Longitudinal motor system changes from acute to chronic spinal cord injury.

BACKGROUND AND PURPOSE: In acute spinal cord injury (SCI), magnetic resonance imaging (MRI) reveals tissue bridges and neurodegeneration for 2 years. This 5-year study aims to track initial lesion changes, subsequent neurodegeneration, and their impact on recovery. METHODS: This prospective longitudinal study enrolled acute SCI patients and healthy controls who were assessed clinically-and by MRI-regularly from 3 days postinjury up to 60 months. We employed histologically cross-validated quantitative MRI sequences sensitive to volume, myelin, and iron changes, thereby reflecting indirectly processes of neurodegeneration and neuroinflammation. General linear models tracked lesion and remote changes in volume, myelin- and iron-sensitive magnetic resonance indices over 5 years. Associations between lesion, degeneration, and recovery (using the Spinal Cord Independence Measure [SCIM] questionnaire and the International Standards for Neurological Classification of Spinal Cord Injury total motor score) were assessed. RESULTS: Patients' motor scores improved by an average of 12.86 (95% confidence interval [CI] = 6.70-19.00) points, and SCIM by 26.08 (95% CI = 17.00-35.20) points. Within 3-28 days post-SCI, lesion size decreased by more than two-thirds (3 days: 302.52 ± 185.80 mm2 , 28 days: 76.77 ± 88.62 mm2 ), revealing tissue bridges. Cervical cord and corticospinal tract volumes transiently increased in SCI patients by 5% and 3%, respectively, accompanied by cervical myelin decreases and iron increases. Over time, progressive atrophy was observed in both regions, which was linked to early lesion dynamics. Tissue bridges, reduced swelling, and myelin content decreases were predictive of long-term motor score recovery and improved SCIM score. CONCLUSIONS: Studying acute changes and their impact on longer follow-up provides insights into SCI trajectory, highlighting the importance of acute intervention while indicating the potential to influence outcomes in the later stages.

Quantifying neurodegeneration of the cervical cord and brain in degenerative cervical myelopathy: A multicentre study using quantitative magnetic resonance imaging.

BACKGROUND AND PURPOSE: Simultaneous assessment of neurodegeneration in both the cervical cord and brain across multiple centres can enhance the effectiveness of clinical trials. Thus, this study aims to simultaneously assess microstructural changes in the cervical cord and brain above the stenosis in degenerative cervical myelopathy (DCM) using quantitative magnetic resonance imaging (MRI) in a multicentre study. METHODS: We applied voxelwise analysis with a probabilistic brain/spinal cord template embedded in statistical parametric mappin (SPM-BSC) to process multi parametric mapping (MPM) including effective transverse relaxation rate (R2*), longitudinal relaxation rate (R1), and magnetization transfer (MT), which are indirectly sensitive to iron and myelin content. Regression analysis was conducted to establish associations between neurodegeneration and clinical impairment. Thirty-eight DCM patients (mean age ± SD = 58.45 ± 11.47 years) and 38 healthy controls (mean age ± SD = 41.18 ± 12.75 years) were recruited at University Hospital Balgrist, Switzerland and Toronto Western Hospital, Canada. RESULTS: Remote atrophy was observed in the cervical cord (p = 0.002) and in the left thalamus (0.026) of the DCM group. R1 was decreased in the periaqueductal grey matter (p = 0.014), thalamus (p = 0.001), corpus callosum (p = 0.0001), and cranial corticospinal tract (p = 0.03). R2* was increased in the primary somatosensory cortices (p = 0.008). Sensory impairments were associated with increased iron-sensitive R2* in the thalamus and periaqueductal grey matter in DCM. CONCLUSIONS: Simultaneous assessment of the spinal cord and brain revealed DCM-induced demyelination, iron deposition, and atrophy. The extent of remote neurodegeneration was associated with sensory impairment, highlighting the intricate and expansive nature of microstructural neurodegeneration in DCM, reaching beyond the stenosis level.

Reliability of spinal cord measures based on synthetic T1-weighted MRI derived from multiparametric mapping (MPM).

