Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial.

STUDY DESIGN: Randomized controlled trial with single-blinded primary outcome assessment. OBJECTIVES: To determine the efficacy and safety of autologous incubated macrophage treatment for improving neurological outcome in patients with acute, complete spinal cord injury (SCI). SETTING: Six SCI treatment centers in the United States and Israel. METHODS: 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). RESULTS: 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). CONCLUSION: 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.

A phase 2 autologous cellular therapy trial in patients with acute, complete spinal cord injury: pragmatics, recruitment, and demographics.

STUDY DESIGN: Post hoc analysis from a randomized controlled cellular therapy trial in acute, complete spinal cord injury (SCI). OBJECTIVES: Description and quantitative review of study logistics, referral patterns, current practice patterns and subject demographics. SETTING: Subjects were recruited to one of six international study centers. METHODS: Data are presented from 1816 patients pre-screened, 75 participants screened and 50 randomized. RESULTS: 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. CONCLUSION: 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.

Robotic assisted spinal surgery--from concept to clinical practice.

After several years of product development, animal trials and human cadaver testing, the SpineAssist--a miniature bone-mounted robotic system--has recently entered clinical use. To the best of the authors' knowledge, this is the only available image-based mechanical guidance system that enables pedicle screw insertion with an overall accuracy in the range of 1 mm in both open and minimally invasive procedures. In this paper, we describe the development and clinical trial process that has brought the SpineAssist to its current state, with an emphasis on the various difficulties encountered along the way and the corresponding solutions. All aspects of product development are discussed, including mechanical design, CT-to-fluoroscopy image registration, and surgical techniques. Finally, we describe a series of preclinical trials with human cadavers, as well as clinical use, which verify the system's accuracy and efficacy.

Transiently increased basilar artery flow velocity following severe head injury: a time course transcranial Doppler study.

BACKGROUND AND PURPOSE: Transcranial Doppler ultrasonography has been used to study changes in cerebral hemodynamics following head injury. However, most studies evaluated the anterior circulation and little information exists on transcranial Doppler of the vertebrobasilar arteries after head injury. METHODS: Thirty-two patients with a Glasgow Coma Scale (GCS) score between 4-8 and 11 patients with a GCS score between 9-14 were studied using transcranial Doppler ultrasonography for the first 10 days after injury. Daily variations in the mean blood flow velocities of all major cerebral arteries were recorded. RESULTS: In patients with GCS score between 4-8, the mean blood flow velocities in the middle cerebral and basilar arteries gradually increased beginning on day 2 postinjury and peaked on the 4th-5th day after injury. Those changes were more prominent, and appeared earlier, in the basilar artery. The ratio between the mean flow velocities of the middle cerebral artery and the basilar artery during the first 4 days was significantly lower than in normal controls, indicating a particular increase of flow velocity in the basilar artery. Nineteen out of 32 patients (60%) with severe head injury showed mean blood flow velocity increased over 75 cm/sec in the basilar artery. Mean blood flow velocity >90 cm/sec in the basilar artery, compatible with vasospasm, was observed in 12 of 32 patients (37%). Spasm in the middle cerebral artery was observed in 12 (37%) of patients; 10 of them also had evidence of basilar artery spasm. On the whole, 14 of 32 (43%) patients had evidence of spasm either in the middle cerebral or basilar arteries or in both. In 5 of 11 patients (50%) with moderate head injury (GCS score 9-14), blood flow velocity in the basilar artery greater than 75 cm/sec was observed, but in only two of them it reached the values over 90 cm/sec. Vasospasm in the middle cerebral artery was noted in one patient. CONCLUSIONS: A significant number of patients develop increased flow velocities compatible with vasospasm in the basilar artery after severe head injury. This phenomenon may represent an additional factor that contributes to the poor outcome of severely head-injured patients.

Application of transcranial doppler ultrasonography for the diagnosis of brain death.

