Leslie R. Morse

Traumatic spinal cord injury in the United States, 1993-2012

IMPORTANCE Acute traumatic spinal cord injury results in disability and use of health care resources, yet data on contemporary national trends of traumatic spinal cord injury incidence and etiology are limited. OBJECTIVE To assess trends in acute traumatic spinal cord injury incidence, etiology, mortality, and associated surgical procedures in the United States from 1993 to 2012. DESIGN, SETTING, AND PARTICIPANTS Analysis of survey data from the US Nationwide Inpatient Sample databases for 1993-2012, including a total of 63,109 patients with acute traumatic spinal cord injury. MAIN OUTCOMES AND MEASURES Age- and sex-stratified incidence of acute traumatic spinal cord injury; trends in etiology and in-hospital mortality of acute traumatic spinal cord injury. RESULTS In 1993, the estimated incidence of acute spinal cord injury was 53 cases (95% CI, 52-54 cases) per 1 million persons based on 2659 actual cases. In 2012, the estimated incidence was 54 cases (95% CI, 53-55 cases) per 1 million population based on 3393 cases (average annual percentage change, 0.2%; 95% CI, -0.5% to 0.9%). Incidence rates among the younger male population declined from 1993 to 2012: for age 16 to 24 years, from 144 cases/million (2405 cases) to 87 cases/million (1770 cases) (average annual percentage change, -2.5%; 95% CI, -3.3% to -1.8%); for age 25 to 44 years, from 96 cases/million (3959 cases) to 71 cases/million persons (2930 cases), (average annual percentage change, -1.2%; 95% CI, -2.1% to -0.3%). A high rate of increase was observed in men aged 65 to 74 years (from 84 cases/million in 1993 [695 cases] to 131 cases/million [1465 cases]; average annual percentage change, 2.7%; 95% CI, 2.0%-3.5%). The percentage of spinal cord injury associated with falls increased significantly from 28% (95% CI, 26%-30%) in 1997-2000 to 66% (95% CI, 64%-68%) in 2010-2012 in those aged 65 years or older (P < .001). Although overall in-hospital mortality increased from 6.6% (95% CI, 6.1%-7.0%) in 1993-1996 to 7.5% (95% CI, 7.0%-8.0%) in 2010-2012 (P < .001), mortality decreased significantly from 24.2% (95% CI, 19.7%-28.7%) in 1993-1996 to 20.1% (95% CI, 17.0%-23.2%) in 2010-2012 (P = .003) among persons aged 85 years or older. CONCLUSIONS AND RELEVANCE Between 1993 and 2012, the incidence rate of acute traumatic spinal cord injury remained relatively stable but, reflecting an increasing population, the total number of cases increased. The largest increase in incidence was observed in older patients, largely associated with an increase in falls, and in-hospital mortality remained high, especially among elderly persons.

Osteoporotic fractures and hospitalization risk in chronic spinal cord injury

SummaryOsteoporosis is a well acknowledged complication of spinal cord injury. We report that motor complete spinal cord injury and post-injury alcohol consumption are risk factors for hospitalization for fracture treatment. The clinical assessment did not include osteoporosis diagnosis and treatment considerations, indicating a need for improved clinical protocols.IntroductionTreatment of osteoporotic long bone fractures often results in lengthy hospitalizations for individuals with spinal cord injury. Clinical features and factors that contribute to hospitalization risk have not previously been described.MethodsThree hundred and fifteen veterans ≥ 1 year after spinal cord injury completed a health questionnaire and underwent clinical exam at study entry. Multivariate Cox regression accounting for repeated events was used to assess longitudinal predictors of fracture-related hospitalizations in Veterans Affairs Medical Centers 1996–2003.ResultsOne thousand four hundred and eighty-seven hospital admissions occurred among 315 participants, and 39 hospitalizations (2.6%) were for fracture treatment. Median length of stay was 35 days. Fracture-related complications occurred in 53%. Independent risk factors for admission were motor complete versus motor incomplete spinal cord injury (hazard ratio = 3.73, 95% CI = 1.46–10.50). There was a significant linear trend in risk with greater alcohol consumption after injury. Record review indicated that evaluation for osteoporosis was not obtained during these admissions.ConclusionsAssessed prospectively, hospitalization in Veterans Affairs Medical Centers for low-impact fractures is more common in motor complete spinal cord injury and is associated with greater alcohol use after injury. Osteoporosis diagnosis and treatment considerations were not part of a clinical assessment, indicating the need for improved protocols that might prevent low-impact fractures and related admissions.

