Upper Limb Robotic Rehabilitation After Stroke: A Multicenter, Randomized Clinical Trial.

BACKGROUND AND PURPOSE: After stroke, only 12% of survivors obtain complete upper limb (UL) functional recovery, while in 30% to 60% UL deficits persist. Despite the complexity of the UL, prior robot-mediated therapy research has used only one robot in comparisons to conventional therapy. We evaluated the efficacy of robotic UL treatment using a set of 4 devices, compared with conventional therapy. METHODS: In a multicenter, randomized controlled trial, 247 subjects with subacute stroke were assigned either to robotic (using a set of 4 devices) or to conventional treatment, each consisting of 30 sessions. Subjects were evaluated before and after treatment, with follow-up assessment after 3 months. The primary outcome measure was change from baseline in the Fugl-Meyer Assessment (FMA) score. Secondary outcome measures were selected to assess motor function, activities, and participation. RESULTS: One hundred ninety subjects completed the posttreatment assessment, with a subset (n = 122) returning for follow-up evaluation. Mean FMA score improvement in the robotic group was 8.50 (confidence interval: 6.82 to 10.17), versus 8.57 (confidence interval: 6.97 to 10.18) in the conventional group, with no significant between-groups difference (adjusted mean difference -0.08, P = 0.948). Both groups also had similar change in secondary measures, except for the Motricity Index, with better results for the robotic group (adjusted mean difference 4.42, P = 0.037). At follow-up, subjects continued to improve with no between-groups differences. DISCUSSION AND CONCLUSIONS: Robotic treatment using a set of 4 devices significantly improved UL motor function, activities, and participation in subjects with subacute stroke to the same extent as a similar amount of conventional therapy. Video Abstract is available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A291).

Nerve ultrasonography findings as possible pitfall in differential diagnosis between hereditary transthyretin amyloidosis with polyneuropathy and chronic inflammatory demyelinating polyneuropathy.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare form of treatable severe progressive sensory-motor and autonomic polyneuropathy. Albeit usually axonal, late-onset ATTRv-PN can show clear demyelinating features at electrodiagnostic studies, sometimes fulfilling CIDP diagnostic criteria. High-resolution nerve ultrasonography (HRUS) is an emerging useful supportive tool in the diagnosis of CIDP. Herein, we present a late-onset ATTRv-PN patient in which both clinical-neurophysiological and HRUS features could have led to a CIDP misdiagnosis. Nerve alterations at HRUS and MRI have already been reported in ATTRv-PN, albeit not in ATTRv-PN patients with clinical and electrodiagnostic features of CIDP. Our case shows that ATTRv-PN could present the same morphological nerve alterations pattern of CIDP at ultrasonography, adding HRUS findings as a further source of misdiagnosis late-onset ATTRv-PN.

Reliability, validity and discriminant ability of the instrumental indices provided by a novel planar robotic device for upper limb rehabilitation.

BACKGROUND: In the last few years, there has been an increasing interest in the use of robotic devices to objectively quantify motor performance of patients after brain damage. Although these robot-derived measures can potentially add meaningful information about the patient's dexterity, as well as be used as outcome measurements after the rehabilitation treatment, they need to be validated before being used in clinical practice. The present work aims to evaluate the reliability, the validity and the discriminant ability of the metrics provided by a novel robotic device for upper limb rehabilitation. METHODS: Forty-eight patients with sub-acute stroke and 40 age-matched healthy subjects were involved in this study. Clinical evaluation included: Fugl-Meyer Assessment for the upper limb, Action Research Arm Test, and Barthel Index. Robotic evaluation of the upper limb performance consisted of 14 measures of motor ability quantifying the dexterity in performing planar reaching movements. Patients were evaluated twice, one day apart, to assess the reliability of the robotic metrics, using the Intraclass Correlation Coefficient. Validity was assessed by analyzing the correlation of the robotic metrics with the clinical scales, by means of the Spearman's Correlation Coefficient. Finally, the ability of the robotic metrics to distinguish between patients with stroke and healthy subjects was investigated with t-tests and the Effect Size. RESULTS: Reliability was found to be excellent for 12 measures and from moderate to good for the remaining 2. Most of the robotic indices were strongly correlated with the clinical scales, while a few showed a moderate correlation and only one was not correlated with the Barthel Index and weakly correlated with the remain two. Finally, all but one the provided metrics were able to discriminate between the two groups, with large effect sizes for most of them. CONCLUSION: We found that all the robotic indices except one provided by a novel robotic device for upper limb rehabilitation are reliable, sensitive and strongly correlated both with motor and disability clinical scales. Therefore, this device is suitable as evaluation tool for the upper limb motor performance of patients with sub-acute stroke in clinical practice. TRIAL REGISTRATION: NCT02879279 .

