Publications by authors named "Leanna Ritchie"

9 Publications

  • Page 1 of 1

Characterization of Hyperacute Neuropathic Pain after Spinal Cord Injury: A Prospective Study.

J Pain 2021 Jul 21. Epub 2021 Jul 21.

International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, British Columbia, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada; Hugill Centre for Anesthesia, Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

There is currently a lack of information regarding neuropathic pain in the very early stages of spinal cord injury (SCI). In the present study, neuropathic pain was assessed using the Douleur Neuropathique 4 Questions (DN4) for the patient's worst pain within the first 5 days of injury (i.e., hyperacute) and on follow-up at 3, 6, and 12 months. Within the hyperacute time-frame (i.e., 5 days), at- and below level neuropathic pain were reported as the worst pain in 23% (n=18) and 5% (n=4) of individuals with SCI, respectively. Compared to the neuropathic pain observed in this hyperacute setting, late presenting neuropathic pain was characterized by more intense painful electrical and cold sensations, but less itching sensations. Phenotypic differences between acute and late neuropathic pain support the incorporation of timing into a mechanism-based classification of neuropathic pain after SCI. The diagnosis of acute neuropathic pain after SCI is challenged by the presence of nociceptive and neuropathic pains, with the former potentially masking the latter. This may lead to an underestimation of the incidence of neuropathic pain during the very early, hyperacute time points post-injury. Trial registration: ClinicalTrials.gov (Identifier: NCT01279811) Perspective: This article presents distinct pain phenotypes of hyperacute and late presenting neuropathic pain after spinal cord injury and highlights the challenges of pain assessments in the acute phase after injury. This information may be relevant to clinical trial design and broaden our understanding of neuropathic pain mechanisms after spinal cord injury.
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http://dx.doi.org/10.1016/j.jpain.2021.06.013DOI Listing
July 2021

Proteomic Portraits Reveal Evolutionarily Conserved and Divergent Responses to Spinal Cord Injury.

Mol Cell Proteomics 2021 Jun 12;20:100096. Epub 2021 Jun 12.

Division of Neurosurgery, University of British Columbia, Vancouver, British Columbia, Canada.

Despite the emergence of promising therapeutic approaches in preclinical studies, the failure of large-scale clinical trials leaves clinicians without effective treatments for acute spinal cord injury (SCI). These trials are hindered by their reliance on detailed neurological examinations to establish outcomes, which inflate the time and resources required for completion. Moreover, therapeutic development takes place in animal models whose relevance to human injury remains unclear. Here, we address these challenges through targeted proteomic analyses of cerebrospinal fluid and serum samples from 111 patients with acute SCI and, in parallel, a large animal (porcine) model of SCI. We develop protein biomarkers of injury severity and recovery, including a prognostic model of neurological improvement at 6 months with an area under the receiver operating characteristic curve of 0.91, and validate these in an independent cohort. Through cross-species proteomic analyses, we dissect evolutionarily conserved and divergent aspects of the SCI response and establish the cerebrospinal fluid abundance of glial fibrillary acidic protein as a biochemical outcome measure in both humans and pigs. Our work opens up new avenues to catalyze translation by facilitating the evaluation of novel SCI therapies, while also providing a resource from which to direct future preclinical efforts.
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http://dx.doi.org/10.1016/j.mcpro.2021.100096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260874PMC
June 2021

Characterization of Cerebrospinal Fluid Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) as a Biomarker of Human Acute Traumatic Spinal Cord Injury.

J Neurotrauma 2021 May 3. Epub 2021 May 3.

International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Center, University of British Columbia, Vancouver, British Columbia, Canada.

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72-96 h post-injury from 32 acute SCI patients who were followed prospectively to determine neurological outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform (Quanterix, Billerica, MA) and correlated to injury severity, time, and neurological recovery. We found that CSF UCH-L1 was significantly elevated by 10- to 100-fold over laminectomy controls in an injury severity- and time-dependent manner. Twenty-four-hour post-injury CSF UCH-L1 concentrations distinguished between American Spinal Injury Association Impairment Scale (AIS) A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6 months with a sensitivity of 100% and a specificity of 86%. AIS A patients who did not improve their AIS grade at 6 months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 h. Similarly, the failure to gain >8 points on the total motor score at 6 months post-injury was associated with higher 24-h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and predict outcome.
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http://dx.doi.org/10.1089/neu.2020.7352DOI Listing
May 2021

Effectiveness of silver alloy-coated silicone urinary catheters in patients with acute traumatic cervical spinal cord injury: Results of a quality improvement initiative.

J Clin Neurosci 2020 Aug 11;78:135-138. Epub 2020 Jun 11.