Endodontic antimicrobial photodynamic therapy: Safety assessment in mammalian cell cultures

OBJECTIVES The purpose of this study was to assess the in vitro synergistic effect of methylene blue (MB) and red light on human gingival fibroblasts and osteoblasts with parameters similar to those that may be applied in a clinical setting for endodontic disinfection. MATERIALS AND METHODS Both cell types were sensitized with 50 microg/mL MB followed by exposure to red light at 665 nm for 5 minutes with an irradiance of 10, 20, and 40 mW/cm(2). After photodynamic therapy (PDT), cell viability and mitochondrial activity were evaluated by the neutral red and MTT assay, respectively. The assessment of PDT-induced apoptosis was investigated by western blot analysis using cleaved poly(ADP-ribose) polymerase-specific antibodies. RESULTS Light at 20 and 40 mW/cm(2) with MB had modest effects at 24 hours on osteoblasts in both assays, whereas sodium hypochlorite completely eliminated cells. Western blot analysis revealed no signs of apoptosis in either cell type. CONCLUSION The data suggest that there is a safe therapeutic window whereby PDT can inactivate endodontic pathogens without affecting host cell viability.

Association between sclerostin and bone density in chronic spinal cord injury.

Spinal cord injury (SCI) results in profound bone loss due to muscle paralysis and the inability to ambulate. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short‐term studies in rodent models have shown increased sclerostin in response to mechanical unloading that is reversed with reloading. These studies suggest that complete spinal cord injury, a condition resulting in mechanical unloading of the paralyzed lower extremities, will be associated with high sclerostin levels. We assessed the relationship between circulating sclerostin and bone density in 39 subjects with chronic SCI and 10 without SCI. We found that greater total limb bone mineral content was significantly associated with greater circulating levels of sclerostin. Sclerostin levels were reduced, not elevated, in subjects with SCI who use a wheelchair compared with those with SCI who walk regularly. Similarly, sclerostin levels were lower in subjects with SCI who use a wheelchair compared with persons without SCI who walk regularly. These findings suggest that circulating sclerostin is a biomarker of osteoporosis severity, not a mediator of ongoing bone loss, in long‐term, chronic paraplegia. This is in contrast to the acute sclerostin‐mediated bone loss shown in animal models of mechanical unloading in which high sclerostin levels suppress bone formation. Because these data indicate important differences in the relationship between mechanical unloading, sclerostin, and bone in chronic SCI compared with short‐term rodent models, it is likely that sclerostin is not a good therapeutic target to treat chronic SCI‐induced osteoporosis.

Spinal Cord Injury-Induced Osteoporosis: Pathogenesis and Emerging Therapies

Spinal cord injury causes rapid, severe osteoporosis with increased fracture risk. Mechanical unloading after paralysis results in increased osteocyte expression of sclerostin, suppressed bone formation, and indirect stimulation of bone resorption. At this time, there are no clinical guidelines to prevent bone loss after SCI, and fractures are common. More research is required to define the pathophysiology and epidemiology of SCI-induced osteoporosis. This review summarizes emerging therapeutics including anti-sclerostin antibodies, mechanical loading of the lower extremity with electrical stimulation, and mechanical stimulation via vibration therapy.

