Randomized controlled trial with single-blinded primary outcome assessment.
To determine the efficacy and safety of autologous incubated macrophage treatment for improving neurological outcome in ...patients with acute, complete spinal cord injury (SCI).
Six SCI treatment centers in the United States and Israel.
Participants with traumatic complete SCI between C5 motor and T11 neurological levels who could receive macrophage therapy within 14 days of injury were randomly assigned in a 2:1 ratio to the treatment (autologous incubated macrophages) or control (standard of care) groups. Treatment group participants underwent macrophage injection into the caudal boundary of the SCI. The primary outcome measure was American Spinal Injury Association (ASIA) Impairment Scale (AIS) A-B or better at ≥6 months. Safety was assessed by analysis of adverse events (AEs).
Of 43 participants (26 treatment, 17 control) having sufficient data for efficacy analysis, AIS A to B or better conversion was experienced by 7 treatment and 10 control participants; AIS A to C conversion was experienced by 2 treatment and 2 control participants. The primary outcome analysis for subjects with at least 6 months follow-up showed a trend favoring the control group that did not achieve statistical significance (P=0.053). The mean number of AEs reported per participant was not significantly different between the groups (P=0.942).
The analysis failed to show a significant difference in primary outcome between the two groups. The study results do not support treatment of acute complete SCI with autologous incubated macrophage therapy as specified in this protocol.
The literature on abdominal and general surgery-related complications following anterior lumbar interbody fusion (ALIF) is scant. In this retrospective review of 60 patients in whom ALIF was ...performed at their institutions between 1996 and 1998, the authors detail the associated complications and their correlation with perioperative factors. The causes, strategies for their avoidance, and the clinical course of these complications are also discussed.
The study group was composed of 31 men and 29 women whose mean age was 42 years (range 29-71 years). The preoperative diagnosis was discogenic back pain in 33 patients (55%); failed back syndrome in 11 (18.3%); pseudarthrosis in five (8.3%); postlaminectomy syndrome in four (6.6%); spondylolisthesis in three (5%); burst fracture in two (3.3%); and malignancy in two (3.3%). A retroperitoneal approach to the spine was used in 57 of the 60 patients. One interspace was exposed in 28 patients (46.6%), two in 28 (46.6%), and three in four (6.6%). Discectomy and interbody fusion in which the authors placed titanium cages or bone dowels was performed in 56 patients and corpectomy with instrumentation in four. Seven (11.6%) of 60 patients had undergone previous abdominal surgery and 29 (48.3%) had undergone previous spinal surgery. The follow-up period averaged 12+/-4 months (mean+/-standard deviation). Twenty-four general surgery-related complications occurred in 23 patients (38.3%), including sympathetic dysfunction in six; vascular injury in four; somatic neural injury in three; sexual dysfunction in three; prolonged ileus in three; wound incompetence in two; and deep venous thrombosis, acute pancreatitis, and bowel injury in one patient each. There were no deaths. The incidence of complications was not associated with underlying diagnosis (p>0.1), age (p>0.5), previous abdominal or spinal surgery (p>0.1), or the number of levels exposed (p>0.1).
This report provides a detailed analysis of the general surgery-related complications following ALIF. Although many of these complications have been recognized in the literature, the significance of sympathetic dysfunction appears to have been underestimated. The high incidence of complications in this series likely reflects the strict criteria. Many of these complications were minor and resolved over time without long-term sequelae.
The mechanisms underlying neuronal pathology and death in the spinal cord (SC) during inflammation remain elusive. We previously showed the important role of plasma membrane calcium ATPases (PMCAs) ...in the survival of SC neurons, in vitro. We also postulated that a decrease in PMCA2 expression could cause neuronal death during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The current studies were undertaken to define the specific contribution of PMCA2 to degeneration of SC neurons, the effectors downstream to PMCA2 mediating neuronal death and the triggers that reduce PMCA2 expression. We report that knockdown of PMCA2 in SC neurons decreases collapsin response mediator protein 1 (CRMP1) levels. This is followed by cell death. Silencing of CRMP1 expression also leads to neuronal loss. Kainic acid reduces both PMCA2 and CRMP1 levels and induces neuronal death. Administration of an alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptor antagonist, at onset or peak of EAE, restores the decreased PMCA2 and CRMP1 levels to control values and ameliorates clinical deficits. Thus, our data link the reduction in PMCA2 expression with perturbations in the expression of CRMP1 and the ensuing death of SC neurons. This represents an additional mechanism underlying AMPA/kainate receptor-mediated excitotoxicity with relevance to neurodegeneration in EAE.
We present a case of delayed progression of adhesive arachnoiditis to arachnoiditis ossificans (AO) in a patient being treated with a high-dose polypharmaceutical intrathecal regimen.