Combined Neurosurgical and Orthopaedic Spine Program, Department of Orthopaedic Surgery, University of British Columbia, Vancouver Spine Surgery Institute, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC V5Z 1M9, Canada. Electronic address:

Patients with acute traumatic cervical spinal cord injury (ATCSCI) have an increased risk of catheter-associated urinary tract infection (CAUTI). The effectiveness of silver alloy-coated silicone urinary catheters (SACC) in preventing CAUTI in ATCSCI is unknown and was the objective of this study. We performed a quality improvement initiative in an attempt to reduce CAUTI in patients undergoing spine surgery at a single quaternary center. Prior to July 2015, all patients received a latex indwelling catheter (LIC). All patients with ATCSCI with limited hand function (AIS A,B, or C) received a SACC. Incidence of CAUTI, microbiology, duration of infection, antibiotic susceptibility, and catheter-associated adverse events were recorded prospectively. We studied 3081 consecutive patients over the three years, of whom 302 (9.8%) had ATCSCI; 63% of ATCSCI patients were ASIA Impairment Scale (AIS) A or B. The overall rate of CAUTI was 19% (585/3081), and was 38% (116/302) in patients with ATCSCI. Of 178 ATCSCI patients with LIC, 100 (56%) developed a CAUTI compared with 28 of 124 (23%) patients with SACC (p < 0.05). Poly-microbial and gram-positive infection was more common in LIC than in SACC (p < 0.05). Median duration of infection was 9 days in SACC group and 12 days in LIC group (p = 0.08). Resistance to trimethoprim (p < 0.001) and ciprofloxacin (p < 0.05) were more common in LIC group. There was no difference in catheter-associated adverse events or length of stay between the groups. This quality improvement initiative illustrates the effectiveness of antiseptic silver alloy-coated silicone urinary catheters in patients with ATCSCI. In our population, the use of SACC reduces the incidence and the complexity of CAUTI.
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http://dx.doi.org/10.1016/j.jocn.2020.05.036DOI Listing
August 2020

Empirical targets for acute hemodynamic management of individuals with spinal cord injury.

Neurology 2019 09 13;93(12):e1205-e1211. Epub 2019 Aug 13.

From the International Collaboration on Repair Discoveries (J.W.S., C.R.W., B.K.K.); MD/PhD Training Program (J.W.S.), School of Kinesiology (C.R.W.), and Department of Orthopaedics (R.C.-M., J.S., T.A., S. Paquette, N.D., C.G.F., M.F.D.), University of British Columbia; Vancouver Spine Program (L.M.B., A.T., L.R.), Vancouver General Hospital, British Columbia; Department of Surgery (J.-M.M.-T., S. Parent), Hôpital du Sacré-Coeur de Montréal, and Chu Sainte-Justine (S.C.), Department of Surgery, Université de Montréal, Quebec; Division of Orthopaedic Surgery (C.B.), London Health Sciences Centre, University of Western Ontario, Canada; Department of Neurological Surgery (S.D.), University of California, San Francisco; Vancouver Spine Surgery Institute (R.C.-M., J.S., T.A., S. Paquette, N.D., C.G.F., M.F.D., B.K.K.); and Division of Neurosurgery (B.K.K.), University of British Columbia, Blusson Spinal Cord Centre, Vancouver, Canada.

Objective: To determine the hemodynamic conditions associated with optimal neurologic improvement in individuals with acute traumatic spinal cord injury (SCI) who had lumbar intrathecal catheters placed to measure CSF pressure (CSFP).

Methods: Ninety-two individuals with acute SCI were enrolled in this multicenter prospective observational clinical trial. We monitored mean arterial pressure (MAP) and CSFP during the first week after injury and assessed neurologic function at baseline and 6 months after injury. We used relative risk iterations to determine transition points at which the likelihood of either improving neurologically or remaining unchanged neurologically was equivalent. These transition points guided our analyses in which we examined the linear relationships between time spent within target hemodynamic ranges (i.e., clinical adherence) and neurologic recovery.

Results: Relative risk transition points for CSFP, MAP, and spinal cord perfusion pressure (SCPP) were linearly associated with neurologic improvement and directed the identification of key hemodynamic target ranges. Clinical adherence to the target ranges was positively and linearly related to improved neurologic outcomes. Adherence to SCPP targets, not MAP targets, was the best indicator of improved neurologic recovery, which occurred with SCPP targets of 60 to 65 mm Hg. Failing to maintain the SCPP within the target ranges was an important detrimental factor in neurologic recovery, particularly if the target range is set lower.