Notch Signal Mediates the Cross-Interaction between M2 Muscarinic Acetylcholine Receptor and Neuregulin/ErbB Pathway: Effects on Schwann Cell Proliferation.

The cross-talk between axon and glial cells during development and in adulthood is mediated by several molecules. Among them are neurotransmitters and their receptors, which are involved in the control of myelinating and non-myelinating glial cell development and physiology. Our previous studies largely demonstrate the functional expression of cholinergic muscarinic receptors in Schwann cells. In particular, the M2 muscarinic receptor subtype, the most abundant cholinergic receptor expressed in Schwann cells, inhibits cell proliferation downregulating proteins expressed in the immature phenotype and triggers promyelinating differentiation genes. In this study, we analysed the in vitro modulation of the Neuregulin-1 (NRG1)/erbB pathway, mediated by the M2 receptor activation, through the selective agonist arecaidine propargyl ester (APE). M2 agonist treatment significantly downregulates NRG1 and erbB receptors expression, both at transcriptional and protein level, and causes the internalization and intracellular accumulation of the erbB2 receptor. Additionally, starting from our previous results concerning the negative modulation of Notch-active fragment NICD by M2 receptor activation, in this work, we clearly demonstrate that the M2 receptor subtype inhibits erbB2 receptors by Notch-1/NICD downregulation. Our data, together with our previous results, demonstrate the existence of a cross-interaction between the M2 receptor and NRG1/erbB pathway-Notch1 mediated, and that it is responsible for the modulation of Schwann cell proliferation/differentiation.

Nerve high-resolution ultrasound in a 2-years follow-up of radial nerve palsy related to humeral shaft fractures.

BACKGROUND: High-resolution nerve ultrasonography (HRUS) could have an emerging importance in diagnosis and follow-up of axonopathic radial palsy associated with humeral shaft fractures due to closed trauma. The aim of our study is to establish the role of HURS in this context through a longitudinal multimodal analysis. METHODS: Clinical, electrodiagnostic (EDX) and HRUS evaluations were prospectively performed at month 1, 3, 6, 12 and 24 from injury, in a continuous series of 19 patients collected in a 5-year study. Clinical severity was scored on MRC of involved muscles, EDX on presence/absence of functional continuity; anatomical continuity and nerve cross sectional area (NCSA) of radial (RN ) and posterior interosseus (PIN) nerves were evaluated through HRUS. RESULTS: All patients showed clinical improvement during follow-up; EDX functional continuity was reached by all patients within 12 months; HRUS revealed RN anatomical continuity in all patients and PIN involvement in 74%. RN NCSA progressively reduced during FU, but it was still significantly higher than contralateral at month 24; PIN NCSA became normal within 24 months. CONCLUSIONS: When anatomical RN continuity is confirmed by HRUS, good functional outcome is reached even in patients with EDX loss of functional continuity. Together with clinical and EDX evaluations, HRUS may provide useful data in the follow-up of radial palsy due to humeral shaft fractures.

Changes of clinical, neurophysiological and nerve ultrasound characteristics in CIDP over time: a 3-year follow-up.