The patient is ...a 39-year-old Caucasian male who was implanted with an intrathecal pump in 2006 to control severe low back pain and administered intrathecal pain medication for a period of 10 years. In 2016, he developed new-onset radicular pain and worsened sensation in his lower extremities. Computed tomography scan of the lumbar spine at that time demonstrated profound calcification of the arachnoid consistent with a diagnosis of AO. It was presumed that prolonged high-dose intrathecal medication precipitated this condition, and his intrathecal medications were titrated down with removal of the pump.
It is unlikely that his condition occurred as a result of prior surgery, with the more likely cause being hyperplasia of the spinal arachnoid, leading to scarring and calcification, due to the high-dose intrathecal regimen. This case highlights the delayed progression from stable arachnoiditis to AO concurring with a regimen of high-dose intrathecal medications. Clinicians should closely monitor patients undergoing intrathecal drug administration, particularly at elevated doses, for indications of damage to the spinal arachnoid mater.
•We present the late progression of adhesive arachnoiditis to arachnoiditis ossificans.•High-dose intrathecal medications may have inflammatory effects within the thecal sac.•Imaging and screening in intrathecal pump patients may prevent serious morbidity.
Post hoc analysis from a randomized controlled cellular therapy trial in acute, complete spinal cord injury (SCI).
Description and quantitative review of study logistics, referral patterns, current ...practice patterns and subject demographics.
Subjects were recruited to one of six international study centers.
Data are presented from 1816 patients pre-screened, 75 participants screened and 50 randomized.
Of the 1816 patients pre-screened, 53.7% did not meet initial study criteria, primarily due to an injury outside the time window (14 days) or failure to meet neurological criteria (complete SCI between C5 motor/C4 sensory and T11). MRIs were obtained on 339 patients; 51.0% were ineligible based on imaging criteria. Of the 75 participants enrolled, 25 failed screening (SF), leaving 50 randomized. The primary reason for SF was based on the neurological exam (51.9%), followed by failure to meet MRI criteria (22.2%). Of the 50 randomized subjects, there were no significant differences in demographics in the active versus control arms. In those participants for whom data was available, 93.8% (45 of 48) of randomized participants received steroids before study entry, whereas 94.0% (47 of 50) had spine surgery before study enrollment.
The 'funnel effect' (large numbers of potentially eligible participants with a small number enrolled) impacts all trials, but was particularly challenging in this trial due to eligibility criteria and logistics. Data collected may provide information on current practice patterns and the issues encountered and addressed may facilitate design of future trials.
Abstract Toll-like receptors (TLRs) are mediators of the innate immune response to exogenous pathogens. They have also been implicated in sterile inflammation associated with systemic injury and ...non-infectious diseases via binding of endogenous ligands, possibly released by damaged cells. Emerging evidence indicates that some TLRs play a role in nervous system injury and especially in injury-elicited pain and sterile inflammation. However, no information is available about the contribution of TLR9, a member of the TLR family, to traumatic spinal cord injury (SCI). Moreover, the therapeutic potential of TLR9 ligands in the functional outcomes of SCI, including pain, has not been explored. We report, for the first time, that the intrathecal administration of a TLR9 antagonist, cytidine–phosphate–guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe contusion SCI, diminishes injury-induced heat hypersensitivity. Investigations on the potential mechanisms underlying the reduction in pain sensitivity indicated an attenuation of the inflammatory reaction manifested by a decrease in the number of CD11b-, CD45- and CD3-immunoreactive cells and a reduction in tumor necrosis factor-α (TNF-α) expression at the epicenter. Conversely, intrathecal delivery of a TLR9 agonist, CpG ODN 1826, increased inflammatory cell numbers and TNF-α expression in the epicenter. The CpG ODN 2088 treatment did not appear to induce systemic adverse effects as shown by spleen histology and serum cytokine levels. We propose that CpG ODN 2088 dampens injury-induced heat hypersensitivity by suppressing the inflammatory response and TNF-α expression. This investigation defines a previously unreported therapeutic role for CpG ODN 2088 in SCI-induced pain.
This study objectively defines the incidence of donor site pain in an independent outcome analysis. In addition, this study identifies the significant discrepancies that are observed when independent ...outcome assessment results are compared with the incidences determined by review of the operating surgeon's documented findings.
A review of patients who underwent iliac bone graft harvesting by a single neurosurgeon was conducted. The presence of iliac crest donor site pain, at a time remote from surgery, as determined by specific questioning and recorded in the neurosurgeon's written evaluation was compared with independent assessment findings obtained in structured telephone questionnaire interviews. During a 4-year period, 105 patients met the inclusion criteria. Both the operating surgeon' and independent interviewer's follow-up evaluations were completed for all study patients. Pain was classified into three categories, i.e., no pain, acceptable pain, or unacceptable pain. Patients were also asked to assess the severity of their donor site pain by using a visual analog scale. Statistical analyses comparing the incidences of iliac crest donor site pain in the operating surgeon's evaluations and the independent assessments were performed.