OBJECTIVE: To determine the clinical validity of transcranial Doppler ultrasonographic (TCD) signs of total cerebral circulatory arrest for confirmation of brain death and to define the test protocol. DESIGN: Study of a diagnostic test. SETTING: General and neurosurgery intensive care units. PATIENTS: 137 patients in a coma (Glasgow Coma Score 3-5), caused by various pathological conditions, observed from January 1992 to July 1998. 84 patients met the clinical criteria of brain death; 43 patients out of 137 received sedative drug therapy and 31 of these developed brain death. RESULTS: Total cerebral circulatory arrest was demonstrated by TCD in 81 patients. All of them proved to be brain dead according to subsequent clinical examination In 29 of 31 patients who had received sedative drug therapy TCD examination showed total cerebral circulatory arrest 12-48 h before the formal confirmation of the diagnosis. In 1 out of 84 clinically brain dead patients a false negative result was obtained. In 2 of 84 cases, no clear signals from intracranial vessels were obtainable. Fifty-three patients who did not meet the clinical criteria for brain death showed no TCD signs of total cerebral circulatory arrest. The specificity of the TCD test for confirmation of brain death was 100 % and the sensitivity 96.5 %. CONCLUSIONS: In agreement with previously published data, we conclude that TCD ultrasonography is a highly specific and sensitive confirmatory test and should be included as an additional test in the protocol for the assessment of brain death.

Traumatic intratumoral hemorrhage as the presenting symptom of a spinal neurinoma. Case report.

Intratumoral hemorrhage as the presenting symptom of spinal tumors is rare. The authors describe a patient who presented with rapidly progressing paraplegia 24 hours after sustaining a minor traumatic injury of the thoracic spine. Radiological evaluation demonstrated a low-thoracic intradural tumor that was resected and found to be a neurinoma in which severe intra- and peritumoral hemorrhage was revealed. The radiological, surgical, and pathological findings are presented and discussed.

Postsurgical prevertebral abscess of the cervical spine.

OBJECTIVES: Prevertebral abscess formation is an uncommon occurrence following cervical spine fusion surgery. Abscesses may present early or in a delayed fashion and require surgical drainage and long-term antibiotic treatment. The issues of osteomyelitis and the need for plate removal remain unresolved. STUDY DESIGN: A case series of six tetraplegic patients admitted for rehabilitation to the Chaim Sheba Medical Center (Tel Hashomer, Israel) is presented. METHODS: Five patients were trauma patients; one patient underwent repeated procedures and irradiation for tumor of the cervical spine. All patients developed prevertebral abscesses after a mean period of 30 days from their fusion surgery. Computed tomography scan was used in all patients to establish the diagnosis and define the extent of the infective process. All patients underwent one or more drainage procedures. The plate was removed in two patients at 1 and 4 months. RESULTS: Infection completely resolved in four patient and was refractory in one patient with malignant tumor, and a chronic small fistula remained in one case. Staphylococcus aureus was the main infective organism, but mixed infections were the rule. Even for a protracted course of infection, no significant osteomyelitis was encountered. CONCLUSIONS: Abscess formation after instrumentation of the neck may be more common than formerly recognized. Despite the prolonged course of disease and treatment, osteomyelitis is not a major concern. There is no automatic indication for plate removal to control infection, although plating may be safely removed after 10 to 12 weeks if the neck is explored and the cervical spine is stable. A high index of suspicion is warranted, and early recognition and diagnosis, prompt surgical drainage under general anesthesia, and long-term antibiotic treatment are key for eradication of the infective process. Prophylactic antibiotics may be of value. Meticulous antisepsis and surgical technique should be maintained to reduce the incidence of these severe complications.

Risks and cost-effectiveness of sublaminar wiring in posterior fusion of cervical spine trauma.

A report on the use of sublaminar wiring in the fusions of 34 patients with cervical spine injuries is given. No neurologic deficits were incurred in the use of this technique. There were no wire failures nor clinically significant complications. When compared with other forms of instrumentation to achieve similar results, the use of sublaminar wire is the most cost-effective.

Spinal cord involvement as the presenting symptom of acute monocytic leukemia.