Targeted therapies using electrical and magnetic neural stimulation for the treatment of chronic pain in spinal cord injury

BACKGROUND Chronic neuropathic pain is one of the most common and disabling symptoms in individuals with spinal cord injury (SCI). Over two-thirds of subjects with SCI suffer from chronic pain influencing quality of life, rehabilitation, and recovery. Given the refractoriness of chronic pain to most pharmacological treatments, the majority of individuals with SCI report worsening of this condition over time. Moreover, only 4-6% of patients in this cohort report improvement. Novel treatments targeting mechanisms associated with pain-maladaptive plasticity, such as electromagnetic neural stimulation, may be desirable to improve outcomes. To date, few, small clinical trials have assessed the effects of invasive and noninvasive nervous system stimulation on pain after SCI. OBJECTIVE We aimed to review initial efficacy, safety and potential predictors of response by assessing the effects of neural stimulation techniques to treat SCI pain. SEARCH STRATEGY A literature search was performed using the PubMed database including studies using the following targeted stimulation strategies: transcranial Direct Current Stimulation (tDCS), High Definition tDCS (HD-tDCS), repetitive Transcranial Magnetical Stimulation (rTMS), Cranial Electrotherapy Stimulation (CES), Transcutaneous Electrical Nerve Stimulation (TENS), Spinal Cord Stimulation (SCS) and Motor Cortex Stimulation (MCS), published prior to June of 2012. We included studies from 1998 to 2012. RESULTS Eight clinical trials and one naturalistic observational study (nine studies in total) met the inclusion criteria. Among the clinical trials, three studies assessed the effects of tDCS, two of CES, two of rTMS and one of TENS. The naturalistic study investigated the analgesic effects of SCS. No clinical trials for epidural motor cortex stimulation (MCS) or HD-tDCS were found. Parameters of stimulation and also clinical characteristics varied significantly across studies. Three out of eight studies showed larger effects sizes (0.73, 0.88 and 1.86 respectively) for pain reduction. Classical neuropathic pain symptoms such as dysesthesia (defined as an unpleasant burning sensation in response to touch), allodynia (pain due to a non-painful stimulus), pain in paroxysms, location of SCI in thoracic and lumbar segments and pain in the lower limbs seem to be associated with a positive response to neural stimulation. No significant adverse effects were reported in these studies. CONCLUSIONS Chronic pain in SCI is disabling and resistant to common pharmacologic approaches. Electrical and magnetic neural stimulation techniques have been developed to offer a potential tool in the management of these patients. Although some of these techniques are associated with large standardized mean differences to reduce pain, we found an important variability in these results across studies. There is a clear need for the development of methods to decrease treatment variability and increase response to neural stimulation for pain treatment. We discuss potential methods such as neuroimaging or EEG-guided neural stimulation and the development of better surrogate markers of response such as TMS-indexed cortical plasticity.

Association Between Mobility Mode and C-Reactive Protein Levels in Men With Chronic Spinal Cord Injury

OBJECTIVE To assess clinical determinants of systemic inflammation in persons with chronic spinal cord injury (SCI). DESIGN Cross-sectional survey. SETTING Veterans Affairs medical center. PARTICIPANTS As part of an epidemiologic study assessing SCI-related health conditions, 63 men with chronic SCI provided a blood sample and information regarding locomotive mode and personal habits. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE Plasma high-sensitivity C-reactive protein (CRP). RESULTS The mean +/- standard deviation age was 56+/-14y, and participants were assessed 21+/-13y after injury. Adjusting for heart disease, hypertension, and body mass index (BMI), the mean CRP in 12 motorized wheelchair users (5.11mg/L) was not significantly greater than 23 participants who used a manual wheelchair (2.19mg/L) (P=.085) but was significantly greater than the 17 who walked with an assistive device (1.41mg/L) (P=.005) and the 12 who walked independently (1.63mg/L) (P=.027). CRP was significantly greater in participants with obesity but was not related to age, smoking, or SCI level and severity. CRP was elevated in participants reporting a urinary tract infection (UTI) or pressure ulcer within a year, but adjustment for this did not account for the elevated CRP in motorized wheelchair users. CONCLUSIONS These results suggest that CRP in chronic SCI is independently related to locomotive mode, BMI, and a history of pressure ulcers and UTI. It is suggested that future studies in SCI investigate whether modifying these factors influence systemic inflammation and cardiovascular health.