Conclusion: We provide an empirical, data-driven approach to aid institutions in setting hemodynamic management targets that accept the real-life challenges of adherence to specific targets. Our results provide a framework to guide the development of widespread institutional management guidelines for acute traumatic SCI.
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http://dx.doi.org/10.1212/WNL.0000000000008125DOI Listing
September 2019

Predicting Injury Severity and Neurological Recovery after Acute Cervical Spinal Cord Injury: A Comparison of Cerebrospinal Fluid and Magnetic Resonance Imaging Biomarkers.

J Neurotrauma 2018 02 6;35(3):435-445. Epub 2017 Nov 6.

3 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .

Biomarkers of acute human spinal cord injury (SCI) could provide a more objective measure of spinal cord damage and a better predictor of neurological outcome than current standardized neurological assessments. In SCI, there is growing interest in establishing biomarkers from cerebrospinal fluid (CSF) and from magnetic resonance imaging (MRI). Here, we compared the ability of CSF and MRI biomarkers to classify injury severity and predict neurological recovery in a cohort of acute cervical SCI patients. CSF samples and MRI scans from 36 acute cervical SCI patients were examined. From the CSF samples taken 24 h post-injury, the concentrations of inflammatory cytokines (interleukin [IL]-6, IL-8, monocyte chemotactic protein-1), and structural proteins (tau, glial fibrillary acidic protein, and S100β) were measured. From the pre-operative MRI scans, we measured intramedullary lesion length, hematoma length, hematoma extent, CSF effacement, cord expansion, and maximal spinal cord compression. Baseline and 6-month post-injury assessments of American Spine Injury Association Impairment Scale (AIS) grade and motor score were conducted. Both MRI measures and CSF biomarker levels were found to correlate with baseline injury grade, and in combination they provided a stronger model for classifying baseline AIS grade than CSF or MRI biomarkers alone. For predicting neurological recovery, the inflammatory CSF biomarkers best predicted AIS grade conversion, whereas structural biomarker levels best predicted motor score improvement. A logistic regression model utilizing CSF biomarkers alone had a 91.2% accuracy at predicting AIS conversion, and was not strengthened by adding MRI features or even knowledge of the baseline AIS grade. In a direct comparison of MRI and CSF biomarkers, the CSF biomarkers discriminate better between different injury severities, and are stronger predictors of neurological recovery in terms of AIS grade and motor score improvement. These findings demonstrate the utility of measuring the acute biological responses to SCI as biomarkers of injury severity and neurological prognosis.
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http://dx.doi.org/10.1089/neu.2017.5357DOI Listing
February 2018

Spinal cord perfusion pressure predicts neurologic recovery in acute spinal cord injury.

Neurology 2017 Oct 15;89(16):1660-1667. Epub 2017 Sep 15.

From the International Collaboration on Repair Discoveries (ICORD) (J.W.S., M.F.D., C.R.W., B.K.K.); MD/PhD Training Program (J.W.S.), Department of Orthopaedics (J.S., C.G.F., M.F.D, B.K.K) and Division of Neurosurgery (T.A., S. Paquette, N.D.), Vancouver Spine Surgery Institute, Blusson Spinal Cord Centre, and School of Kinesiology (C.R.W.), University of British Columbia; Vancouver Spine Program (L.M.B., A.T., L.R.), Vancouver General Hospital; Department of Surgery, Hôpital du Sacré-Coeur de Montréal (J.-M.M.-T., S. Parent), and Chu Sainte-Justine, Department of Surgery (S.C.), Université de Montréal; Division of Orthopaedic Surgery (C.B.), London Health Sciences Centre, University of Western Ontario, Canada; and Department of Neurological Surgery (S.D.), University of California, San Francisco.

Objective: To determine whether spinal cord perfusion pressure (SCPP) as measured with a lumbar intrathecal catheter is a more predictive measure of neurologic outcome than the conventionally measured mean arterial pressure (MAP).

Methods: A total of 92 individuals with acute spinal cord injury were enrolled in this multicenter prospective observational clinical trial. MAP and CSF pressure (CSFP) were monitored during the first week postinjury. Neurologic impairment was assessed at baseline and at 6 months postinjury. We used logistic regression, systematic iterations of relative risk, and Cox proportional hazard models to examine hemodynamic patterns commensurate with neurologic outcome.

Results: We found that SCPP (odds ratio 1.039, = 0.002) is independently associated with positive neurologic recovery. The relative risk for not recovering neurologic function continually increased as individuals were exposed to SCPP below 50 mm Hg. Individuals who improved in neurologic grade dropped below SCPP of 50 mm Hg fewer times than those who did not improve ( = 0.012). This effect was not observed for MAP or CSFP. Those who were exposed to SCPP below 50 mm Hg were less likely to improve from their baseline neurologic impairment grade ( = 0.0056).