Spinal cord involvement in leukemia is rare and has been described only once in association with acute monocytic leukemia. A patient whose presenting symptom of acute monocytic leukemia was the syndrome of cauda equina compression due to an epidural and retroperitoneal leukemic mass is reported. Peripheral blood smears were normal throughout the evolution of the disease. The radiological, surgical, and pathological findings are presented, and the therapeutic, along with the prognostic implications of spinal cord involvement by leukemia are discussed.

Spinal epidural abscess: contemporary trends in etiology, evaluation, and management.

BACKGROUND: Despite advances in neuroimaging and neurosurgical treatment, spinal epidural abscess remains a challenging problem; early diagnosis is often difficult and treatment is delayed. Optimal management is unclear, and morbidity and mortality are significant. To define contemporary trends in etiology and management, and establish diagnostic and therapeutic guidelines, we reviewed our 10-year experience with spinal epidural abscess. METHODS: We examined medical records, laboratory data, radiological (CT and MRI) studies, and operative reports from 75 cases of spinal epidural abscess between 1983 and 1992. Demographic characteristics, frequency, clinical features, pathogens, risk factors, surgical and medical treatment, and outcome were analyzed. RESULTS: We found a significant increase in the frequency of spinal epidural abscess over the 10-year period (p-value = 0.0195). Intravenous drug abuse was present in 28 patients (33%), diabetes mellitus in 22 patients (27%), and prior spinal surgery in 11 patients (17%). Back pain, progressive neurologic deficit, and low grade fever remained the distinguishing diagnostic features. Erythrocyte sedimentation rate was elevated in 48 of 50 patients (95%); peripheral leukocyte count was elevated in 45 patients (60%). MRI was the most effective technique for diagnosing spinal epidural abscess, revealing or suggesting the diagnosis in all 59 patients (100%) studied. Sites of spinal epidural abscess were equally distributed along the spinal axis. Staphylococcus aureus was the predominant organism (67% of patients, with 15% having a methicillin-resistant strain); 8% of patients had Streptococcal species. Most patients had open surgical drainage followed by prolonged antibiotic treatment; 22 patients were managed with antibiotics alone; 50 patients (66%) had a good clinical outcome after treatment. Multiple medical problems, prior spinal surgery, and methicillin-resistant Staphylococci were correlated with a significantly worse outcome. CONCLUSIONS: The frequency of diagnosis of spinal epidural abscess is increasing. To prevent serious morbidity and mortality, early diagnosis is essential. Patients with localized back pain who are at risk for developing such abscesses or who have an increased erythrocyte sedimentation rate and/or neurologic deficit should have an immediate MRI scan with contrast enhancement. Surgical drainage and prolonged antibiotic use are the cornerstones of treatment, although selected patients may be treated conservatively.

Ventriculoperitoneal shunt malfunction due to migration of the abdominal catheter into the scrotum.

A case is reported in which the peritoneal portion of a ventriculoperitoneal shunt migrated into the scrotum via an indirect inguinal hernia and caused cerebrospinal fluid hydrocele with shunt malfunction.

Miniature robotic guidance for spine surgery--introduction of a novel system and analysis of challenges encountered during the clinical development phase at two spine centres.

