Dose profiles and x-ray energy optimization for microbeam radiation therapy by high-dose, high resolution dosimetry using Sm-doped fluoroaluminate glass plates and Monte Carlo transport simulation.

Microbeam radiation therapy (MRT) utilizes highly collimated synchrotron generated x-rays to create narrow planes of high dose radiation for the treatment of tumors. Individual microbeams have a typical width of 30-50 µm and are separated by a distance of 200-500 µm. The dose delivered at the center of the beam is lethal to cells in the microbeam path, on the order of hundreds of Grays (Gy). The tissue between each microbeam is spared and helps aid in the repair of adjacent damaged tissue. Radiation interactions within the peak of the microbeam, such as the photoelectric effect and incoherent (atomic Compton) scattering, cause some dose to be delivered to the valley areas adjacent to the microbeams. As the incident x-ray energy is modified, radiation interactions within a material change and affect the probability of interactions, as well as the directionality and energy of ionizing particles (electrons) that deposit energy in the valley regions surrounding the microbeam peaks. It is crucial that the valley dose between microbeams be minimal to maintain the effectiveness of MRT. Using a monochromatic x-ray source with x-ray energies ranging from 30 to 150 keV, a detailed investigation into the effect of incident x-ray energy on the dose profiles of microbeams was performed using samarium doped fluoroaluminate (FA) glass as the medium. All dosimetric measurements were carried out using a purpose-built fluorescence confocal microscope dosimetric technique that used Sm-doped FA glass plates as the irradiated medium. Dose profiles are measured over a very a wide range of x-ray energies at micrometer resolution and dose distribution in the microbeam are mapped. The measured microbeam profiles at different energies are compared with the MCNP6 radiation transport code, a general transport code which can calculate the energy deposition of electrons as they pass through a given material. The experimentally measured distributions can be used to validate the results for electron energy deposition in fluoroaluminate glass. Code validation is necessary for using transport codes in future treatment planning for MRT and other radiation therapies. It is shown that simulated and measured micro beam-profiles are in good agreement, and micrometer level changes can be observed using this high-resolution dosimetry technique. Full width at 10% of the maximum peak (FW@10%) was used to quantify the microbeam width. Experimental measurements on FA glasses and simulations on the dependence of the FW@10% at various energies are in good agreement. Simulations on energy deposited in water indicate that FW@10% reaches a local minimum around energies 140 keV. In addition, variable slit width experiments were carried out at an incident x-ray energy of 100 keV in order to determine the effect of the narrowing slit width on the delivered peak dose. The microbeam width affects the peak dose, which decreases with the width of the microbeam. Experiments suggest that a typical microbeam width for MRT is likely to be between 20-50 µm based on this work.

Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury.

STUDY DESIGN: Retrospective, longitudinal analysis of motor recovery data from individuals with cervical (C4-C7) sensorimotor complete spinal cord injury (SCI) according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). OBJECTIVES: To analyze the extent and patterns of spontaneous motor recovery over the first year after traumatic cervical sensorimotor complete SCI. METHODS: Datasets from the European multicenter study about SCI (EMSCI) and the Sygen randomized clinical trial were examined for conversion of American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, change in upper extremity motor score (UEMS) or motor level, as well as relationships between these measures. RESULTS: There were no overall differences between the EMSCI and Sygen datasets in motor recovery patterns. After 1 year, up to 70% of subjects spontaneously recovered at least one motor level, but only 30% recovered two or more motor levels, with lesser values at intermediate time points. AIS grade conversion did not significantly influence motor level changes. At 1 year, the average spontaneous improvement in bilateral UEMS was 10-11 motor points. There was only moderate relationship between a change in UEMS and a change in cervical motor level (r(2)=0.30, P<0.05). Regardless of initial cervical motor level, most individuals recover a similar number of motor points or motor levels. CONCLUSION: Careful tracking of cervical motor recovery outcomes may provide the necessary sensitivity and accuracy to reliably detect a subtle, but meaningful treatment effect after sensorimotor complete cervical SCI. The distribution of the UEMS change may be more important functionally than the total UEMS recovered.