Short MRI acquisition time, high signal-to-noise ratio, and high reliability are crucial for image quality when scanning healthy volunteers and patients. Cross-sectional cervical cord area (CSA) has been suggested as a marker of neurodegeneration and potential outcome measure in clinical trials and is conventionally measured on T1-weigthed 3D Magnetization Prepared Rapid Acquisition Gradient-Echo (MPRAGE) images. This study aims to reduce the acquisition time for the comprehensive assessment of the spinal cord, which is typically based on MPRAGE for morphometry and multi-parameter mapping (MPM) for microstructure. The MPRAGE is replaced by a synthetic T1-w MRI (synT1-w) estimated from the MPM, in order to measure CSA. SynT1-w images were reconstructed using the MPRAGE signal equation based on quantitative maps of proton density (PD), longitudinal (R1) and effective transverse (R2*) relaxation rates. The reliability of CSA measurements from synT1-w images was determined within a multi-center test-retest study format and validated against acquired MPRAGE scans by assessing the agreement between both methods. The response to pathological changes was tested by longitudinally measuring spinal cord atrophy following spinal cord injury (SCI) for synT1-w and MPRAGE using linear mixed effect models. CSA measurements based on the synT1-w MRI showed high intra-site (Coefficient of variation [CoV]: 1.43% to 2.71%) and inter-site repeatability (CoV: 2.90% to 5.76%), and only a minor deviation of -1.65 mm2 compared to MPRAGE. Crucially, by assessing atrophy rates and by comparing SCI patients with healthy controls longitudinally, differences between synT1-w and MPRAGE were negligible. These results demonstrate that reliable estimates of CSA can be obtained from synT1-w images, thereby reducing scan time significantly.

Safety and Feasibility of Lumbar Cerebrospinal Fluid Pressure and Intraspinal Pressure Studies in Cervical Stenosis: A Case Series.

INTRODUCTION: Degenerative cervical myelopathy (DCM) leads to functional impairment by compression of the spinal cord and nerve roots. In DCM, the dynamics of cerebrospinal fluid pressure (CSFP) and intraspinal pressure (ISP), as well as spinal cord perfusion pressure (SCPP) remain not investigated yet. Recent technical advances have enabled investigation of these parameters in acute spinal cord injury (SCI). We aim to investigate the properties of CSFP/ISP and spinal cord hemodynamics during and after decompressive surgery in DCM. MATERIALS AND METHODS: Four patients with DCM were enrolled; during surgery and 24 h postoperative, ISP at level was measured in one patient, and CSFP was measured in two patients. In one patient, CSFP was recorded at bedside before surgery. RESULTS: All measurements were conducted without adverse events and were well tolerated. With CSFP analysis, post-decompression Queckenstedt's test was responsive in two patients (i.e., jugular vein compression resulted in an elevation of CSFP pressure). In the patient whose CSFP was tested at bedside, Queckenstedt's test was not responsive before decompression. Individual optimum SCPPs were calculated to be between 70 and 75 mmHg. CONCLUSION: ISP and CSFP can reflect spinal compression and sufficient decompression. A better understanding and systematic monitoring possibly lead to improved hemodynamic management and may allow early recognition of postoperative complications such as swelling and bleeding.

In cervical spondylotic myelopathy spinal cord motion is focally increased at the level of stenosis: a controlled cross-sectional study.

STUDY DESIGN: Level-, age-, and gender-matched controlled cross-sectional cohort study. OBJECTIVES: To investigate alterations of spinal cord (SC) motion within cervical spondylotic myelopathy (CSM) across the cervical spinal segments and its relation to cerebrospinal fluid (CSF)-flow, anatomic conditions, and clinical parameters. SETTING: University Hospital Balgrist, Zurich, Switzerland. METHODS: Overall, 12 patients suffering from CSM at level C5 and 12 controls underwent cardiac-gated 2D phase-contrast-MRI at level C2 and C5 and standard MRI sequences. Parameters of interest: Velocity measurements of SC and CSF (area under the curve = total displacement (normalization for duration of the heart cycle), total displacement ratio (C5/C2; intraindividual normalization for confounders)), spinal canal diameters, clinical motor- and sensory scores, and performance measures. RESULTS: Interrater reliability was excellent for SC motion at both levels and for CSF flow at C2, but not reliable for CSF flow at C5. Within controls, SC motion at C2 positively correlated with SC motion at C5 (p = 0.000); this correlation diminished in patients (p = 0.860). SC total displacement ratio was significantly increased in patients (p = 0.029) and correlated with clinical impairment (p = 0.017). Morphometric measures of the extent of stenosis were not related to SC motion or clinical symptoms. CONCLUSION: The findings revealed physiological interactions of CSF flow and SC motion across the cervical spine in healthy controls while being diminished in CSM patients. Findings of focally increased SC motion at the level of stenosis were related to clinical impairment and might be promising as a diagnostic and prognostic marker in CSM. SPONSORSHIP: CRPP Neurorehab of the University of Zurich, Switzerland.

Potential thresholds of critically increased cardiac-related spinal cord motion in degenerative cervical myelopathy.

