Contribution of mechanoreceptors to spinal cord injury-induced mechanical allodynia.

ABSTRACT: Evidence from previous studies supports the concept that spinal cord injury (SCI)-induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree mechanoreceptors contribute. Sensorimotor activation-based interventions (eg, treadmill training) have been shown to reduce NP after experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. The aim of the present study was to understand the contribution of mechanoreceptors with respect to mechanical allodynia in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B expressing mechanoreceptors before SCI, mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. Peptidergic nociceptor sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. However, skin-nerve preparations of contusion SCI mice 7 days after injury yielded hyperexcitability in nociceptors, not in mechanoreceptors, which makes a substantial direct contribution of mechanoreceptors to NP maintenance unlikely. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors seem to be the main drivers of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early-onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions.

Magnetic resonance neurography in spinal cord injury: Imaging findings and clinical significance.

BACKGROUND AND PURPOSE: It is unknown whether changes to the peripheral nervous system following spinal cord injury (SCI) are relevant for functional recovery or the development of neuropathic pain below the level of injury. Magnetic resonance neurography (MRN) at 3 T allows detection and localization of structural and functional nerve damage. This study aimed to combine MRN and clinical assessments in individuals with chronic SCI and nondisabled controls. METHODS: Twenty participants with chronic SCI and 20 controls matched for gender, age, and body mass index underwent MRN of the L5 dorsal root ganglia (DRG) and the sciatic nerve. DRG volume, sciatic nerve mean cross-sectional area (CSA), fascicular lesion load, and fractional anisotropy (FA), a marker for functional nerve integrity, were calculated. Results were correlated with clinical assessments and nerve conduction studies. RESULTS: Sciatic nerve CSA and lesion load were higher (21.29 ± 5.82 mm2 vs. 14.08 ± 4.62 mm2 , p < 0.001; and 8.70 ± 7.47% vs. 3.60 ± 2.45%, p < 0.001) in individuals with SCI compared to controls, whereas FA was lower (0.55 ± 0.11 vs. 0.63 ± 0.08, p = 0.022). DRG volumes were larger in individuals with SCI who suffered from neuropathic pain compared to those without neuropathic pain (223.7 ± 53.08 mm3 vs. 159.7 ± 55.66 mm3 , p = 0.043). Sciatic MRN parameters correlated with electrophysiological results but did not correlate with the extent of myelopathy or clinical severity of SCI. CONCLUSIONS: Individuals with chronic SCI are subject to a decline of structural peripheral nerve integrity that may occur independently from the clinical severity of SCI. Larger volumes of DRG in SCI with neuropathic pain support existing evidence from animal studies on SCI-related neuropathic pain.

Noxious radiant heat evokes bi-component nociceptive withdrawal reflexes in spinal cord injured humans-A clinical tool to study neuroplastic changes of spinal neural circuits.

Investigating nocifensive withdrawal reflexes as potential surrogate marker for the spinal excitation level may widen the understanding of maladaptive nociceptive processing after spinal cord injury (SCI). The aim of this prospective, explorative cross-sectional observational study was to investigate the response behavior of individuals with SCI to noxious radiant heat (laser) stimuli and to assess its relation to spasticity and neuropathic pain, two clinical consequences of spinal hyperexcitability/spinal disinhibition. Laser stimuli were applied at the sole and dorsum of the foot and below the fibula head. Corresponding reflexes were electromyography (EMG) recorded ipsilateral. Motor responses to laser stimuli were analyzed and related to clinical readouts (severity of injury/spasticity/pain), using established clinical assessment tools. Twenty-seven participants, 15 with SCI (age 18-63; 6.5 years post-injury; AIS-A through D) and 12 non-disabled controls, [non-disabled controls (NDC); age 19-63] were included. The percentage of individuals with SCI responding to stimuli (70-77%; p < 0.001), their response rates (16-21%; p < 0.05) and their reflex magnitude (p < 0.05) were significantly higher compared to NDC. SCI-related reflexes clustered in two time-windows, indicating involvement of both A-delta- and C-fibers. Spasticity was associated with facilitated reflexes in SCI (Kendall-tau-b p ≤ 0.05) and inversely associated with the occurrence/severity of neuropathic pain (Fisher's exact p < 0.05; Eta-coefficient p < 0.05). However, neuropathic pain was not related to reflex behavior. Altogether, we found a bi-component motor hyperresponsiveness of SCI to noxious heat, which correlated with spasticity, but not neuropathic pain. Laser-evoked withdrawal reflexes may become a suitable outcome parameter to explore maladaptive spinal circuitries in SCI and to assess the effect of targeted treatment strategies. Registration: https://drks.de/search/de/trial/DRKS00006779.