The influence of cancellous bone density on load sharing in human lumbar spine: a comparison between an intact and a surgically altered motion segment.

The aim of the current study is twofold: first, to compare load sharing in compression between an intact and a surgically repaired lumbar spine motion segment L3/4 using a biomechanically validated finite element approach; second, to analyse the influence of bone mineral density on load sharing. Six cadaveric human lumbar spine segments (three segments L2/3 and three segments L4/5) were taken from fresh human cadavers. The intact segments were tested under axial compression of 600 N, first without preload and then following instrumented stabilisation. These results were compared to a finite element model simulating the effect of identical force on the intact segments and the segments with constructs. The predictions of both the intact and the surgically altered finite element model were always within one standard deviation of the mean stiffness as analysed by the biomechanical study. Thus, the finite element model was used to analyse load sharing under compression in an intact and a surgically repaired human lumbar spine segment model, using a variety of E moduli for cancellous bone of the vertebral bodies. In both the intact and the surgically altered model, 89% of the applied load passed through the vertebral bodies and the disc if an E modulus of 25 MPa was used for cancellous bone density. Using 10 MPa--representing soft, osteoporotic bone--this percentage decreased, but it increased using 100 MPa in both the intact and the altered segment. Thus, it is concluded that reconstruction of both the disc and the posterior elements with the implants used in the study recreates the ability of the spine to act as a load-sharing construction in compression. The similarity in load sharing between normal and instrumented spines appears to depend on assumed bone density, and it may also depend on applied load and loading history.

Recruitment and early treatment in a multicenter study of acute spinal cord injury.

STUDY DESIGN: Post hoc secondary analysis of data from 1992 to 1998 in the trial of Sygen in Acute Spinal Cord Injury. OBJECTIVES: Quasi-epidemiologic understanding of injury and treatment patterns and of recruitment in an SCI trial. No drug efficacy results. SUMMARY OF BACKGROUND DATA: The most recent large epidemiologic study was the National SCI Database by Stover and colleagues around 1980. METHODS: Emphasis on descriptive, rather than inferential, statistics: consistent with secondary analysis. RESULTS: The study involved 760 patients at 28 centers in North America. Cervical injuries were more common than thoracic, and complete injuries were more common than incomplete injuries. Recruitment in the complete cervical stratum was 332, but the incomplete thoracic strata had only 31 patients combined. Vital signs at arrival and on randomization show fair stability. Clock times show more injuries on weekends and nights but suggest immediate attention was given. Elapsed times to treatment (especially EMT and Medevac arrival) are short. The rate of direct admission to tertiary centers, traction weight, and time to surgery vary among centers. Inpatient rehabilitation appeared driven by insurance in addition to severity. CONCLUSIONS: The imbalances in favor of cervical and of complete injuries would make it hard for studies to attain results for SCI in general. The vital signs and time patterns suggest local protocol-driven stabilization to prevent secondary physiologic injury early after SCI. Some features of care vary among centers, but the sparseness of prospective data in specific injury and treatment categories suggests that treatment guidelines have limited empirical support and should be made cautiously.

Measurements and recovery patterns in a multicenter study of acute spinal cord injury.

STUDY DESIGN: Post hoc, secondary analysis of data from 1992 to 1998 in the trial of Sygen in acute spinal cord injury. OBJECTIVES: Quasi-epidemiologic understanding of measurement tools and of recovery patterns. No drug efficacy results. SUMMARY OF BACKGROUND DATA: Many authors have studied individual scales for measuring the severity of spinal cord injury. METHODS: Emphasis on descriptive, rather than inferential, statistics: consistent with secondary analysis. RESULTS: Of the 760 patients, 43 died within 365 days. The rate was higher for complete injuries (7.1% vs. 3.2%, P = 0.017). Marked recovery at 26 weeks was more frequent in those with better baseline American Spinal Injury Association (ASIA) Impairment Scale (AIS) scores, but was not different for methylprednisolone within versus after 3 hours. Light touch scores improved at each visit, more so in those with higher scores at baseline. Bladder control similarly improved. Motor and sensory scores exhibited departures from assumptions underlying normal-theory statistical techniques: t test and analysis of variance. Furthermore, they were mixtures of differing distributions from different study strata, so that overall conclusions depend on the mixture of patients seen. CONCLUSIONS: The prognosis of these patients with spinal cord injury seen at 28 centers in North America during the mid-1990s appears better than was often assumed earlier. The general patterns are similar across different measurement scales, although there are intriguing differences. The patterns in different strata are different in specifics, and complete injuries do less well. Pooling data from different strata may result in probability distributions that depart from normal-theory assumptions and give misleading results depending on recruitment patterns.