Introduction: New diagnostic techniques are a substantial research focus in degenerative cervical myelopathy (DCM). This cross-sectional study determined the significance of cardiac-related spinal cord motion and the extent of spinal stenosis as indicators of mechanical strain on the cord. Methods: Eighty-four DCM patients underwent MRI/clinical assessments and were classified as MRI+ [T2-weighted (T2w) hyperintense lesion in MRI] or MRI- (no T2w-hyperintense lesion). Cord motion (displacement assessed by phase-contrast MRI) and spinal stenosis [adapted spinal canal occupation ratio (aSCOR)] were related to neurological (sensory/motor) and neurophysiological readouts [contact heat evoked potentials (CHEPs)] by receiver operating characteristic (ROC) analysis. Results: MRI+ patients (N = 31; 36.9%) were more impaired compared to MRI- patients (N = 53; 63.1%) based on the modified Japanese Orthopedic Association (mJOA) subscores for upper {MRI+ [median (Interquartile range)]: 4 (4-5); MRI-: 5 (5-5); p < 0.01} and lower extremity [MRI+: 6 (6-7); MRI-: 7 (6-7); p = 0.03] motor dysfunction and the monofilament score [MRI+: 21 (18-23); MRI-: 24 (22-24); p < 0.01]. Both patient groups showed similar extent of cord motion and stenosis. Only in the MRI- group displacement identified patients with pathologic assessments [trunk/lower extremity pin prick score (T/LEPP): AUC = 0.67, p = 0.03; CHEPs: AUC = 0.73, p = 0.01]. Cord motion thresholds: T/LEPP: 1.67 mm (sensitivity 84.6%, specificity 52.5%); CHEPs: 1.96 mm (sensitivity 83.3%, specificity 65.6%). The aSCOR failed to show any relation to the clinical assessments. Discussion: These findings affirm cord motion measurements as a promising additional biomarker to improve the clinical workup and to enable timely surgical treatment particularly in MRI- DCM patients. Clinical trial registration: www.clinicaltrials.gov, NCT02170155.

Spinal cord motion assessed by phase-contrast MRI - An inter-center pooled data analysis.

BACKGROUND: Phase-contrast MRI of CSF and spinal cord dynamics has evolved among diseases caused by altered CSF volume (spontaneous intracranial hypotension, normal pressure hydrocephalus) and by altered CSF space (degenerative cervical myelopathy (DCM), Chiari malformation). While CSF seems to be an obvious target for possible diagnostic use, craniocaudal spinal cord motion analysis offers the benefit of fast and reliable assessments. It is driven by volume shifts between the intracranial and the intraspinal compartments (Monro-Kellie hypothesis). Despite promising initial reports, comparison of spinal cord motion data across different centers is challenged by reports of varying value, raising questions about the validity of the findings. OBJECTIVE: To systematically investigate inter-center differences between phase-contrast MRI data. METHODS: Age- and gender matched, retrospective, pooled-data analysis across two centers: cardiac-gated, sagittal phase-contrast MRI of the cervical spinal cord (segments C2/C3 to C7/T1) including healthy participants and DCM patients; comparison and analysis of different MRI sequences and processing techniques (manual versus fully automated). RESULTS: A genuine craniocaudal spinal cord motion pattern and an increased focal spinal cord motion among DCM patients were depicted by both MRI sequences (p < 0.01). Higher time-resolution resolved steeper and larger peaks, causing inter-center differences (p < 0.01). Comparison of different processing methods showed a high level of rating reliability (ICC > 0.86 at segments C2/C3 to C6/C7). DISCUSSION: Craniocaudal spinal cord motion is a genuine finding. Differences between values were attributed to time-resolution of the MRI sequences. Automated processing confers the benefit of unbiased and consistent analysis, while data did not reveal any superiority.

Increased cranio-caudal spinal cord oscillations are the cardinal pathophysiological change in degenerative cervical myelopathy.