Lower Motoneuron Dysfunction Impacts Spontaneous Motor Recovery in Acute Cervical Spinal Cord Injury.

Paresis after spinal cord injury (SCI) is caused by damage to upper and lower motoneurons (LMNs) and may differentially impact neurological recovery. This prospective monocentric longitudinal observational study investigated the extent and severity of LMN dysfunction and its impact on upper extremity motor recovery after acute cervical SCI. Pathological spontaneous activity at rest and/or increased discharge rates of motor unit action potentials recorded by needle electromyography (EMG) were taken as parameters for LMN dysfunction and its relation to the extent of myelopathy in the first available spine magnetic resonance imaging (MRI) was determined. Motor recovery was assessed by standardized neurological examination within the first four weeks (acute stage) and up to one year (chronic stage) after injury. Eighty-five muscles of 17 individuals with cervical SCI (neurological level of injury from C1 to C7) and a median age of 54 (28-59) years were examined. The results showed that muscles with signs of LMN dysfunction peaked at the lesion center (Χ2 [2, n = 85] = 6.6, p = 0.04) and that the severity of LMN dysfunction correlated with T2-weighted hyperintense MRI signal changes in routine spine MRI at the lesion site (Spearman ρ = 0.31, p = 0.01). Muscles exhibiting signs of LMN dysfunction, as indicated by pathological spontaneous activity at rest and/or increased discharge rates of motor unit action potentials, were associated with more severe paresis in both the acute and chronic stages after SCI (Spearman ρ acute = -0.22, p = 0.04 and chronic = -0.31, p = 0.004). Moreover, the severity of LMN dysfunction in the acute stage was also associated with a greater degree of paresis (Spearman ρ acute = -0.24, p = 0.03 and chronic = -0.35, p = 0.001). While both muscles with and without signs of LMN dysfunction were capable of regaining strength over time, those without LMN dysfunctions had a higher potential to reach full strength. Muscles with signs of LMN dysfunction in the acute stage displayed increased amplitudes of motor unit action potentials with chronic-stage needle EMG, indicating reinnervation through peripheral collateral sprouting as compensatory mechanism (Χ2 [1, n = 72] = 4.3, p = 0.04). Thus, LMN dysfunction represents a relevant factor contributing to motor impairment and recovery in acute cervical SCI. Defined recovery mechanisms (peripheral reinnervation) may at least partially underlie spontaneous recovery in respective muscles. Therefore, assessment of LMN dysfunction could help refine prediction of motor recovery after SCI.

Impact of Heterotopic Ossification on Functional Recovery in Acute Spinal Cord Injury.

