Yun-An Tsai

Acidic fibroblast growth factor for repair of human spinal cord injury: a clinical trial

OBJECT The study aimed to verify the safety and feasibility of applying acidic fibroblast growth factor (aFGF) with fibrin glue in combination with surgical neurolysis for nonacute spinal cord injury. METHODS This open-label, prospective, uncontrolled human clinical trial recruited 60 patients with spinal cord injuries (30 cervical and 30 thoracolumbar). The mean patient age was 36.5 ± 15.33 (mean ± SD) years, and the male/female ratio was 3:1. The mean time from injury to treatment was 25.7 ± 26.58 months, and the cause of injury included motor vehicle accident (26 patients [43.3%]), fall from a height (17 patients [28.3%]), sports (4 patients [6.7%]), and other (13 patients [21.7%]). Application of aFGF with fibrin glue and duraplasty was performed via laminectomy, and an adjuvant booster of combined aFGF and fibrin glue (2 ml) was given at 3 and 6 months postsurgery via lumbar puncture. Outcome measurements included the American Spinal Injury Association (ASIA) motor scores, sensory scores, impairment scales, and neurological levels. Examination of functional independence measures, visual analog scale, MR imaging, electrophysiological and urodynamic studies, hematology and biochemistry tests, tumor markers, and serum inflammatory cytokines were all conducted. All adverse events were monitored and reported. Exclusions were based on refusal, unrelated adverse events, or failure to participate in the planned rehabilitation. RESULTS Forty-nine patients (26 with cervical and 23 with thoracolumbar injuries) completed the 24-month trial. Compared with preoperative conditions, the 24-month postoperative ASIA motor scores improved significantly in the cervical group (from 27.6 ± 15.55 to 37.0 ± 19.93, p < 0.001) and thoracolumbar group (from 56.8 ± 9.21 to 60.7 ± 10.10, p < 0.001). The ASIA sensory scores also demonstrated significant improvement in light touch and pinprick in both groups: from 55.8 ± 24.89 to 59.8 ± 26.47 (p = 0.049) and 56.3 ± 23.36 to 62.3 ± 24.87 (p = 0.003), respectively, in the cervical group and from 75.7 ± 15.65 to 79.2 ± 15.81 (p < 0.001) and 78.2 ± 14.72 to 82.7 ± 16.60 (p < 0.001), respectively, in the thoracolumbar group. At 24-month follow-up, the ASIA impairment scale improved significantly in both groups (30% cervical [p = 0.011] and 30% thoracolumbar [p = 0.003]). There was also significant improvement in neurological level in the cervical (from 5.17 ± 1.60 to 6.27 ± 3.27, p = 0.022) and thoracolumbar (from 18.03 ± 4.19 to 18.67 ± 3.96, p = 0.001) groups. The average sum of motor items in functional independence measure also had significant improvement in both groups (p < 0.05). The walking/wheelchair locomotion subscale showed increased percentages of patients who were ambulatory (from 3.4% to 13.8% and from 17.9% to 35.7% in the cervical and thoracolumbar groups, respectively). There were no related adverse events. CONCLUSIONS The use of aFGF for spinal cord injury was safe and feasible in the present trial. There were significant improvements in ASIA motor and sensory scale scores, ASIA impairment scales, neurological levels, and functional independence measure at 24 months after treatment. Further large-scale, randomized, and controlled investigations are warranted to evaluate the efficacy and long-term results.

Nerve repair using acidic fibroblast growth factor in human cervical spinal cord injury: a preliminary Phase I clinical study