When evaluated at a time remote from surgery, the true incidence of iliac crest donor site pain after graft harvest procedures (34%) was significantly greater than previously appreciated by the neurosurgeon (8%). Although occasional or mild pain was observed for 31% of patients, only 3% of all patients experienced unacceptable pain.
Independent outcome assessment values should be provided to patients in preoperative discussions regarding donor site morbidity. Objective outcome analysis, based on independent observations, is crucial for the most accurate interpretation of perceptions of iliac crest donor site pain.
Ventriculoperitoneal (VP) shunting is a common neurosurgical procedure in the pediatric population. Atlantoaxial rotatory fixation (AARF) is not uncommon in this same group. We present the first ...reported case of AARF following a VP shunt procedure. A 10-year-old boy, with hydrocephalus and a left temporal arachnoid cyst since birth, underwent a revision of his VP and cystoperitoneal shunts. A second operation was performed 2 days later to optimize catheter placement. Postoperative neck pain was attributed to tunneling of the subcutaneous catheter. 2 months after surgery, the child had minimal neck discomfort but maintained his head in a "cock-robin" position. Plain radiographs and computed tomographic (CT) images confirmed AARF. The child was admitted and placed in halo traction. After 3 days of traction, analgesics, sedation, and muscle relaxants, anatomic re-alignment of the C1-C2 vertebral complex was confirmed on CT scan. Following 3 months of immobilization in a halo-vest apparatus, the halo was removed. At 8-year follow-up, the clinical examination is normal and repeat imaging studies remain normal. Due to surgical positioning, and postoperative signs attributed to normal postoperative pain, an AARF was not initially recognized. This case represents the first time that AARF has been reported following a VP shunt procedure.
The authors evaluated the accuracy of placement of thoracic pedicle screws by performing postoperative computerized tomography (CT) scanning. A grading system is presented by which screw placement is ...classified in relation to neurological, bone, and intrathoracic landmarks.
One hundred eighty-five thoracic pedicle screws were implanted in 27 patients with the assistance of computer image guidance or fluoroscopy. Postoperative CT scanning was conducted to determine a grade for each screw: Grade I, entirely contained within pedicle; Grade II, violates lateral pedicle but screw tip entirely contained within the vertebral body (VB); Grade III, tip penetrates anterior or lateral VB; Grade IV, breaches medial or inferior pedicle; and Grade V, violates pedicle or VB and endangers spinal cord, nerve root, or great vessels and requires immediate revision. Based on anatomical morphometry, the spine was subdivided into upper (T1-2), middle (T3-6), and lower (T7-12) regions. Statistical analyses were performed to compare regions. The mean follow-up period was 37.6 months. The following postoperative CT scanning-documented grades were determined: Grade I, 160 screws (86.5%); Grade II, 15 (8.1%); Grade III, six (3.2%); Grade IV, three (1.6%); and Grade V, one (0.5%). Among cases involving screw misplacements, Grade II placement was most common, and this occurred most frequently in the middle thoracic region.
The authors' grading system has advantages over those previously described; however, further study to determine its reliability, reproducibility, and predictive value of clinical sequelae is warranted. Postoperative CT scanning should be considered the gold standard for evaluating thoracic pedicle screw placement.
The second National Acute Spinal Cord Injury Study demonstrated that there were neurological benefits from "spinal cord injury" doses of methylprednisolone for blunt spinal cord injuries. In this ...review, we examined the relative risk/benefit ratio of intravenously treating spinal gunshot wound victims with steroids.
A retrospective review was conducted of 254 consecutive patients who were treated between 1979 and 1994 for gunshot wounds to the spine (C1-L1) and a spinal cord injury. Three subgroups were established based on the administration of the steroids methylprednisolone (National Acute Spinal Cord Injury Study 2 protocol), dexamethasone (initial dose, 10-100 mg), and no steroids. All patients who received steroids were initially treated at another hospital and then transferred. No patients received steroids at our institution. The data analyzed included neurological outcome and infectious and noninfectious complications.
No statistically significant neurological benefits were demonstrable from the use of steroids (methylprednisolone, dexamethasone). Infectious complications were increased in both groups receiving steroids (not statistically significant). Gastrointestinal complications were significantly increased in the dexamethasone group (P = 0.021), and pancreatitis was significantly increased in the methylprednisolone group (P = 0.040). The mean duration of follow-up was 56.3 months.
In this retrospective, nonrandomized review, no neurological benefits were detectable from intravenously administered steroids after a gunshot wound to the spine. Both infectious and noninfectious complication rates were higher in the groups receiving steroids. Patients who sustain a spinal cord injury secondary to a gunshot wound to the spine should not be treated with steroids until the efficacy of such treatment is proven in a controlled study.
PDF