The Sygen multicenter acute spinal cord injury study.

STUDY DESIGN: Randomized, double-blind, sequential, multicenter clinical trial of two doses of Sygen versus placebo. OBJECTIVES: To determine efficacy and safety of Sygen in acute spinal cord injury. SUMMARY OF BACKGROUND DATA: An earlier, single-center trial in 28 patients showed an improvement (50.0% vs. 7.1%, P = 0.034) in marked recovery with Sygen. METHODS: Standard clinical trial techniques. RESULTS: The prospectively planned analysis at the prespecified endpoint time for all patients was negative. There was a significant effect in all patients in the primary outcome variable (the percentage of marked recovery) at week 8, the end of the dosing period. There was a significant effect in all patients in the time at which marked recovery is first achieved. Restricted to severity Group B, which has small sample size, the primary efficacy analysis showed a trend but did not reach significance. There is a large, consistent and, at some time points, significant effect in the primary outcome variable in the nonoperated patients through week 26. The American Spinal Injury Association motor, light touch, and pinprick scores showed a consistent trend in favor of Sygen, as also did bowel function, bladder function, sacral sensation, and anal contraction. The less severely injured patients appeared to have a greater beneficial drug effect. Evidence against an effect of Sygen was minimal and scattered. CONCLUSIONS: Although not proven in the primary efficacy analysis of this trial, Sygen appears to be beneficial in patients with severe spinal cord injury.

Motion of threaded cages in posterior lumbar interbody fusion.

A high rate of pseudarthrosis and a high overall rate of implant migration requiring surgical revision has been reported following posterior lumbar interbody fusion using BAK threaded cages. The high rate of both pseudarthrosis and implant migration may be due to poor fixation of the implant. The purpose of this study was to analyse the motion of threaded cages in posterior lumbar interbody fusion. Six cadaveric human lumbar spine segments (three L2/3 and three L4/5 segments) were prepared for biomechanical testing. The segments were tested, without preload, under forces of axial compression (600 N), torsion (25 Nm) and shearing force (250 N). The tests were performed first with the segments in an intact state, and subsequently following instrumented stabilisation with two BAK cages via a posterior approach. These results were compared with those of a finite element model simulating the effects of identical forces on the segments with constructs. As the results were comparable, the finite element model was used for analysing the motion of BAK cages within the disc space. Motion of the implants was not seen in compression. In torsion, a rolling motion was noted, with a range of motion of 10.6 degrees around the central axis of the implant when left/right torsion (25 Nm) was applied. The way the implants move within the segment may be due to their special shape: the thread of the implants can not prevent the BAK cages rolling within the disc space.

Anterior cervical plating for the treatment of neoplasms in the cervical vertebrae.

OBJECT: To assess clinical outcome and survival in patients with cervical vertebral spinal neoplasms after they have undergone anterior decompression and cervical plate stabilization (ACPS) by using either autologous bone graft or polymethylmethacrylate (PMMA) as the anterior load-bearing support structure. METHODS: This was a retrospective case study composed of 30 patients harboring cervical spinal vertebral neoplasms who underwent anterior cervical decompression and (ACPS) within a 7-year period. Postoperative immobilization included treatment in a halo brace in two cases and in a hard cervical collar for the remaining patients. Postoperatively most patients underwent radio- and/or chemotherapy. All patients except one benefited from a significantly improved quality of life with decreased pain and/or improved neurological status. The mean Kaplan-Meier survivoral estimate was 35.8 months (range 8 days-11.3 years, with 10 patients alive at most recent follow-up contact). Patients achieved long-term or lifelong mechanical stability in the cervical spine, and only one patient required a repeated posterior stabilization procedure. No hardware-related complications occurred. One patient died 8 days postoperatively of pneumonia. A nonsignificant difference in survival (p = 0.2164) was observed between patients harboring metastatic neoplasms (26.8 months) and those harboring lymphomatous and multiple myeloma neoplasms (54 months). CONCLUSIONS: Favorable clinical outcome of both neurological symptoms and pain can be achieved using ACPS after surgery for neoplasms in the cervical vertebrae. Furthermore, long-term or lifelong cervical spine mechanical stability with bone fusion is achieved using this technique even when radiation therapy is delivered to the site of the bone graft.