OBJECT The aim of this study was to assess functional outcomes of nerve repair using acidic fibroblast growth factor (FGF) in patients with cervical spinal cord injury (SCI). METHODS Nine patients who had cervical SCI for longer than 5 months were included in pre- and postoperative assessments of their neurological function. The assessments included evaluating activities of daily living, associated functional ability, and degree of spasticity, motor power, sensation, and pain perception. After the first set of assessments, the authors repaired the injured segment of the spinal cord using a total laminectomy followed by the application of fibrin glue containing acidic FGF. Clinical evaluations were conducted 1, 2, 3, 4, 5, and 6 months after the surgery. Preoperative versus postoperative differences in injury severity and grading of key muscle power and sensory points were calculated using the Wilcoxon signed-rank test. RESULTS The preoperative degree of injury severity, as measured using the American Spinal Injury Association (ASIA) scoring system, showed that preoperative motor (52.4 +/- 25.9 vs 68.6 +/- 21.5), pinprick (61.0 +/- 34.9 vs 71.6 +/- 31.0), and light touch scores (57.3 +/- 33.9 vs 71.9 +/- 30.2) were significantly lower than the respective postoperative scores measured 6 months after surgery (p = 0.005, 0.012, and 0.008, respectively). CONCLUSIONS Based on the significant difference in ASIA motor and sensory scale scores between the preoperative status and the 6-month postoperative follow-up, this novel nerve repair strategy of using acidic FGF may have a role in the repair of human cervical SCI. Modest nerve regeneration occurred in all 9 patients after this procedure without any observed adverse effects. This repair strategy thus deserves further investigation, clinical consideration, and refinement.

Intermittent theta burst stimulation over ipsilesional primary motor cortex of subacute ischemic stroke patients: A pilot study

BACKGROUND We demonstrated that prolonged transcranial magnetic intermittent theta burst stimulation (iTBS, 1200 pulses/session=iTBS1200) produces longer-lasting facilitation in corticospinal excitability than ordinary form of iTBS in healthy subjects. OBJECTIVE Here we show the safety and small-scale efficacy of iTBS1200 over ipsilesional primary motor cortex (M1) in subacute stroke patients. METHODS Twelve patients with first-time, subacute ischemic stroke of the middle cerebral artery were randomized into two groups that received 10 daily-sessions of either iTBS1200 or sham stimulation (n=6/group) over ipsilesional M1 hand region in addition to medical and rehabilitation treatments. The primary outcome measures were safety and tolerability. The secondary outcome measures included the National Institute of Health Stroke Scale (NIHSS), Upper Extremity Fugl-Meyer Test (UE-FMT), Action Research Arm Test (ARAT), active motor thresholds (aMTs)/motor-evoked potentials (MEPs) from the extensor carpi radialis (ECR), and magnetoencephalography on post-intervention day 1 and post-stroke day 60. RESULTS iTBS or sham stimulation was well tolerated by all patients without seizures or significant adverse effects. Compared with the matched controls, the iTBS group showed measurable improvements in the NIHSS and the proximal UE-FMT scores on post-intervention day 1 and post-stroke day 60. Nevertheless, the hand ARAT scores, aMT and MEPs from the paretic ECR were not different between groups. Post-movement beta synchronization increased over iTBS-conditioned M1 on post-intervention day 1 in testable patients. CONCLUSIONS Repetitive sessions of iTBS1200 over ipsilesional M1 of subacute stroke patients are safe and the potential benefits encourage a larger trial to determine the efficacy in stroke patients. (ClinicalTrials.gov: NCT-01323881).

Intermittent theta burst stimulation over primary motor cortex enhances movement-related beta synchronisation

OBJECTIVE The objective of this study is to investigate how transcranial magnetic intermittent theta burst stimulation (iTBS) with a prolonged protocol affects human cortical excitability and movement-related oscillations. METHODS Using motor-evoked potentials (MEPs) and movement-related magnetoencephalography (MEG), we assessed the changes of corticospinal excitability and cortical oscillations after iTBS with double the conventional stimulation time (1200 pulses, iTBS1200) over the primary motor cortex (M1) in 10 healthy subjects. Continuous TBS (cTBS1200) and sham stimulation served as controls. RESULTS iTBS1200 facilitated MEPs evoked from the conditioned M1, while inhibiting MEPs from the contralateral M1 for 30 min. By contrast, cTBS1200 inhibited MEPs from the conditioned M1. Importantly, empirical mode decomposition-based MEG analysis showed that the amplitude of post-movement beta synchronisation (16-26 Hz) was significantly increased by iTBS1200 at the conditioned M1, but was suppressed at the nonconditioned M1. Alpha (8-13 Hz) and low gamma-ranged (35-45 Hz) rhythms were not notably affected. Movement kinetics remained consistent throughout. CONCLUSIONS TBS1200 modulated corticospinal excitability in parallel with the direction of conventional paradigms with modestly prolonged efficacy. Moreover, iTBS1200 increased post-movement beta synchronisation of the stimulated M1, and decreased that of the contralateral M1, probably through interhemispheric interaction. SIGNIFICANCE Our results provide insight into the underlying mechanism of TBS and reinforce the connection between movement-related beta synchronisation and corticospinal output.

