous MSCs therapy. METHODS: Patients were selected based on the following criteria: chronic American Spinal Injury Association B status patients who had more than 12 months of cervical injury, and no neurological changes during the recent 3 months of vigorous rehabilitation. We injected 1.6 × 10 autologous MSCs into the intramedullary area at the injured level and 3.2 × 10 autologous MSCs into the subdural space. Outcome data were collected over 6 months regarding neurological examination, magnetic resonance imaging with diffusion tensor imaging, and electrophysiological analyses. RESULTS: Among the 16 patients, only 2 showed improvement in neurological status (unilateral right C8 segment from grade 1 to grade 3 in 1 patient and bilateral C6 from grade 3 to grade 4 and unilateral right C8 from grade 0 to grade 1 in 1 patient). Both patients with neurological improvement showed the appearance of continuity in the spinal cord tract by diffusion tensor imaging. There were no adverse effects associated with MSCs injection. CONCLUSION: Single MSCs application to intramedullary and intradural space is safe, but has a very weak therapeutic effect compared with multiple MSCs injection. Further clinical trials to enhance the effect of MSCs injection are necessary.

The effects of visual and auditory cues on freezing of gait in patients with Parkinson disease.

OBJECTIVE: The aims of this study was to investigate the effects of visual and auditory cues on the freezing of gait in Parkinson disease patients (PDF) compared with Parkinson disease patients without freezing of gait (PDNF). DESIGN: Fifteen PDF, 10 PDNF, and 10 age-matched healthy volunteers were recruited. Subjects walked back and forth on a 7-m walkway under three different conditions: baseline condition without cues, with visual cues, and with auditory cues. Visual cues consisted of white stripes located along the walkway. For auditory cues, a metronome was used. Gait was analyzed using three-dimensional computerized analysis. RESULTS: In the PDF group, both visual and auditory cues significantly affected visuospatial and kinematic gait parameters. PDF group benefited more from visual cues than auditory cues. In the PDNF and healthy volunteer groups, visual cues significantly decreased patient velocity. Auditory cues affected some kinematic parameters on PDNF group. Compared among three groups, visual cues more positively affected the PDF group, and auditory cues more positively affected kinematic parameters in the PDNF group. CONCLUSIONS: This study suggests that gait training using visual and auditory cues can improve PDF patient gait and that auditory cues enhance gait in PDNF patients with hypokinetic gait patterns.

Effects of different dilutions of botulinum toxin type A treatment for children with cerebral palsy with spastic ankle plantarflexor: a randomized controlled trial.

OBJECTIVE: The aim of this study was to investigate the influence of different volumes of saline vehicle on the effects of botulinum toxin type A in reducing ankle plantarflexor spasticity and improving gait pattern in children with cerebral palsy. DESIGN: Children with cerebral palsy having ankle plantarflexor spasticity were recruited. They were divided randomly into 2 groups. Botulinum toxin type A mixed with 2 ml or 8 ml saline was injected into the gastrocnemius in each group. Passive range of movement of ankle joint, Modified Ashworth Scale, and results of 3-dimensional motion analysis obtained at pre-treatment, 4, 12, and 24 weeks after treatment were compared. RESULTS: Ankle dorsiflexion was increased and ankle plantarflexor spasticity was decreased significantly after botulinum toxin type A treatment. Linear parameters were generally improved, and these improvements persisted until 12-24 weeks. The ankle dorsiflexion angle in the stance phase was also increased, and this increase was maintained until 24 weeks, as revealed by 3-dimensional gait analysis. However, no significantly different effect of varying the amount of saline vehicle was detected. CONCLUSION: Botulinum toxin type A improved physical findings and gait pattern in patients with cerebral palsy. The volume of saline mixed with botulinum toxin type A did not result in significant differences in physical evaluation or gait analysis. However, the large-volume group revealed side-effects more frequently and showed no clinical benefits compared with the small-volume group. We conclude that 2 ml of dilution is preferable for botulinum toxin type A treatment in children.

A comparison of young and old using three-dimensional motion analyses of gait, sit-to-stand and upper extremity performance.

BACKGROUND AND AIMS: To investigate the gait, sit-to-stand and upper extremity performance in the elderly compared with young adults. METHODS: Individuals over 60 and under 35 years old, with no medical, neurological or orthopedic problems participated in this study. Three-dimensional motion analyses of gait, sit-to-stand and upper extremity performance were performed, and results in the two age groups were compared. RESULTS: Compared with the younger cohort, the gait pattern of the elderly included slower velocity, decreased single stance period, decreased maximal knee extension, and decreased ankle dorsiflexion and plantarflexion. On sit-to-stand, the elderly had decreased knee extension angle, minimal knee extension and maximal ankle plantarflexion moment. On hand-at-object, the elderly had reduced maximal angle of shoulder flexion and increased maximal angle of anterior pelvic tilt. On hand-to-head and hand-to-mouth, the elderly had decreased maximal angle of shoulder flexion. CONCLUSIONS: The most debilitating motion factors in the elderly were limitation of shoulder flexion and decreased knee extension and ankle plantarflexion. Therapeutic programs for elderly individuals should target maintenance of flexibility and strengthening of ankle plantarflexors, strengthening knee extensors, and maintenance of the shoulder joint ROM.