Prevention of peridural fibrosis: current methodologies.

Lumbar discectomy is a common surgical procedure with a physician-reported 'good' outcome of 85%-95% for successfully relieving pre-operative sciatic pain. Up to 40% of patients post-operatively, however, have persistent limitations in activity. Peridural fibrosis is a natural consequence of the normal post-operative healing that can cause symptoms by tethering the nerve roots. ADCON-L was developed to decrease the peridural fibrosis reaction. Cell culture analysis demonstrated that ADCON-L blocked the ingrowth of fibroblasts, and animal laminectomy models demonstrated a major decrease in the amount of peridural fibrosis. ADCON-L has been studied in two prospective randomized multicenter trials, one in Europe with 298 patients and the other in the United States with 223 patients at the interim analysis. Noting the differences in the quantity of peridural scar on post-operative MRI and in clinical outcome between the two groups assessed the effect of the addition of ADCON-L to the surgical procedure. Both studies had statistically significant positive beneficial effects in both the radiologic index and the clinical outcome scores. These two studies provide the evidence for the clinical use of ADCON-L to improve outcomes after lumbar discectomy.

Clinical trials of pharmacotherapy for spinal cord injury.

Spinal cord injury remains with limited natural recovery and only a few general ineffective treatment options. Recent publications have reported enhanced neurologic recovery with the use of methylprednisolone and GM-1 ganglioside. The results of the Maryland GM-1 Ganglioside Study reported a significant drug effect with respect to the fraction of patients that had a change of two or more Frankel grades from entrance into the study to 1-year follow-up. This study formed the basis for the currently ongoing larger placebo-controlled multicentered study using Sygen GM-1 following acute spinal cord injury. This study has entered 797 patients and is expected to present results in early 1998.

Reoperation in patients after anterior cervical plate stabilization in degenerative disease.

STUDY DESIGN: Consecutive case retrospective chart review. OBJECTIVES: First, to assess whether the number of' patients requiring a second cervical surgical intervention was changed as a result of using anterior cervical plate stabilization, and second, to determine the additional risks and/or benefits associated with the hardware implantation. SUMMARY OF BACKGROUND DATA: The optimal technique of performing stabilization, arthrodesis, and alignment of a cervical segment after discectomy with neural decompression in degenerative disease has yet to be determined. METHODS: The charts of 402 patients who had undergone an anterior cervical discectomy and arthrodesis for degenerative disease performed both with and without anterior cervical plate stabilization were reviewed, and reoperation data were compiled. The average follow-up time was 3.8 years (range, 1.5-9.4 years). RESULTS: Of 365 patients with 1- or 2-level cervical arthrodesis, 22 required a second surgical intervention (20 bone alone, 2 with anterior cervical plate stabilization). The Log-Rank test, which uses all patients and their total follow-up periods, was statistically significant favoring anterior cervical plate stabilization at one and two levels (P = 0.015). CONCLUSIONS: The addition of anterior cervical plate stabilization in one- and two-level cervical degenerative disease supplements the internal stabilization initially provided by the bone graft, and yields a lower reoperation rate.

Anterior cervical plate stabilization in one- and two-level degenerative disease: overtreatment or benefit?