BACKGROUND: Instrumented spinal fusion surgery is increasingly performed. Breaching of the pedicle occurs in 3-55% of screws; clinically significant screw misplacements occur in 0-7% of all transpedicular screw placements. Several techniques have reduced this incidence but none gained popularity due to cost as well as staff issues. Surgical robots offer distinct added value in accuracy and minimal invasiveness. The aim of this study is to introduce the SpineAssist--a novel spine surgery miniature robot, to discuss the various reasons that had prevented full success with its use, to identify patients related, technical related, and surgeon related issues, and to offer ways to avoid them. METHODS: The SpineAssist miniature robotic system is presented, including a short description of the system, its mode of action and a short summary of the surgical procedure.15 patients had undergone lumbar fusion procedures using the robotic system as part of clinical trials in two Israeli spine centres. A group of 9 procedures was identified within this prospective cohort. This group represents a wide array of technical challenges and human errors which were encountered during the clinical development phase of the SpineAssist. These 9 cases were conducted in two different sites by different surgical teams, over a period of 9 months, with an average interval of 7 weeks between consecutive cases. The cases were analysed for patient, system, surgeon and technical issues causing the difficulty. Conclusions were drawn as to how to avoid these hurdles in the future. RESULTS: In six cases the system operated smoothly, resulting in accurate screws placement according to the pre-operative plan, this was confirmed by a post-operative CT scan. Technical and surgical challenges which are associated with the system early development stage were encountered during 9 procedures. On the technical side, the following phenomena were evident: 1) failure of the software to automatically achieve satisfying CT-to-fluoro image registration and 2) failure of the hospital's peripheral equipment/logistics preventing registration. On the clinical side of things, the following issues were encountered: 1) failure to avoid excessive pressure on the guiding arm caused by surrounding soft tissues, leading to a shift in the entry point and trajectory of the tool guide. 2) a surgeon applying too much force on the tool guide at the tip of the robotic arm, causing deviation from plan. 3) pre-operative plan out of the reach of the robot arm and 4) attachment of the clamp to the spinous process in a suboptimal orientation. CONCLUSIONS: It is expected that following a steep learning curve in the range of 5-10 cases, recommended to take place within 2-3 weeks time, the surgical team will gain sufficient experience in operating the SpineAssist miniature robotic device in order to achieve excellent surgical results. The system may be used for wide range of applications including but not limited to pedicle screws, trans-facet and trans-laminar screws, biopsy needles, vertebroplasty or kyphoplasty tools and more. The preoperative plan has to be logical, intraoperative fluoro images taken with care, gentle surgical technique must be kept - maintaining the integrity of the posterior elements, and avoiding pressure between the robot arms and the soft tissues. During the clinical development phase discussed in this study, both teams used an early version of the system. Based on the results of this study several significant software and hardware improvements have already been implemented. It is our hope that describing and analysing our findings will help in planning and preparing for the clinical utilization of the SpineAssist system in future sites and will shorten their learning curve. By the time this article is published wider clinical experience will have been gathered and we expect to soon follow up with an analysis of clinical utilization of this system in a larger study group.

Delayed intraventricular tension pneumocephalus complicating posterior fossa surgery for cerebellar medulloblastoma.

A child is described in whom intraventricular tension pneumocephalus developed 10 days after removal of a cerebellar medulloblastoma and 1 day after suture removal. The tension pneumocephalus was associated with hydrocephalus and CSF leakage from the suture line. The symptoms of the pneumocephalus were rapidly progressing loss of consciousness and hemiplegia which were promptly reversed upon aspiration of the intracranial air. A large amount of intraventricular air present in the immediate postoperative period was, however, clinically silent. The characteristics of this unusual presentation, its relation to asymptomatic pneumocephalus, hydrocephalus and the preventive and therapeutic measures required to deal with such conditions are discussed.

The sky is a limit: errors in prehospital diagnosis by flight physicians.

The medical records and air evacuation reports of 186 trauma patients were examined to determine the type and characteristics of missed diagnoses. More than 35% of all cases of hypovolemic shock were not identified, nor were two cases of respiratory distress. Although unconsciousness was always identified correctly, almost 7% of all cases with partial unconsciousness were not recorded. Of 443 diagnoses, 337 were correctly recorded by the flight physician, slightly more than 76%. The flight physicians missed 10 critical diagnoses, all of which were feasible, 56 important diagnoses, 42 of which were feasible, and 40 relatively marginal diagnoses, 27 of which were feasible. Injuries to the head, face, and limbs were usually diagnosed correctly, and were missed only in a few cases. Of considerable clinical relevance was the observation that flight physicians missed a significant number of critical and important feasible diagnoses of five types: (1) more than half of all feasible diagnoses in the eyes; (2) a third of feasible diagnoses of cervical spine injuries; and a significant percentage of injuries to the (3) abdomen, (4) chest, and (5) pelvis. Blunt diagnoses were missed more often than penetrating injuries. Feasible diagnoses were missed in two of the four cases of paralysis, approximately one third of all crush injuries, and one quarter of all fractures. This study illuminates preventable errors of physicians during air evacuation and indicates particular types of serious, feasible diagnoses that flight physicians are prone to miss. Medicine in the sky may pose limits to our diagnostic abilities but the limits could be pushed further.