OBJECTIVES: To evaluate, in a prospective study, high-resolution ultrasound (HRUS) changes of nerve segments in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and their relationships with clinical and electrodiagnostic (EDX) characteristics. METHODS: Twenty-three consecutive patients with CIDP were included in a 3-year follow-up (FU) study. Each patient underwent neurologic examination, EDX and HRUS study. HRUS was performed on median, ulnar and peroneal nerves, yielding a total of 319 scanned nerve segments. INCAT and MRC-sum scores, motor nerve conduction velocity (NCV), compound muscle action potential (cMAP) amplitude, and nerve cross-sectional area (NCSA) were collected at baseline and at FU end, and were used for statistical analysis. Twenty-two healthy individuals, matched to patients for age and BMI, served as controls. RESULTS: NCSA was higher in patients than in controls (p < 0.0001) and showed significant direct correlation with disease severity, and inverse correlation with NCV and cMAP amplitude, both at baseline and at FU end. Disease duration, clinical scores and EDX were predictors of NCSA enlargement at both time points. During FU, NCSA increased in 51% of nerve segments (p = 0.006), in correlation with INCAT increase and with NCV and cMAP reduction. Considering EDX changes in subgroups that reflect the different types of nerve damage, NCSA significantly increased in those nerve segments that from normal EDX switched to prevalent myelinopathic EDX characteristics. CONCLUSIONS: Peripheral nerve size tends to increase over time in patients with CIDP, in correlation with clinical and EDX changes, in particular in those nerve segments that undergo a predominantly demyelinating damage.

Technological rehabilitation versus conventional rehabilitation following hip replacement: A prospective controlled study.

BACKGROUND: Among new technological rehabilitation systems, there are proprioceptive platforms. These could be useful to improve static and dynamic balance. OBJECTIVE: To evaluate technological proprioceptive rehabilitation compared to conventional rehabilitation in patients after total hip arthroplasty (THA). METHODS: Sixty-four patients after THA were divided in two groups: a conventional group (CG) and a technological group (TG) treated with proprioceptive platforms. Before (T0) and after 20 sessions (T1), we recorded static and dynamic balance. Clinical and disability scales (Modified Harris Hip Score, Barthel Index, Deambulation Index), pain scales (ID-PAIN, DN4, VAS) and QoL scale (SF-36) were administered to patients during T0 and T1. Mann-Whitney U test was used for stabilometric and dynamic assessments to detect differences between groups of patients and healthy subjects. The Wilcoxon signed-rank test was used for the within-group analysis and the ANCOVA test for the analysis between groups of patients. RESULTS: All scales improved significantly in both groups after treatment (p< 0.05). Static balance improved in both groups, but there were greater improvements in the TG than in the CG. All dynamic balance indexes showed significant improvements only in the TG after treatment. CONCLUSIONS: Both treatments improved the clinical, disability, pain, and QoL scales, as well as static balance, but only proprioceptive technological rehabilitation improved dynamic balance. Rehabilitation through proprioceptive platforms can indeed improve static and dynamic balance, which are both crucial for the patient's safety and autonomy.

Nerve high-resolution ultrasonography in peripheral nerve injuries associated with supracondylar humeral fractures in children.

To evaluate nerve high-resolution ultrasonography (HRUS) as diagnostic tool in children with supracondylar humeral fractures (SHF)-related peripheral nerve injuries (PNIs), we selected at least one illustrative case for each upper limb nerve usually involved in SHF (i.e. median, radial and ulnar nerve), in which HRUS evaluation added a useful contribution in diagnostic and therapeutic choices. We selected four patients (3 males, 1 female, aged between 7 and 12 years). Involved nerves were median (2), radial (1) and ulnar (1). HRUS results can actively modify the management of children with SHF-related PNIs, especially when combined with clinical and EDX. HRUS should be used routinely in evaluation of children with SHF-related PNIs.

Muscle involvement in myasthenia gravis: Expanding the clinical spectrum of Myasthenia-Myositis association from a large cohort of patients.