Introduction: Degenerative cervical myelopathy (DCM) is the most common cause of non-traumatic incomplete spinal cord injury, but its pathophysiology is poorly understood. As spinal cord compression observed in standard MRI often fails to explain a patient's status, new diagnostic techniques to assess DCM are one of the research priorities. Minor cardiac-related cranio-caudal oscillations of the cervical spinal cord are observed by phase-contrast MRI (PC-MRI) in healthy controls (HCs), while they become pathologically increased in patients suffering from degenerative cervical myelopathy. Whether transversal oscillations (i.e., anterior-posterior and right-left) also change in DCM patients is not known. Methods: We assessed spinal cord motion simultaneously in all three spatial directions (i.e., cranio-caudal, anterior-posterior, and right-left) using sagittal PC-MRI and compared physiological oscillations in 18 HCs to pathological changes in 72 DCM patients with spinal canal stenosis. The parameter of interest was the amplitude of the velocity signal (i.e., maximum positive to maximum negative peak) during the cardiac cycle. Results: Most patients suffered from mild DCM (mJOA score 16 (14-18) points), and the majority (68.1%) presented with multisegmental stenosis. The spinal canal was considerably constricted in DCM patients in all segments compared to HCs. Under physiological conditions in HCs, the cervical spinal cord oscillates in the cranio-caudal and anterior-posterior directions, while right-left motion was marginal [e.g., segment C5 amplitudes: cranio-caudal: 0.40 (0.27-0.48) cm/s; anterior-posterior: 0.18 (0.16-0.29) cm/s; right-left: 0.10 (0.08-0.13) cm/s]. Compared to HCs, DCM patients presented with considerably increased cranio-caudal oscillations due to the cardinal pathophysiologic change in non-stenotic [e.g., segment C5 amplitudes: 0.79 (0.49-1.32) cm/s] and stenotic segments [.g., segment C5 amplitudes: 0.99 (0.69-1.42) cm/s]). In contrast, right-left [e.g., segment C5 amplitudes: non-stenotic segment: 0.20 (0.13-0.32) cm/s; stenotic segment: 0.11 (0.09-0.18) cm/s] and anterior-posterior oscillations [e.g., segment C5 amplitudes: non-stenotic segment: 0.26 (0.15-0.45) cm/s; stenotic segment: 0.11 (0.09-0.18) cm/s] remained on low magnitudes comparable to HCs. Conclusion: Increased cranio-caudal oscillations of the cervical cord are the cardinal pathophysiologic change and can be quantified using PC-MRI in DCM patients. This study addresses spinal cord oscillations as a relevant biomarker reflecting dynamic mechanical cord stress in DCM patients, potentially contributing to a loss of function.

Infarction following chiasmatic low grade glioma resection.

INTRODUCTION: The current SIOP (International Society for Paediatric Oncology)-LGG (low grade glioma) study protocol allows chiasmatic tumours identified as LGG on the basis of neuroradiological characteristics to be treated without histological verification. As some tumours do not respond well to treatment, the search for molecular tissue markers will gain importance for future studies. Anecdotal observations of infarctions after surgery for chiasmatic tumours during central reviewing initiated this study. MATERIALS AND METHODS: In 84 patients, histology was obtained during 102 interventions in the years 1992-2009 by 33 biopsies, 67 partial/subtotal and 2 total resections. Median age at the time of operation was 5 years (mean 5 years 11 months). We could identify 17 infarctions following partial resection of chiasmatic LGG. Biopsies were not complicated by infarction. Children developing infarction were considerably younger (median 3 years; mean 4 years 5 months) than the patients without infarction (median 5 years 4 months; mean 6 years 2 months). A total of 51 patients with cerebellar LGG (median 7 years; mean 7 years 4 months) served as a control group, with 65 surgical procedures (2 biopsies, 22 partial/subtotal resections and 41 total resections) performed in the years 2004-2009. Only one total resection (1.5%) in this group was followed by infarction. CONCLUSION: Partial/subtotal resections of chiasmatic LGG in our study population bear a considerable risk for infarction especially in young children. As there is currently no evidence for a better outcome after tumour resection, we suggest that the sampling of tumour tissue should be performed via biopsies whenever possible.

Extent of Cord Pathology in the Lumbosacral Enlargement in Non-Traumatic versus Traumatic Spinal Cord Injury.

This study compares remote neurodegenerative changes caudal to a cervical injury in degenerative cervical myelopathy (DCM; i.e., non-traumatic) and incomplete traumatic spinal cord injury (tSCI) patients, using magnetic resonance imaging (MRI)-based tissue area measurements and diffusion tensor imaging (DTI). Eighteen mild-to-moderate DCM patients with sensory impairments (modified Japanese Orthopedic score: 16.2 ± 1.9), 14 incomplete tetraplegic tSCI patients (American Spinal Injury Association Impairment Scale C and D), and 20 healthy controls were recruited. All participants received DTI and T2*-weighted scans in the lumbosacral enlargement (caudal to injury) and at C2/C3 (rostral to injury). MRI readouts included DTI metrics in the white matter (WM) columns and cross-sectional WM and gray matter area. One-way analysis of variance with Tukey's post hoc comparison (p < 0.05) was used to assess group differences. In the lumbosacral enlargement, compared with DCM, tSCI patients exhibited decreased fractional anisotropy in the lateral (tSCI vs. DCM, -11.9%, p = 0.007) and ventral WM column (-8.0%, p = 0.021), and showed a trend toward lower values in the dorsal column (-8.9%, p = 0.068). At C2/C3, compared with controls, fractional anisotropy was lower in both groups in the dorsal (DCM vs. controls, -7.9%, p = 0.024; tSCI vs. controls, -10.0%, p = 0.007) and in the lateral column (DCM: -6.2%, p = 0.039; tSCI: -13.3%, p < 0.001), while tSCI patients had lower fractional anisotropy than DCM patients in the lateral column (-7.6%, p = 0.029). WM areas were not different between patient groups but were lower compared with controls in the lumbosacral enlargement (DCM: -16.9%, p < 0.001; tSCI: -10.5%, p = 0.043) and at C2/C3 (DCM: -16.0%, p < 0.001; tSCI: -18.1%, p < 0.001). In conclusion, mild-to-moderate DCM and incomplete tSCI lead to similar degree of degeneration of the dorsal and lateral columns at C2/C3, but tSCI results in more widespread white matter damage in the lumbosacral enlargement. These remote changes are likely to contribute to the patients' impairment and recovery. DTI is a sensitive tool to assess remote pathological changes in DCM and tSCI patients.