Daily but not pulse calcitriol therapy improves growth in experimental uremia.

Calcitriol (C) pulse therapy is widely used to suppress secondary renal hyperparathyroidism. However, high C serum concentrations may have an antiproliferative effect on growth cartilage cells and may suppress growth rate. The study was designed to evaluate whether daily C and pulse C therapy have differential effects on growth in uremic rats. Female Sprague-Dawley rats (150 g, n=5-10 per group) underwent two-stage subtotal nephrectomy (U). The duration of uremia was 14-18 days. The animals were fed a standard diet or a diet with a low-calcium content. Rats on a low-calcium diet were randomized for recombinant human growth hormone (rhGH) treatment (2.5 IU/kg per day) or solvent. C was injected subcutaneous twice daily (15 pmol/day) or intraperitoneal (105 pmol) twice per week. Weight gain and length gain was determined weekly. After sacrifice, total body calcium was determined by total body neutron activation analysis. Bone micromorphometric analysis of third lumbar vertebra and double staining with tetracycline for determination of mineralization rate were performed. Whereas daily C significantly increased total body length gain within 2 weeks, pulse C did not (U solvent 4.0+/-0.3 cm, UC bolus 4.3+/-0.4 cm, UC daily 5.3+/-0.3 cm, P<0.05). A low-calcium diet reduced and rhGH increased basal length gain and weight gain; regardless of these preconditions, daily but not bolus C increased length gain significantly. C both daily and in bolus form reduced bone osteoid content, but daily C improved mineral apposition rate more than C bolus. Total body calcium corrected for body weight decreased with a low-calcium diet, was lowest with concomitant rhGH treatment, and was not improved by C. In conclusion, daily but not bolus C treatment improves growth in uremic rats.

Substance abuse, traumatic brain injury and neuropsychological outcome.

The neuropsychological performance of 119 patients with severe closed traumatic brain injury (TBI) who had received toxicology screens at the time of trauma centre admission was examined. Three groups were created: normal screen, positive alcohol screen, or positive abused drugs screen (with or without the presence of alcohol). The admitting Glasgow Coma Scale (GCS) score was significantly lower in the positive alcohol screen group than the normal screen group, while the three groups did not differ in length of post-traumatic amnesia (PTA) or years of education. Neuropsychological assessment was conducted during inpatient rehabilitation, following resolution of PTA. Normal screen patients obtained significantly better scores than the abused-drugs patients on the Full Scale IQ (FIQ) and Verbal IQ (VIQ) indices of the Wechsler Adult Intelligence Scale-Revised and the Verbal Memory, General Memory, Attention-Concentration, and Delayed Recall indices of the Wechsler Memory Scale-Revised. Normal screen patients also scored significantly higher than positive alcohol screen patients on FIQ and VIQ indices and all five indices from the Wechsler Memory Scale-Revised. These data suggest the existence of an additive effect of substance abuse on neuropsychological outcome in TBI. Findings have potential implications for both acute management and rehabilitation of TBI.

Prehospital stabilization of the cervical spine for penetrating injuries of the neck - is it necessary?

The purpose of this study was to assess the specific indications, benefits and risks associated with cervical spine stabilization during pre-hospital care of penetrating neck injuries. We retrospectively reviewed hospital charts and autopsy reports of 44 military casualties in Israel with a penetrating neck injury during a period of 4.5 years. A review of the literature was also carried out. In eight of 36 hospitalized casualties (22%) a life-threatening sign was diagnosed in the exposed neck - large or expanding haematoma, or subcutaneous emphysema. Surgical stabilization of the cervical spine was not performed for any of the casualties. It was concluded that life threatening complications due to penetrating neck injury are common and may be overlooked if the neck is covered by a stabilization device. It is extremely rare for a penetrating injury to result in an unstable cervical spine. New management guidelines concerning pre-hospital stabilization are suggested.