Objective: In spinal cord injury (SCI), heterotopic ossification is a frequent secondary complication, commonly associated with limited range of motion of affected joints, which could lead to secondary disability in activities of daily living. Additionally, heterotopic ossifications might challenge the effect of regeneration-promoting therapies on neurological and functional recovery. This study evaluated the impact of heterotopic ossification on clinical recovery within the first year after SCI. Methods: The study was conducted as a monocentric longitudinal paired cohort study. Recruitment was based on consecutive sampling in the framework of the European Multicenter about Spinal Cord Injury (EMSCI). Recovery profiles were determined using standardized neurological and functional clinical assessments within the 1st year following SCI. All study participants underwent at least two comprehensive standardized neurological and functional clinical examinations according to the International Standards for Neurological Classification of SCI and the Spinal Cord Independence Measure, respectively. Data regarding the diagnosis and treatment of heterotopic ossification were obtained by reviewing the patient medical records. The most similar "digital twin" from the entire EMSCI database were matched in terms of age, acute neurological and functional status to each individual with SCI, and heterotopic ossification. Results: Out of 25 participants diagnosed with heterotopic ossification, 13 individuals were enrolled and matched to control individuals. Most individuals presented with motor complete injury (75%). Ossifications were most frequently located at the hip joints (92%) and mainly occurred within the first 3 months after SCI. Individuals with heterotopic ossification achieved around 40% less functional improvement over time compared to their matched counterparts, whereas neurological recovery was not altered in individuals with SCI and heterotopic ossification. Conclusion: Heterotopic ossification-a common complication of SCI-unfavorably affects functional recovery, which in the end is most relevant for the best possible degree of independence in activities of daily living. Upon presentation with heterotopic ossification, neurological improvement achieved through potential restorative therapies might not translate into clinically meaningful functional improvement. Diagnostic algorithms and effective early prevention/treatment options for heterotopic ossification need to be established to ensure the best possible functional outcome. Clinical Trial Registration: NCT01571531 (https://clinicaltrials.gov).

Theoretical and practical training improves knowledge of the examination guidelines of the International Standards for Neurological Classification of Spinal Cord Injury.

STUDY DESIGN: Prospective pre-post study. OBJECTIVES: International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) represents the most frequently used assessment to determine the level and severity of a spinal cord injury (SCI). The guidelines for ISNCSCI are complex and challenging. Knowledge of its correct execution needs to be imparted precisely. The aim of this study was to investigate whether hands-on instructional courses can increase the knowledge of the ISNCSCI examination guidelines. SETTING: European Multicenter Study about SCI. METHODS: Before and after the instructional courses, participants were asked to complete questionnaires. The set of questions covered the most important aspects of the examination guidelines. Attendees were asked to self-rate their occupation and experience in ISNCSCI. RESULTS: The comparison of pretest and posttest results of 164 attendees from 2014 to 2018 revealed an improvement of knowledge reflected by an increase of correct answers from 66 ± 17% before to 89 ± 11% after the course (p < 0.01). The improvement was not associated with occupation (p > 0.1). However, the correctness of pretest results differed concerning both the period of experience with ISNCSCI (p < 0.05) and the course language (p < 0.01), while the frequency of execution resulted in differences in the posttest (p = 0.01). CONCLUSIONS: Instructional courses substantially improve knowledge of the ISNCSCI examination guidelines. Differences in knowledge present before the course leveled off after the course. Comprehensive theoretical training is strongly recommended to ensure reliability and validity of ISNCSCI examinations in clinical routine and research. Albeit being practiced in the instructional courses, the benefit of hands-on training still needs to be systematically evaluated in future studies.

Revisiting the Examination of Sharp/Dull Discrimination as Clinical Measure of Spinothalamic Tract Integrity.