Intraoperative Monitoring of CSF Pressure in Patients with Degenerative Cervical Myelopathy (COMP-CORD Study): A Prospective Cohort Study.

Degenerative cervical myelopathy (DCM) is hallmarked by spinal canal narrowing and related cord compression and myelopathy. Cerebrospinal fluid (CSF) pressure dynamics are likely disturbed due to spinal canal stenosis. The study aimed to investigate the diagnostic value of continuous intraoperative CSF pressure monitoring during surgical decompression. This prospective single center study (NCT02170155) enrolled DCM patients who underwent surgical decompression between December 2019 and May 2021. Data from n = 17 patients were analyzed and symptom severity graded with the modified Japanese Orthopedic Score (mJOA). CSF pulsations were continuously monitored with a lumbar intrathecal catheter during surgical decompression. Mean patient age was 62 ± 9 years (range 38-73; 8 female), symptoms were mild-moderate in most patients (mean mJOA 14 ± 2, range 10-18). Measurements were well tolerated without safety concerns. In 15/16 patients (94%), CSF pulsations increased at the time of surgical decompression. In one case, responsiveness could not be evaluated for technical reasons. Unexpected CSF pulsation decrease was related to adverse events (i.e., CSF leakage). Median CSF pulsation amplitudes increased from pre-decompression (0.52 mm Hg, interquartile range [IQR] 0.71) to post-decompression (0.72 mm Hg, IQR 0.96; p = 0.001). Mean baseline CSF pressure increased with lower magnitude than pulsations, from 9.5 ± 3.5 to 10.3 ± 3.8 mm Hg (p = 0.003). Systematic relations of CSF pulsations were confined to surgical decompression, independent of arterial blood pressure (p = 0.927) or heart rate (p = 0.102). Intraoperative CSF pulsation monitoring was related to surgical decompression while in addition adverse events could be discerned. Further investigation of the clinical value of intraoperative guidance for decompression in complex DCM surgery is promising.

Comparison of axial and sagittal spinal cord motion measurements in degenerative cervical myelopathy.

BACKGROUND AND PURPOSE: The timing of decision-making for a surgical intervention in patients with mild degenerative cervical myelopathy (DCM) is challenging. Spinal cord motion phase contrast MRI (PC-MRI) measurements can reveal the extent of dynamic mechanical strain on the spinal cord to potentially identify high-risk patients. This study aims to determine the comparability of axial and sagittal PC-MRI measurements of spinal cord motion with the prospect of improving the clinical workup. METHODS: Sixty-four DCM patients underwent a PC-MRI scan assessing spinal cord motion. The agreement of axial and sagittal measurements was determined by means of intraclass correlation coefficients (ICCs) and Bland-Altman analyses. RESULTS: The comparability of axial and sagittal PC-MRI measurements was good to excellent at all cervical levels (ICCs motion amplitude: .810-.940; p < .001). Significant differences between axial and sagittal amplitude values could be found at segments C3 and C4, while its magnitude was low (C3: 0.07 ± 0.19 cm/second; C4: -0.12 ± 0.30 cm/second). Bland-Altman analysis showed a good agreement between axial and sagittal PC-MRI scans (coefficients of repeatability: minimum -0.23 cm/second at C2; maximum -0.58 cm/second at C4). Subgroup analysis regarding anatomic conditions (stenotic vs. nonstenotic segments) and different velocity encoding (2 vs. 3 cm/second) showed comparable results. CONCLUSIONS: This study demonstrates good comparability between axial and sagittal spinal cord motion measurements in DCM patients. To this end, axial and sagittal PC-MRI are both accurate and sensitive in detecting pathologic cord motion. Therefore, such measures could identify high-risk patients and improve clinical decision-making (ie, timing of decompression).

Combined Neurophysiologic and Neuroimaging Approach to Reveal the Structure-Function Paradox in Cervical Myelopathy.