This consecutive case retrospective chart review of 356 patients compares the reoperation rate of one- and two-level anterior cervical discectomies for degenerative disease with and without anterior cervical plate stabilization (ACPS). A total of 210 patients underwent surgery without ACPS (bone alone) and 146 patients underwent surgery with the addition of ACPS. Follow-up ranged from 1 to 9 years. A total of 22 patients with one- or two-level cervical arthrodesis required a second surgical intervention (19 bone alone, 3 with ACPS). Reoperations were performed in the bone-alone group for pseudarthrosis in 12 cases and for progression of degenerative disease in 7 cases. The reoperations in the ACPS group were performed for pseudarthrosis in one case and settling of the graft with screw fracture before fusion in two cases. The log-rank test, which uses all patients and their total follow-up periods, was statistically significant in favoring ACPS (p = 0.05). Furthermore, the reoperation rate after 1 year was also significantly lower when ACPS was utilized compared with bone alone (p = 0.0308, Fisher's exact test, two tailed). These data provide evidence that the addition of ACPS in one- and two-level cervical degenerative disease does not constitute overtreatment but rather supplements the internal stabilization initially provided by the bone graft and yields a lower reoperation rate.

Intraventricular rupture of a purulent brain abscess: case report.

The mortality of patients with brain abscesses has decreased significantly from 38% in the 1950s to 25% in the 1980s (P = 0.003, Fisher's exact test by decade of report; asymptotic P values based on chi 2 distribution with 3 degrees of freedom, 28 series, 2825 total patients). This decrease in mortality has been attributed to improved diagnostic imaging, the evolution of neurosurgical techniques and understanding of intracranial pressure pathophysiology, greater critical care understanding, and newer antibiotics. However, the mortality associated with the intraventricular rupture of brain abscesses (IVROBA) remained consistently high (at or above 80% once IVROBA was identified) throughout these decades. Although 129 cases (84.5% mortality, 20 survivors) of IVROBA were located in these series and an additional six case reports of survival after IVROBA were found in the literature, treatment advice and detailed clinical description of these surviving cases are sparse or absent. A case of IVROBA with good quality of survival is presented along with the aggressive five-component therapeutic plan used. The five components are: 1) open craniotomy with debridement of abscess cavity, 2) lavage of the ventricular system, 3) 6 weeks of intravenous antibiotics, 4) intraventricular gentamicin twice daily for 6 weeks, and 5) intraventricular drainage for 6 weeks.

Past and current clinical studies with GM-1 ganglioside in acute spinal cord injury.

Two recent prospective, randomized, placebo-controlled, double-blinded clinical drug studies in acute spinal cord injury have reported enhancement of neurologic recovery of motor function. The drugs investigated in these studies were methylprednisolone and GM-1 ganglioside. Before these studies, the treatment of patients with spinal cord injuries had been restricted to prevention of further injury to the spinal cord, limiting secondary damage following the initial injury, increasing the patient's ability to function through intensive rehabilitation, and facilitating any spontaneous recovery of neurologic function. Methylprednisolone is a steroid administered at very high levels, and GM-1 is a complex acidic glycolipid found at high levels in cell membranes in the mammalian central nervous system with known neuroprotective and neurofunctional restoration potential. This article summarizes the previously reported Maryland GM-1 clinical trial and presents the clinical and statistical design of a larger clinical trial being conducted with the purpose of verifying a beneficial GM-1 drug effect when administered with methylprednisolone in acute spinal cord injury.

Secondary mania following traumatic brain injury.

OBJECTIVE: In this study patients were examined during the first year after traumatic brain injury to determine the presence of secondary mania. METHOD: A consecutive series of 66 patients with closed-head injury were evaluated in the hospital and at 3-, 6-, and 12-month follow-ups. The patients were examined with a semistructured psychiatric interview and scales for measurement of impairment in activities of daily living, intellectual function, and social functioning. Patients fulfilling the DSM-III-R criteria for mania were compared to patients with major depression and to patients without affective disturbances in regard to their background characteristics, impairment variables, and lesion locations. RESULTS: Six patients (9%) met the criteria for mania at some point during follow-up. The presence of temporal basal polar lesions was significantly associated with secondary mania even when the effect of other lesion locations was taken into account. Secondary mania was not found to be associated with the severity of brain injury, degree of physical or cognitive impairment, level of social functioning, or previous family or personal history of psychiatric disorder. The duration of mania, however, appeared to be brief, lasting approximately 2 months. CONCLUSIONS: The 9% frequency of secondary mania in these patients with traumatic brain injury is significantly greater than that seen in other brain-injured populations (e.g., patients with stroke). The major correlate was the presence of a temporal basal polar lesion.