Circulating sclerostin is elevated in short-term and reduced in long-term SCI

Spinal cord injury (SCI) causes profound bone loss due to muscle paralysis resulting in the inability to walk. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short-term studies in rodent models have demonstrated increased sclerostin in response to mechanical unloading that is reversed with reloading. Although sclerostin inhibition has been proposed as a potential therapy for bone loss, it is not known if sclerostin levels vary with duration of SCI in humans. We analyzed circulating sclerostin in 155 men with varying degrees of SCI who were 1 year or more post-injury. We report that sclerostin levels are greatest in subjects with short-term SCI (≤5 years post-injury) and decrease significantly over the first 5 years post-injury. There was no association between sclerostin and injury duration in subjects with long-term SCI (>5 years post-injury). In subjects with long-term SCI, sclerostin levels were positively associated with lower extremity bone density and bone mineral content. These data suggest that sclerostin levels are initially increased after SCI in response to mechanical unloading. This response is time-limited and as bone loss progresses, circulating sclerostin is lowest in subjects with severe osteoporosis. These findings support a dual role for sclerostin after SCI: a therapeutic target in acute SCI, and a biomarker of osteoporosis severity in chronic SCI.

Sclerostin: a candidate biomarker of SCI-induced osteoporosis

SummaryWe assessed several circulating proteins as candidate biomarkers of bone status in men with chronic spinal cord injury. We report that sclerostin is significantly associated with bone mineral content and bone density at all skeletal sites tested. We found no association between bone and any other tested biomarker.IntroductionSpinal cord injury results in severe osteoporosis. To date, no circulating biomarker of spinal cord injury (SCI)-induced osteoporosis has been identified. We recently reported that circulating sclerostin is associated with bone density in chronic SCI. In this study, we assessed several circulating proteins as candidate biomarkers of bone in men with chronic SCI.MethodsWe assessed the relationship between bone mineral content or bone density and the following circulating bone-related proteins: sclerostin, DKK-1, soluble receptor activator of nuclear factor kappa B ligand, osteoprotegerin, osteocalcin, and c-telopeptide in 39 men with chronic SCI and 10 men with no SCI.ResultsAfter adjusting for age, lower sclerostin levels were significantly associated with lower bone mineral content and bone density at all skeletal sites tested (p = 0.0002−0.03). No other circulating protein was associated with bone mineral content or bone mineral density (p = 0.18−0.99).ConclusionThese findings suggest that circulating sclerostin reflects the severity of bone loss and is a candidate biomarker of osteoporosis severity in chronic SCI.

Dual Energy X-Ray Absorptiometry of the Distal Femur May Be More Reliable than the Proximal Tibia in Spinal Cord Injury

OBJECTIVE To evaluate the precision of dual energy x-ray absorptiometry scanning at 2 skeletal sites at the knee (proximal femur and distal tibia) in people with SCI. DESIGN Cross-sectional. SETTING Veterans Affairs Medical Center. PARTICIPANTS Subjects (N=20) with chronic SCI. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Precision as determined by root mean square coefficient of variation (RMS-CV) and root mean square standard deviation (RMS-SD). RESULTS At the distal femur the root RMS-CV was 3.01% and the RMS-SD was 0.025g/cm2. At the proximal tibia the RMS-CV was 5.91% and the RMS-SD was 0.030g/cm2. CONCLUSIONS Precision at the distal femur is greater than at the proximal tibia and we recommend it as the preferred site for the longitudinal assessment of bone mineral density at the knee in chronic SCI.