OBJECTIVE: To explore the so-called "structure-function paradox" in individuals with focal spinal lesions by means of tract-specific MRI coupled with multi-modal evoked potentials and quantitative sensory testing. METHODS: Individuals with signs and symptoms attributable to cervical myelopathy (i.e., no evidence of competing neurological diagnosis) were recruited in the Balgrist University Hospital, Zurich, Switzerland between February 2018 and March 2019. We evaluated the relationship between the extent of structural damage within spinal nociceptive pathways (i.e., dorsal horn, spinothalamic tract, anterior commissure) assessed with atlas-based MRI , and 1) the functional integrity of spinal nociceptive pathways measured with contact heat-, cold-, and pinprick- evoked potentials and 2) clinical somatosensory phenotypes assessed with quantitative sensory testing. RESULTS: Sixteen individuals (mean age 61 years) with either degenerative (N=13) or post-traumatic (N=3) cervical myelopathy participated in the study. Most individuals presented with mild myelopathy (modified Japanese Orthopaedic Association score (mJOA)>15; N=13). 71% of individuals presented with structural damage within spinal nociceptive pathways on MRI. Yet, 50% of these individuals presented with complete functional sparing (i.e., normal contact heat-, cold-, and pinprick- evoked potentials). The extent of structural damage within spinal nociceptive pathways was neither associated with functional integrity of thermal (heat: p=0.57; cold: p=0.49) and mechano-nociceptive pathways (p=0.83) nor with the clinical somatosensory phenotype (heat: p=0.16; cold: p=0.37; mechanical: p=0.73). The amount of structural damage to the spinothalamic tract did not correlate with spinothalamic conduction velocity (p>0.05; rho=-0.11). CONCLUSIONS: Our findings provide neurophysiological evidence to substantiate that structural damage in the spinal cord does not equate to functional somatosensory deficits. This study recognizes the pronounced structure-function paradox in cervical myelopathies and underlines the inevitable need for a multi-modal phenotyping approach to reveal the eloquence of lesions within somatosensory pathways.

Tracking White and Gray Matter Degeneration along the Spinal Cord Axis in Degenerative Cervical Myelopathy.

This study aims to determine tissue-specific neurodegeneration across the spinal cord in patients with mild-moderate degenerative cervical myelopathy (DCM). Twenty-four mild-moderate DCM and 24 healthy subjects were recruited. In patients, a T2-weighted scan was acquired at the compression site, whereas in all participants a T2*-weighted and diffusion-weighted scan was acquired at the cervical level (C2-C3) and in the lumbar enlargement (i.e., rostral and caudal to the site of compression). We quantified intramedullary signal changes, maximal canal and cord compression, white (WM) and gray matter (GM) atrophy, and microstructural indices from diffusion-weighted scans. All patients underwent clinical (modified Japanese Orthopaedic Association; mJOA) and electrophysiological assessments. Regression analysis assessed associations between magnetic resonance imaging (MRI) readouts and electrophysiological and clinical outcomes. Twenty patients were classified with mild and 4 with moderate DCM using the mJOA scale. The most frequent site of compression was at the C5-C6 level, with maximum cord compression of 38.73% ± 11.57%. Ten patients showed imaging evidence of cervical myelopathy. In the cervical cord, WM and GM atrophy and WM microstructural changes were evident, whereas in the lumbar cord only WM showed atrophy and microstructural changes. Remote cervical cord WM microstructural changes were pronounced in patients with radiological myelopathy and associated with impaired electrophysiology. Lumbar cord WM atrophy was associated with lower limb sensory impairments. In conclusion, tissue-specific neurodegeneration revealed by quantitative MRI is already apparent across the spinal cord in mild-moderate DCM before the onset of severe clinical impairments. WM microstructural changes are particularly sensitive to remote pathologically and clinically eloquent changes in DCM.

Study protocol for an observational study of cerebrospinal fluid pressure in patients with degenerative cervical myelopathy undergoing surgical deCOMPression of the spinal CORD: the COMP-CORD study.