Modifications to the transverse Caspar cervical retractor blades optimized for a single-level anterior cervical discectomy.

A modification of the transverse Caspar cervical soft-tissue retractor blades for their use in a single-level anterior cervical discectomy is presented. These modified retractor blades are similarly inserted into the elevated anterior mesial portion of the longus colli muscles. However, they allow a smaller skin incision, less soft-tissue dissection, and do not require use of the superior and inferior smooth retractor blades, while providing the same surgical vision and operative ability in the disc space as does the four-bladed Caspar retractor system.

GM-1 ganglioside and motor recovery following human spinal cord injury.

Neurological deficit resulting from spinal cord injury varies widely in severity, ranging from transient abnormal reflexes to lifelong complete absence of motor and sensory function. Medical treatment to aid damaged neurons to recover function has been very limited; therapeutic efforts have focused primarily on initial stabilization of fractures, hemodynamic resuscitation, and then aggressive rehabilitation to enhance the full development of any remaining neuronal activity. Pharmacological treatment to improve restoration of neurological function may be possible, however, as indicated by many animal studies and a few clinical studies with a number of agents. A recent clinical trial of GM-1 ganglioside conducted in patients with spinal cord injuries showed that GM-1 ganglioside enhanced the recovery of neurological function 1 year after major spinal cord injury. In addition to GM-1 ganglioside treatment, these patients received aggressive medical and surgical treatment, as well as methylprednisolone. Neurological recovery was assessed with the Frankel scale and the American Spinal Injury Association (ASIA) motor scale. The findings show enhanced motor recovery compared with placebo in the lower extremities, but not in the upper extremities, over time. This corresponds to improved function of axons passing through the site of injury. Analysis of individual motor groups showed that neurological recovery in the GM-1 ganglioside-treated patients increased in initially paralyzed muscles, enabling them to regain useful motor function; paretic muscles were not found to be strengthened. The study provides the basis for larger studies of GM-1 ganglioside and methylprednisolone, which are currently under way.

Depression in patients with acute traumatic brain injury.

OBJECTIVE: This study was undertaken to examine patients with closed head injuries for the presence of depressive disorders. METHOD: A consecutive series of 66 patients with closed head injuries but no significant spinal cord or other organ system injury were examined by means of a semistructured psychiatric interview. The Hamilton Rating Scale for Depression as well as scales measuring impairment in activities of daily living, intellectual functioning, and social functioning were administered. The patients' CT scans were also examined. RESULTS: Seventeen patients had major depression and two had minor depression. The presence of left dorsolateral frontal lesions and/or left basal ganglia lesions and, to a lesser extent, parietal-occipital and right hemisphere lesions was associated with an increased probability of developing major depression. Compared to the nondepressed group, the group with major depression had a higher frequency of previous psychiatric disorder and showed evidence of poorer social functioning. CONCLUSIONS: Major depression occurs in about one-quarter of patients after traumatic brain injury. This is the same frequency as in other major disorders such as stroke. Major depression appears to be provoked by one or more factors that include poor premorbid social functioning and previous psychiatric disorder or injury to certain critical brain locations.

GM-1 ganglioside in human spinal cord injury.

Spinal cord injury is typically a devastating injury with no or only limited neurologic recovery. Recent papers have reported enhancement of neurologic recovery following spinal cord injury with both methylprednisolone and GM-1 ganglioside. This paper provides additional details of the GM-1 study and a further analysis of recovery of motor function for each of the ten neurologic levels assessed in the study. This additional analysis provides further evidence that the largest enhanced recovery of motor function in the GM-1 treatment group occurred in the muscles of the lower extremities and is consistent with the enhanced recovery occurring in the white matter tracts passing through the level of injury.