Conclusions: We demonstrate that maintaining SCPP above 50 mm Hg is a strong predictor of improved neurologic recovery following spinal cord injury. This suggests that SCPP (the difference between MAP and CSFP) can provide useful information to guide the hemodynamic management of patients with acute spinal cord injury.
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http://dx.doi.org/10.1212/WNL.0000000000004519DOI Listing
October 2017

A Targeted Proteomics Analysis of Cerebrospinal Fluid after Acute Human Spinal Cord Injury.

J Neurotrauma 2017 06 7;34(12):2054-2068. Epub 2017 Apr 7.

1 International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Centre, University of British Columbia , Vancouver, British Columbia, Canada .

Efforts to validate novel therapies in acute clinical trials for spinal cord injury (SCI) are impeded by the lack of objective quantitative measures that reflect injury severity and accurately predict neurological recovery. Therefore, a strong rationale exists for establishing neurochemical biomarkers that objectively quantify injury severity and predict outcome. Here, we conducted a targeted proteomics analysis of cerebrospinal fluid (CSF) samples derived from 29 acute SCI patients (American Spinal Injury Association Impairment Scale [AIS] A, B, or C) acquired at 24, 48, and 72 h post-injury. From a total of 165 proteins, we identified 27 potential biomarkers of injury severity (baseline AIS A, B, or C), with triosephosphate isomerase having the strongest relationship to AIS grade. The majority of affected proteins (24 of 27) were more abundant in samples from AIS A patients than in those from AIS C patients, suggesting that for the most part, these proteins are released into the CSF more readily with more severe trauma to the spinal cord. We then analyzed the relationship between CSF protein abundance and neurological recovery. For AIS grade improvement over 6 months, we identified 34 proteins that were associated with AIS grade conversion (p < 0.05); however, these associations were not statistically significant after adjusting for multiple comparisons. For total motor score (TMS) recovery over 6 months, after adjusting for baseline neurological injury level, we identified 46 proteins with a statistically significant association with TMS recovery. Twenty-two of these proteins were among the 27 proteins that were related to baseline AIS grade, consistent with the notion that protein markers that reflect a more severe injury also appropriately predict a poorer recovery of motor function. In summary, this study provides a description of the CSF proteome changes that occur after acute human SCI, and reveals a number of protein candidates for further validation as potential biomarkers of injury severity.
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http://dx.doi.org/10.1089/neu.2016.4879DOI Listing
June 2017

Cerebrospinal Fluid Biomarkers To Stratify Injury Severity and Predict Outcome in Human Traumatic Spinal Cord Injury.

J Neurotrauma 2017 02 15;34(3):567-580. Epub 2016 Aug 15.

1 Department of Orthopedics, Vancouver Spine Surgery Institute , Vancouver, British Columbia, Canada .

Neurologic impairment after spinal cord injury (SCI) is currently measured and classified by functional examination. Biological markers that objectively classify injury severity and predict outcome would greatly facilitate efforts to evaluate acute SCI therapies. The purpose of this study was to determine how well inflammatory and structural proteins within the cerebrospinal fluid (CSF) of acute traumatic SCI patients predicted American Spinal Injury Association Impairment Scale (AIS) grade conversion and motor score improvement over 6 months. Fifty acute SCI patients (29 AIS A, 9 AIS B, 12 AIS C; 32 cervical, 18 thoracic) were enrolled and CSF obtained through lumbar intrathecal catheters to analyze interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, tau, S100β, and glial fibrillary acidic protein (GFAP) at 24 h post-injury. The levels of IL-6, tau, S100β, and GFAP were significantly different between patients with baseline AIS grades of A, B, or C. The levels of all proteins (IL-6, IL-8, MCP-1, tau, S100β, and GFAP) were significantly different between those who improved an AIS grade over 6 months and those who did not improve. Linear discriminant analysis modeling was 83% accurate in predicting AIS conversion. For AIS A patients, the concentrations of proteins such as IL-6 and S100β correlated with conversion to AIS B or C. Motor score improvement also was strongly correlated with the 24-h post-injury CSF levels of all six biomarkers. The analysis of CSF can provide valuable biological information about injury severity and recovery potential after acute SCI. Such biological markers may be valuable tools for stratifying individuals in acute clinical trials where variability in spontaneous recovery requires large recruitment cohorts for sufficient power.
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http://dx.doi.org/10.1089/neu.2016.4435DOI Listing
February 2017
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