Myastenia-Inflammatory Myopathy (MG-IM) association has been described in less than 50 cases, as isolated reports or in few case series. In most cases, MG and IM onset occur simultaneously even if the overlapping clinical manifestations could lead to delay the diagnosis in the early stage of disease. In these cases, thymic pathology is present in more than 50% of cases. Pathological findings can be consistent of polymyositis (63%), dermatomyositis (25%) or granulomatosis (12%). Accurate clinical manifestations and severity of IM in MG, including muscle specific antibodies (MSA) and muscle MRI, have not been systematically investigated and focal or mild subclinical myositis have not been reported. We observed that focal myositis or asymptomatic CK elevation can also occur in MG. In this review we have also retrospectively re-analyzed the clinical, serological, pathological and muscle imaging data from 13 patients with MG- IM from our cohort of 441 MG patients (2,9%). Clinical onset occurred simultaneously in 10/13 patients, whereas in 2 patients the IM appeared later in MG disease course (range 10-14 years) and conversely in 1 patient MG symptoms occurred later in IM disease course (4 years). Median age at disease onset was 51 year (range 24-73 years) regardless of clinical onset (MG or IM). Median clinical follow-up was 88 months (range 31-237 months). IM was suspected by CK elevation in all patients (ranging 800-3000 UI/L at first detection) and non-fatigable muscle weakness unresponsive to acetylcholinesterase inhibitors. All the patients presented mild to moderate MG symptoms. Three main categories of muscle involvement, sometimes overlapping, were recognizable: distal, proximal and subclinical myositits, leading to three main clinical groups (A,B,C) and two overlapping subgroups (A/B and B/C). Thymus pathology was present in 10/13 patients. Anti-AChR was detected in al all patients associated with anti-Titin and -RyR1 in those patients with thymoma. No MSA, nor MAA antibodies were detected. Muscle biopsy confirmed IM in all patients. In conclusion we redefined the clinical spectrum of muscle involvement in MG-IM association, which represent a continuum among 3 main clinical groups: distal, proximal and subclinical muscle involvement. Minimal muscle involvement and focal myositis could be underestimated among myasthenic patients and early aggressive immunotherapy could be required in focal group.

Defocused Shock Wave Therapy for Chronic Soft Tissue Wounds in the Lower Limbs: A Pilot Study.

Chronic soft tissue wounds of the lower limbs are debilitating, painful and often unresponsive to advanced dressing treatments. Extracorporeal shock wave therapy (ESWT) could represent an alternative treatment. Ten patients with chronic soft tissue wounds of the legs, unresponsive to advanced dressing treatments for more than 3 mo, underwent three defocused ESWT sessions at 72-h intervals. In every session, the sum of 300 standard pulses + 100 pulses per square centimeter was applied at 0.15 mJ/mm2 and 4 Hz over the edge of the wound. The wound size in square centimeters, Bates-Jensen Wound Assessment Tool and visual analogue scale were used as outcome measures. A significant reduction in wound size and Bates-Jensen Wound Assessment Tool and visual analogue scale values from pre-treatment to 90 d was observed. Seven of ten ulcers healed completely and nine of ten patients reported complete pain relief. Defocused ESWT represents a non-invasive, feasible strategy for difficult-to-treat soft tissue wounds of the lower limbs.

Peripheral nerve ultrasound changes in CIDP and correlations with nerve conduction velocity.

OBJECTIVE: To evaluate the ultrasound (US) characteristics of peripheral nerves in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and their correlations with electrodiagnostic (EDX) characteristics. METHODS: Nineteen patients with CIDP and 19 healthy controls matched by age and body mass index were included in a blind case-control, observational study. All patients underwent a neurologic examination (including inflammatory neuropathy cause and treatment [INCAT] and Medical Research Council [MRC] sum score) and an EDX study. Each patient and each control underwent a US study of 14 nerve segments, yielding a total number of 266 segments scanned in each group. RESULTS: US changes, characterized by an increased nerve cross-sectional area (NCSA), were detected in 53% of the 266 patient nerve segments. Mean NCSA was higher in nerve segments of patients than in those of controls (p < 0.001). Nerve segments with abnormal US belonged to patients with longer disease duration, lower MRC sum score, higher INCAT score, and progressive disease form (all p < 0.0001). All the aforementioned variables were independently associated with the occurrence of US changes. Motor nerve conduction was significantly lower in nerve segments with increased NCSA than in those with normal NCSA (p < 0.0001). NCSA in segments with prevalent myelin damage was higher than that in segments with prevalent axonal damage (p = 0.001) or in segments with normal EDX characteristics (p < 0.0001). NCSA and motor nerve conduction velocity were inversely correlated in nerve segments with EDX evidence of myelin damage (R = 0.599; p < 0.0001). Conduction blocks were associated with increased NCSA (p = 0.001). CONCLUSIONS: US may, similar to MRI, have a supporting role in the diagnosis of CIDP. US and EDX changes are correlated.

M2 muscarinic receptor activation regulates Schwann cell differentiation and myelin organization.