A virtual reality-based system for hand function analysis

The goal of this study was to demonstrate the usability and usefulness of virtual reality technology in assessing hand functions. Ten healthy, non-disabled right-handed adult volunteers were recruited. Each volunteer used a dataglove to insert three-dimensional virtual representations of a cylinder and a prism into the target holes. To verify the reliability of the tests, each subject was retested twice. The performance testing assessed the visual-motor coordination a person needs to achieve a task accurately and within a set time. For each trial, the root mean square (RMS) value of the hand movement trajectory was projected onto the X, Y, and Z axes. This projection enabled us to measure the extent of the genuine, summative displacement of the manipulating hand. The reproducibility of the virtual reality assessment was analyzed using the intraclass correlation (ICC) approach. The total ICC values of 10 subjects demonstrated a high task completion time and RMS on the X and Z axes for the transferring of the prism. However, the values were low for the transferring of the cylinder. Because the individual coefficients of variations (CVs) varied widely in the moving of both the cylinder and the prism, the total (CVs) showed a high reading for the task completion time. Although rehabilitation clinics routinely carry out peg-moving exercises for disabled patients, our model provides a valuable quantitative real time and off-line measure of whole hand functions.

Quantitative measures of functional outcomes and quality of life in patients with C5 palsy

Background: It is generally understood that postoperative C5 palsy can occur with anterior or posterior decompression surgery, but functional measures of the palsy have not been well documented. This study aimed to investigate the incidence of C5 palsy in different surgical procedures, examine the correlations between muscle strength, upper extremity functional measures, and health‐related quality of life, and to observe potential risk factors contributing to C5 palsy. Methods: Our investigation involved a retrospective study design. A total of 364 patients who underwent decompression surgery were indicated within the selected exclusion criteria. Additionally, 12 C5 palsy patients were recruited. The relationships between the manual muscle test (MMT), the action research arm test (ARAT), the Jebsen test of hand function (JTHF), and the European quality of life‐5 dimensions (EQ‐5D) were studied, and univariate analyses were performed to search possible risk factors and recovery investigation. Results: The data analyzed in the 12 cases and C5 palsy incidences (3.3%) were: 0.7% in anterior procedures (n = 2), 8.8% in posterior procedures (n = 6), and 36.4% in combined procedures (n = 4). Moderate‐to‐high correlations were observed between the ARAT, JTHF, EQ‐5D visual analog scale scores, and MMT (r = 0.636–0.899). There were significant differences in patient age, etiology of cervical lesion, variable decompression procedures, and the number of decompression levels between the C5 palsy and non‐C5 palsy groups. For female patients (p = 0.018) and number of decompression levels (p = 0.028), there were significant differences between the complete recovery and the incomplete recovery groups. Conclusion: Patients undergoing combined anterior–posterior decompression surgery had the highest incidence of C5 palsy, and correlations between the ARAT, JTHF, EQ‐5D visual analog scale clinical tools, and MMT scores supported these findings. Female status and lower decompression levels could also be predictive factors for complete recovery, although additional research is needed to substantiate these findings.

The influence of shoulder pain on functional limitation, perceived health, and depressive mood in patients with traumatic paraplegia

Abstract Objective To assess whether functional activity, perceived health, and depressive symptoms differ between individuals with traumatic paraplegia with and without shoulder pain. Design Cross sectional and comparative investigation using the unified questionnaire. Setting Neural Regeneration and Repair Division unit of Taipei Veterans General Hospital in Taiwan. Participants Seventy-six patients with paraplegia (23 with and 53 without shoulder pain) who had experienced spinal cord injury at American Spinal Injury Association Impairment Scale T2 to T12 neurologic level (at least 6 months previously). Outcome measures Spinal Cord Independence Measure (SCIM), a single item from the Medical Outcomes Study 36-Item Short-Form Health Survey, and Patient Health Questionnaire-9 (PHQ-9) depression scale. Results Shoulder pain was prevalent in 30% patients. Patients with shoulder pain had significantly worse perceived health and greater depressive symptoms than those without. No significant difference was found in functional ability between groups. Greater shoulder pain intensity was related to higher depressive scores (r = 0.278, P = 0.017) and lower self-perceived health scores (r = −0.433, P < 0.001) but not SCIM scores (P = 0.342). Conclusion Although shoulder pain was unrelated to functional limitation, it was associated with lower perceived health and higher depressive mood levels.