INTRODUCTION: Degenerative cervical myelopathy (DCM) is a disabling spinal disorder characterised by sensorimotor deficits of upper and lower limbs, neurogenic bladder dysfunction and neuropathic pain. When suspected, cervical MRI helps to reveal spinal cord compression and rules out alternative diagnoses. However, the correlation between radiological findings and symptoms is weak. Cerebrospinal fluid pressure (CSFP) analysis may complement the appreciation of cord compression and be used for intraoperative and postoperative monitorings in patients undergoing surgical decompression. METHODS AND ANALYSIS: Twenty patients diagnosed with DCM undergoing surgical decompression will receive standardised lumbar CSFP monitoring immediately before, during and 24 hours after operation. Rest (ie, opening pressure, CSF pulsation) and stimulated (ie, Valsalva, Queckenstedt's) CSFP-findings in DCM will be compared with 20 controls and results from CSFP monitoring will be related to clinical and neurophysiological findings. Arterial blood pressure will be recorded perioperatively and postoperatively to calculate spinal cord perfusion pressure and spinal vascular reactivity index. Furthermore, measures of CSFP will be compared with markers of spinal cord compression by means of MR imaging. ETHICS AND DISSEMINATION: The study protocol conformed to the latest revision of the Declaration of Helsinki and was approved by the local Ethics Committee of the University Hospital of Zurich (KEK-ZH number PB-2016-00623). The main publications from this study will cover the CSFP fluid dynamics and pressure analysis preoperative, perioperative and postoperative correlated with imaging, clinical scores and neurophysiology. Other publications will deal with preoperative and postoperative spinal perfusion. Furthermore, we will disseminate an analysis on waveform morphology and the correlation with blood pressure and ECG. Parts of the data will be used for computational modelling of cervical stenosis. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02170155).

The Damaged Spinal Cord Is a Suitable Target for Stem Cell Transplantation.

Background. Given individuals with spinal cord injury (SCI) approaching 2 million, viable options for regenerative repair are desperately needed. Human central nervous system stem cells (HuCNS-SC) are self-renewing, multipotent adult stem cells that engraft, migrate, and differentiate in appropriate regions in multiple animal models of injured brain and spinal cord. Preclinical improved SCI locomotor function provided rationale for the first-in-human SCI clinical trial of HuCNS-SC cells. Evidence of feasibility and long-term safety of cell transplantation into damaged human cord is needed to foster translational progression of cellular therapies. Methods. A first-ever, multisite phase I/IIa trial involving surgical transplantation of 20 million HuCNS-SC cells into the thoracic cord in 12 AIS A or B subjects (traumatic, T2-T11 motor-complete, sensory-incomplete), aged 19 to 53 years, demonstrated safety and preliminary efficacy. Six-year follow-up data were collected (sensory thresholds and neuroimaging augmenting clinical assessments). Findings. The study revealed short- and long-term surgical and medical safety (well-tolerated immunosuppression in population susceptible to infections). Preliminary efficacy measures identified 5/12 with reliable sensory improvements. Unfortunately, without thoracic muscles available for manual muscle examination, thoracic motor changes could not be measured. Lower limb motor scores did not change during the study. Cervical cord imaging revealed, no tumor formation or malformation of the lesion area, and secondary supralesional structural changes similar to SCI control subjects. Interpretation. Short- and long-term safety and feasibility support the consideration of cell transplantation for patients with complete and incomplete SCI. This report is an important step to prepare, foster, and maintain the therapeutic development of cell transplantation for human SCI.

Width and neurophysiologic properties of tissue bridges predict recovery after cervical injury.

OBJECTIVE: To assess whether preserved dorsal and ventral midsagittal tissue bridges after traumatic cervical spinal cord injury (SCI) encode tract-specific electrophysiologic properties and are predictive of appropriate recovery. METHODS: In this longitudinal study, we retrospectively assessed MRI scans at 1 month after SCI that provided data on width and location (dorsal vs ventral) of midsagittal tissue bridges in 28 tetraplegic patients. Regression analysis assessed associations between midsagittal tissue bridges and motor- and sensory-specific electrophysiologic recordings and appropriate outcome measures at 12 months after SCI. RESULTS: Greater width of dorsal midsagittal tissue bridges at 1 month after SCI identified patients who were classified as being sensory incomplete at 12 months after SCI (p = 0.025), had shorter sensory evoked potential (SEP) latencies (r = -0.57, p = 0.016), and had greater SEP amplitudes (r = 0.61, p = 0.001). Greater width of dorsal tissue bridges predicted better light-touch score at 12 months (r = 0.40, p = 0.045) independently of baseline clinical score and ventral tissue bridges. Greater width of ventral midsagittal tissue bridges at 1 month identified patients who were classified as being motor incomplete at 12 months (p = 0.002), revealed shorter motor evoked potential (MEP) latencies (r = -0.54, p = 0.044), and had greater ratios of MEP amplitude to compound muscle action potential amplitude (r = 0.56, p = 0.005). Greater width of ventral tissue bridges predicted better lower extremity motor scores at 12 months (r = 0.41, p = 0.035) independently of baseline clinical score and dorsal tissue bridges. CONCLUSION: Midsagittal tissue bridges, detectable early after SCI, underwrite tract-specific electrophysiologic communication and are predictors of appropriate sensorimotor recovery. Neuroimaging biomarkers of midsagittal tissue bridges may be integrated into the diagnostic workup, prediction of recovery, and patients' stratification in clinical trials.