Glial cells express acetylcholine receptors. In particular, rat Schwann cells express different muscarinic receptor subtypes, the most abundant of which is the M2 subtype. M2 receptor activation causes a reversible arrest of the cell cycle. This negative effect on Schwann cell proliferation suggests that these cells may possibly progress into a differentiating program. In this study we analyzed the in vitro modulation, by the M2 agonist arecaidine, of transcription factors and specific signaling pathways involved in Schwann cell differentiation. The arecaidine-induced M2 receptor activation significantly upregulates transcription factors involved in the promyelinating phase (e.g., Sox10 and Krox20) and downregulates proteins involved in the maintenance of the undifferentiated state (e.g., c-jun, Notch-1, and Jagged-1). Furthermore, arecaidine stimulation significantly increases the expression of myelin proteins, which is accompanied by evident changes in cell morphology, as indicated by electron microscopy analysis, and by substantial cellular re-distribution of actin and cell adhesion molecules. Moreover, ultrastructural and morphometric analyses on sciatic nerves of M2/M4 knockout mice show numerous degenerating axons and clear alterations in myelin organization compared with wild-type mice. Therefore, our data demonstrate that acetylcholine mediates axon-glia cross talk, favoring Schwann cell progression into a differentiated myelinating phenotype and contributing to compact myelin organization.

Direct interaction of Gas41 and Myc encoded by amplified genes in nervous system tumours.

In order to understand better the role of the human Tip60 complex component Gas41, we analysed its expression levels in brain tumours and searched for possible interactors. Two-hybrid screening of a human foetal brain library allowed identification of some molecular interactors of Gas41. Among them we found n-Myc transcription factor. The interaction between Gas41 and n-Myc was validated by pull-down experiments. We showed that Gas41 is able to bind both n-Myc and c-Myc proteins, and that the levels of expression of Gas41 and Myc proteins were similar to each other in such brain tumors as neuroblastomas and glioblastomas. Finally, in order to identify which region of Gas41 is involved in the interaction with Myc proteins, we analysed the ability of Gas41 to substitute for its orthologue Yaf9 in yeast; we showed that the N-terminal portions of the two proteins, containing the YEATS domains, are interchangeable, while the C-terminal portions are species-specific. In fact we found that Gas41 C-terminal portion is required for Myc protein interaction in human.

Acetylcholine inhibits cell cycle progression in rat Schwann cells by activation of the M2 receptor subtype.

Cultures of Schwann cells from neonatal rat sciatic nerves were treated with acetylcholine agonists and the effects on cell proliferation evaluated. (3)[H]-thymidine incorporation shows that acetylcholine (ACh) receptor agonists inhibit cell proliferation, and FACS analysis demonstrates cell-cycle arrest and accumulation of cells in the G1 phase. The use of arecaidine, a selective agonist of muscarinic M2 receptors reveals that this effect depends mainly on M2 receptor activation. The arecaidine dependent-block in G1 is reversible because removal of arecaidine from the culture medium induces progression to the S phase. The block of the G1-S transition is also characterized by modulation of the expression of several cell-cycle markers. Moreover, treatment with ACh receptor agonist causes both a decrease in the PCNA protein levels in Schwann cell nuclei and an increase in p27 and p53 proteins. Finally, immuno-electron microscopy demonstrates that M2 receptors are expressed by Schwann cells in vivo. These results indicate that ACh, by modulating Schwann cell proliferation through M2 receptor activation, might contribute to their progression to a more differentiated phenotype.

Rat Schwann cells express M1-M4 muscarinic receptor subtypes.

The expression of different muscarinic receptor subtypes was analyzed in immature Schwann cells obtained from sciatic nerve of 2-day neonatal rats. By using RT-PCR analysis, we demonstrated the presence of M1, M2, M3, and M4 receptor subtypes in cultured Schwann cells, with M2 displaying the highest expression levels. Muscarinic subtypes were also quantified by immunoprecipitation and [3H]QNB binding. With this approach, we found the levels of receptor expression to be M2 > M3 > M1. M4 is expressed at very low levels, and M5 receptor was not detectable. Moreover, we also demonstrated that stimulation of the receptors by muscarinic agonists activates previously described signal transduction pathways, leading to a decrease of cAMP and an increase of IP3 levels not associated with an efficient intracellular Ca2+ release. The presence and activity of particular muscarinic receptors in immature Schwann cells suggest that ACh may play an important role in Schwann cell development.