The comparison of electrophysiologic findings of traumatic brachial plexopathies in a tertiary care center

This study was undertaken to demonstrate the distribution of causative factors of brachial plexopathy (BP), to assess the association between the mechanism of injuries and the predominant level of the brachial plexus involved in the injuries, and to characterize the extent and degree of severity of injury in patients with BPI. It consisted of a cross-sectional, retrospective review of electrophysiological data of 5547 patients with 117 patients being identified as having BPI, of whom 86 patients were recruited into the study. The patients were divided into six subgroups according to the mechanism of the damage. The injury was subdivided according to the brachial plexus levels predominantly affected, and each component of the four major anatomical plexus levels-root, trunk, cord and nerve levels was analyzed. The affiliation between the type of injuries and the specified brachial plexus levels was calculated via a two-tailed Fishers exact test. These findings demonstrated that the type of brachial plexus injury (BPI) is significantly related to the brachial plexus level involved. The motorcycle and birth injury groups were affected at the trunk level, the fall group at the nerve level, the automobile group at the cord level, and the blunt injury group at the cord or nerve level. Moreover, the majority of patients in the motorcycle, fall, and pedestrian groups suffered from severe, incomplete lesions, while the neurophysiological results of the other groups varied.

Repairing the ventral root is sufficient for simultaneous motor and sensory recovery in multiple complete cervical root transection injuries

AIM In multiple cervical root transection injuries, motor and sensory recovery has been demonstrated after repairing both dorsal and ventral roots with autologous grafts applied to the dorsal and ventral aspects, respectively. However, in clinical situations, autologous grafts may not be sufficient to repair both roots in this situation. In this study, the authors evaluated whether repairing ventral root alone is sufficient for simultaneous sensory and motor function recovery. MAIN METHODS In the transected group, the left 6th-8th cervical roots were pulled and transected at the spinal cord junction. In the repair group, the transected root was anastomosed to a single autologous nerve graft, which was inserted into the ventral horn through a pial incision. Acidic fibroblast growth factor mixed with fibrin glue was applied to the surgical area. Motor function, sensory function, cortical somatosensory evoked potentials (SSEPs), axon tracing, and CGRP(+) fibers were evaluated. KEY FINDINGS The repaired rats exhibited simultaneous sensory and motor function recovery. At the 16th weeks, SSEPs reappeared in all animals of the repair group, but not in the transected group. Retrograde axon tracing demonstrated an increased number of sensory neurons in the dorsal root ganglia and regenerating nerve fibers in the dorsal horn. CGRP(+) fibers were significantly increased in the repair group and restricted to laminae I and II. SIGNIFICANCE This is the first report that in multiple root avulsions with insufficient grafts, repairing ventral roots alone leads to both sensory recovery and motor recovery. This finding may help patients with multiple cervical root avulsions.

Functional improvement in chronic human spinal cord injury: Four years after acidic fibroblast growth factor

Few treatments have proven effective for patients with chronic spinal cord injury (SCI). This study aimed to evaluate the efficacy and safety of acidic fibroblast growth factor (aFGF) in human SCI. This was an open-label prospective clinical trial of aFGF with an extended follow-up to 48 months. All patients were treated with aFGF 3 times, including once directly applied to the injured spinal cord during neurolysis surgery, and twice via lumbar punctures at 3- and 6-months post-operation. Every patient was evaluated with standardized measurements of neurological functions. The trial initially enrolled 60 patients (30 cervical and 30 thoracolumbar SCI), but only 46 (21 cervical- and 25 thoracolumbar-SCI) completed the follow-up. The ASIA impairment scales, motor, pin prick, light touch, and FIM motor subtotal scores were all improved in both groups, except that the ASIA scores of light touch only demonstrated tendency of increase in the cervical-SCI group. All patients had a decrease in dependence, and there were no major adverse events or other oncological problems throughout the follow-up. At 48 months, the study demonstrated that aFGF was safe, feasible, and could yield modest functional improvement in chronic SCI patients. Further randomized control investigations are warranted for validation of its optimal dosage.