Objective: Revisiting the sharp/dull discrimination as clinical measure of spinothalamic tract function considering the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Three clinically relevant factors were evaluated as to their impact on reliability: (1) the localization of dermatomes in relation to the sensory level, (2) the examination tool, and (3) the threshold of correct answers for grading of a preserved sharp/dull discrimination. Design: Prospective monocentric psychometric study. Setting: Spinal Cord Injury Center, Heidelberg University Hospital, Germany. Participants: Convenient sample of 21 individuals with subacute spinal cord injury (age: 31-82 years) and 20 individuals without spinal cord injury (age: 24-63 years). Assessment: All participants underwent three assessments for sharp/dull discrimination, applying five commonly used examination tools in seven dermatomes, performed by three trained examiners under conditions in accordance with ISNCSCI. Main Outcome Measures: Assessment of interrater reliability by determining both the Fleiss kappa (κ) coefficient and the percentage agreement between raters. Data were dichotomized regarding the ISNCSCI threshold. Results: Interrater reliability in individuals with SCI was overall substantial (κ = 0.68; CI 0.679-0.681) and moderate (κ = 0.54; CI 0.539-0.543) in dermatomes below the sensory level. All applied tools led to at least moderate reliability below the sensory level (lowest κ = 0.44; CI 0.432-0.440), with the officially endorsed safety pin achieving the highest (substantial) reliability (κ = 0.64; CI 0.638-0.646). Percentage agreement differed between non-SCI (97.3%) and formally intact above level dermatomes in SCI (89.2%). Conclusions: Sharp/dull discrimination as a common clinical examination technique for spinothalamic tract function is a reliable assessment. Independent from the used examination tools, reliability was substantial, with the medium-sized safety pin delivering the most favorable results. Notwithstanding this, all other tools could be considered if a safety pin is not available. Regarding interrater reliability and guessing probability, a threshold of 80% correct responses for preserved sharp/dull discrimination appears to be most suitable, which is in line with current clinical approaches and ISNCSCI. The causal attribution of the identified differences in sharp/dull discrimination between clinically intact dermatomes of individuals with SCI and unaffected dermatomes of individuals without SCI requires future work. Clinical Trial Registration Number (German Clinical Trials Register): DRKS00015334 (https://www.drks.de).

Goal attainment in mobility after acute rehabilitation of mobility-restricting paralysis syndromes with regard to the ambulatory therapeutic level of participation NeuroMoves : A German national multicenter observational cohort study.

BACKGROUND: A central goal of rehabilitation in patients with paralysis syndromes after stroke or spinal cord injury (SCI) is to restore independent mobility as a pedestrian or wheelchair user. However, after acute rehabilitation, the mobility frequently deteriorates in the ambulatory setting, despite the delivery of rehabilitative interventions such as physical therapy or the prescription of assistive devices. The aim of the NeuroMoves study is to identify factors that are associated with changes of mobility in the ambulatory setting after acute inpatient rehabilitation, with a particular focus on participation according to the ICF (International Classification of Functioning, Disability and Health). METHODS: The NeuroMoves study is intended as a national multicenter observational cohort study with 9 clinical sites in Germany. A total of 500 patients with mobility-restricting paralysis syndromes (i.e. stroke or SCI) are to be recruited during acute inpatient rehabilitation prior to discharge to the ambulatory setting. Patients will have 8 months of follow-up in the ambulatory setting. Three study visits at the clinical sites (baseline, midterm, and final) are planned at 4-months intervals. The baseline visit is scheduled at the end of the acute inpatient rehabilitation. During the visits, demographical data, neurological, functional, quality of life, and implementation measures will be assessed. At baseline, each study participant receives an activity tracker (sensor for recording ambulatory mobility) along with a tablet computer for home use over the 8 months study duration. While mounted, the activity tracker records mobility data from which the daily distance covered by walking or wheelchair use can be calculated. Customized applications on the tablet computer remind the study participants to answer structured questionnaires about their health condition and treatment goals for physical therapy. Using the study participants' tablet, therapists will be asked to answer structured questionnaires concerning treatment goals and therapeutic measures they have applied. The primary analysis concerns the association between mobility (daily distance covered) and the degree of participation-oriented rehab interventions. Further exploratory analyses are planned. DISCUSSION: The findings could inform healthcare decision-making regarding ambulatory care in Germany focusing on mobility-promoting interventions for patients with mobility-restricting paralysis syndromes. STUDY REGISTRATION: German Clinical Trials Register, DRKS-ID: DRKS00020487 (18.02.2020).

Trainer in a pocket - proof-of-concept of mobile, real-time, foot kinematics feedback for gait pattern normalization in individuals after stroke, incomplete spinal cord injury and elderly patients.