In vivo evidence of remote neural degeneration in the lumbar enlargement after cervical injury.

OBJECTIVE: To characterize remote secondary neurodegeneration of spinal tracts and neurons below a cervical spinal cord injury (SCI) and its relation to the severity of injury, the integrity of efferent and afferent pathways, and clinical impairment. METHODS: A comprehensive high-resolution MRI protocol was acquired in 17 traumatic cervical SCI patients and 14 controls at 3T. At the cervical lesion, a sagittal T2-weighted scan provided information on the width of preserved midsagittal tissue bridges. In the lumbar enlargement, high-resolution T2*-weighted and diffusion-weighted scans were used to calculate tissue-specific cross-sectional areas and diffusion indices, respectively. Regression analyses determined associations between MRI readouts and the electrophysiologic and clinical measures. RESULTS: At the cervical injury level, preserved midsagittal tissue bridges were present in the majority of patients. In the lumbar enlargement, neurodegeneration-in terms of macrostructural and microstructural MRI changes-was evident in the white matter and ventral and dorsal horns. Patients with thinner midsagittal tissue bridges had smaller ventral horn area, higher radial diffusivity in the gray matter, smaller motor evoked potential amplitude from the lower extremities, and lower motor score. In addition, smaller width of midsagittal tissue bridges was also associated with smaller tibialis sensory evoked potential amplitude and lower light-touch score. CONCLUSIONS: This study shows extensive tissue-specific cord pathology in infralesional spinal networks following cervical SCI, its magnitude relating to lesion severity, electrophysiologic integrity, and clinical impairment of the lower extremity. The clinical eloquence of remote neurodegenerative changes speaks to the application of neuroimaging biomarkers in diagnostic workup and planning of clinical trials.

Sensorimotor plasticity after spinal cord injury: a longitudinal and translational study.

Objective: The objective was to track and compare the progression of neuroplastic changes in a large animal model and humans with spinal cord injury. Methods: A total of 37 individuals with acute traumatic spinal cord injury were followed over time (1, 3, 6, and 12 months post-injury) with repeated neurophysiological assessments. Somatosensory and motor evoked potentials were recorded in the upper extremities above the level of injury. In a reverse-translational approach, similar neurophysiological techniques were examined in a porcine model of thoracic spinal cord injury. Twelve Yucatan mini-pigs underwent a contusive spinal cord injury at T10 and tracked with somatosensory and motor evoked potentials assessments in the fore- and hind limbs pre- (baseline, post-laminectomy) and post-injury (10 min, 3 h, 12 weeks). Results: In both humans and pigs, the sensory responses in the cranial coordinates of upper extremities/forelimbs progressively increased from immediately post-injury to later time points. Motor responses in the forelimbs increased immediately after experimental injury in pigs, remaining elevated at 12 weeks. In humans, motor evoked potentials were significantly higher at 1-month (and remained so at 1 year) compared to normative values. Conclusions: Despite notable differences between experimental models and the human condition, the brain's response to spinal cord injury is remarkably similar between humans and pigs. Our findings further underscore the utility of this large animal model in translational spinal cord injury research.

Electrophysiological Multimodal Assessments Improve Outcome Prediction in Traumatic Cervical Spinal Cord Injury.

Outcome prediction after spinal cord injury (SCI) is essential for early counseling and orientation of the rehabilitative intervention. Moreover, prognostication of outcome is crucial to achieving meaningful stratification when conceiving clinical trials. Neurophysiological examinations are commonly employed for prognostication after SCI, but whether neurophysiology could improve the functional prognosis based on clinical predictors remains an open question. Data of 224 patients included in the European Multicenter Study about Spinal Cord Injury were analyzed with bootstrapping analysis and multivariate logistical regression to derive prediction models of complete functional recovery in the chronic stage after traumatic cervical SCI. Within 40 days after SCI, we evaluated age, gender, the motor and sensory cumulative scores of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), and neurophysiological variables (motor evoked potentials, sensory evoked potentials, nerve conduction study) as possible predictors. Positive outcome was defined by a Spinal Cord Independence Measure total score of 100. Analyzing clinical variables, we derived a prediction model based on the ISNCSCI total motor score and age: the area under the receiver operating curve (AUC) was 0.936 (95% confidence interval [CI]: 0.904-0.968). Adding neurophysiological variables to the model, the AUC increased significantly: 0.956 (95% CI: 0.930-0.982; p = 0.019). More patients could be correctly classified by adding the electrophysiological data. Our study demonstrates that neurophysiological assessment improves the prediction of functional prognosis after traumatic cervical SCI, and suggests the use of neurophysiology to optimize patient information, rehabilitation, and discharge planning and the design of future clinical trials.