BACKGROUND: Walking disabilities negatively affect inclusion in society and quality of life and increase the risk for secondary complications. It has been shown that external feedback applied by therapists and/or robotic training devices enables individuals with gait abnormalities to consciously normalize their gait pattern. However, little is known about the effects of a technically-assisted over ground feedback therapy. The aim of this study was to assess whether automatic real-time feedback provided by a shoe-mounted inertial-sensor-based gait therapy system is feasible in individuals with gait impairments after incomplete spinal cord injury (iSCI), stroke and in the elderly. METHODS: In a non-controlled proof-of-concept study, feedback by tablet computer-generated verbalized instructions was given to individuals with iSCI, stroke and old age for normalization of an individually selected gait parameter (stride length, stance or swing duration, or foot-to-ground angle). The training phase consisted of 3 consecutive visits. Four weeks post training a follow-up visit was performed. Visits started with an initial gait analysis (iGA) without feedback, followed by 5 feedback training sessions of 2-3 min and a gait analysis at the end. A universal evaluation and FB scheme based on equidistant levels of deviations from the mean normal value (1 level = 1 standard deviation (SD) of the physiological reference for the feedback parameter) was used for assessment of gait quality as well as for automated adaptation of training difficulty. Overall changes in level over iGAs were detected using a Friedman's Test. Post-hoc testing was achieved with paired Wilcoxon Tests. The users' satisfaction was assessed by a customized questionnaire. RESULTS: Fifteen individuals with iSCI, 11 after stroke and 15 elderly completed the training. The average level at iGA significantly decreased over the visits in all groups (Friedman's test, p < 0.0001), with the biggest decrease between the first and second training visit (4.78 ± 2.84 to 3.02 ± 2.43, p < 0.0001, paired Wilcoxon test). Overall, users rated the system's usability and its therapeutic effect as positive. CONCLUSIONS: Mobile, real-time, verbalized feedback is feasible and results in a normalization of the feedback gait parameter. The results form a first basis for using real-time feedback in task-specific motor rehabilitation programs. TRIAL REGISTRATION: DRKS00011853 , retrospectively registered on 2017/03/23.

International standards for neurological classification of spinal cord injury: impact of the revised worksheet (revision 02/13) on classification performance.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: Comparison of the classification performance between the worksheet revisions of 2011 and 2013 of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). SETTINGS: Ongoing ISNCSCI instructional courses of the European Multicenter Study on Human Spinal Cord Injury (EMSCI). For quality control all participants were requested to classify five ISNCSCI cases directly before (pre-test) and after (post-test) the workshop. PARTICIPANTS: One hundred twenty-five clinicians working in 22 SCI centers attended the instructional course between November 2011 and March 2015. Seventy-two clinicians completed the post-test with the 2011 revision of the worksheet and 53 with the 2013 revision. INTERVENTIONS: Not applicable. OUTCOME MEASURES: The clinicians' classification performance assessed by the percentage of correctly determined motor levels (ML) and sensory levels, neurological levels of injury (NLI), ASIA Impairment Scales and zones of partial preservations. RESULTS: While no group differences were found in the pre-tests, the overall performance (rev2011: 92.2% ± 6.7%, rev2013: 94.3% ± 7.7%; P = 0.010), the percentage of correct MLs (83.2% ± 14.5% vs. 88.1% ± 15.3%; P = 0.046) and NLIs (86.1% ± 16.7% vs. 90.9% ± 18.6%; P = 0.043) improved significantly in the post-tests. Detailed ML analysis revealed the largest benefit of the 2013 revision (50.0% vs. 67.0%) in a case with a high cervical injury (NLI C2). CONCLUSION: The results from the EMSCI ISNCSCI post-tests show a significantly better classification performance using the revised 2013 worksheet presumably due to the body-side based grouping of myotomes and dermatomes and their correct horizontal alignment. Even with these proven advantages of the new layout, the correct determination of MLs in the segments C2-C4 remains difficult.