Neurological and functional outcomes of subdural hematoma evacuation in patients over 70 years of age.

BACKGROUND: Subdural hematoma (SDH) is a common disease entity treated by neurosurgical intervention. Although the incidence increases in the elderly population, there is a paucity of studies examining their surgical outcomes. OBJECTIVES: To determine the neurological and functional outcomes of patients over 70 years of age undergoing surgical decompression for subdural hematoma. MATERIALS AND METHODS: We retrospectively reviewed data on 45 patients above 70 years who underwent craniotomy or burr holes for acute, chronic or mixed subdural hematomas. We analyzed both neurological and functional status before and after surgery. RESULTS: Forty-five patients 70 years of age or older were treated in our department during the study period. There was a significant improvement in the neurological status of patients from admission to follow up as assessed using the Markwalder grading scale (1.98 vs. 1.39; P =0.005), yet no improvement in functional outcome was observed as assessed by Glasgow Outcome Score. Forty-one patients were admitted from home, however only 20 patients (44%) were discharged home, 16 (36%) discharged to nursing home or rehab, 6 (13%) to hospice and 3 (7%) died in the postoperative period. Neurological function improved in patients who were older, had a worse pre-operative neurological status, were on anticoagulation and had chronic or mixed acute and chronic hematoma. However, no improvement in functional status was observed. CONCLUSION: Surgical management of SDH in patients over 70 years of age provides significant improvement in neurological status, but does not change functional status.

Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I safety trial, technical note, and lumbar safety outcomes.

BACKGROUND: No United States-based clinical trials have attempted delivery of biological therapies directly to the spinal cord for treatment of amyotrophic lateral sclerosis (ALS) because of the lack of a meaningful US Food and Drug Administration-authorized cell candidate and a validated delivery approach. OBJECTIVE: To assess safety of delivery of a neural stem cell-based treatment into the upper lumbar segments of the ALS spinal cord in the first US Food and Drug Administration-authorized phase I trial. METHODS: Each microinjection series comprised 5 injections (10 µL/injection) separated by 4 mm. Each injection deposited 100,000 neural stem cells derived from a fetal spinal cord. Twelve patients were treated with either unilateral or bilateral injections. Group A, nonambulatory patients, underwent unilateral (n = 3) or bilateral (n = 3) lumbar microinjections. Groups B and C were ambulatory (n = 3 each) and, respectively, received unilateral or bilateral injections. Patients are followed clinically and radiologically to assess potential toxicity of the procedure. RESULTS: Twelve patients have received a transplant. There was one instance of transient intraoperative somatosensory-evoked potentials depression. In the immediate postoperative period, there was 1 episode of urinary retention requiring Foley catheter reinsertion. By discharge, none had a documented motor function decrement. Two patients required readmission and reoperation for cerebrospinal fluid leak or suprafascial wound dehiscence (n = 1 each). Two deaths occurred at 8 and 13 months postsurgery; neither was related to the surgical transplant. CONCLUSION: Our experience in 12 patients supports the procedural safety of unilateral and bilateral intraspinal lumbar microinjection. Completion of this phase I safety trial is planned by proceeding to cervical and combined cervical + lumbar microinjections in ALS patients.

Current dosing paradigm for stereotactic radiosurgery alone after surgical resection of brain metastases needs to be optimized for improved local control.

PURPOSE: To describe the use of radiosurgery (RS) alone to the resection cavity after resection of brain metastases as an alternative to adjuvant whole-brain radiotherapy (WBRT). METHODS AND MATERIALS: Sixty-two patients with 64 cavities were treated with linear accelerator-based RS alone to the resection cavity after surgical removal of brain metastases between March 2007 and August 2010. Fifty-two patients (81%) had a gross total resection. Median cavity volume was 8.5 cm(3). Forty-four patients (71%) had a single metastasis. Median marginal and maximum doses were 18 Gy and 20.4 Gy, respectively. Sixty-one cavities (95%) had gross tumor volume to planning target volume expansion of ≥1 mm. RESULTS: Six-month and 1-year actuarial local recurrence rates were 14% and 22%, respectively, with a median follow-up period of 9.7 months. Six-month and 1-year actuarial distant brain recurrence, total intracranial recurrence, and freedom from WBRT rates were 31% and 51%, 41% and 63%, and 91% and 74%, respectively. The symptomatic cavity radiation necrosis rate was 8%, with 2 patients (3%) undergoing surgery. Of the 11 local failures, 8 were in-field, 1 was marginal, and 2 were both (defined as in-field if ≥90% of recurrence within the prescription isodose and marginal if ≥90% outside of the prescription isodose). CONCLUSIONS: The high rate of in-field cavity failure suggests that geographic misses with highly conformal RS are not a major contributor to local recurrence. The current dosing regimen derived from Radiation Therapy Oncology Group protocol 90-05 should be optimized in this patient population before any direct comparison with WBRT.

Intramuscular administration of a VEGF zinc finger transcription factor activator (VEGF-ZFP-TF) improves functional outcomes in SOD1 rats.

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron loss leading to paralysis and death. Vascular endothelial growth factor (VEGF) has angiogenic, neurotrophic, and neuroprotective properties, and has preserved neuromuscular function and protected motor neurons in rats engineered to overexpress the human gene coding the mutated G93A form of the superoxide dismutase-1 (SOD1). We assessed the effects of intramuscular administration of a plasmid that encodes a zinc finger protein transcription factor (ZFP-TF) engineered to induce VEGF expression in the SOD1 rat model of ALS. Weekly injections of the plasmid preserved ipsilateral hindlimb grip strength and markedly improved rotarod performance in SOD1 rats compared to the vehicle-treated group. The number of motor neurons and the proportion of innervated neuromuscular junctions were similar in both groups. In conclusion, our data suggest that administration of the VEGF-ZFP-TF may be neuroprotective and has potential as a safe and practical approach for the management of motor disability in ALS.

Platform and cannula design improvements for spinal cord therapeutics delivery.

BACKGROUND: Only recently have data been published attempting to validate a technology and technique suitable for targeted delivery of biological payloads to the human spinal cord. OBJECTIVE: To characterize the development and evolution of a spine-stabilized microinjection platform as a vehicle for biologics delivery to the cervical and thoracolumbar spine on the basis of preclinical experience in both non-Good Laboratory Practice (GLP) experimental series and GLP studies. METHODS: Our laboratory completed > 100 cervical and lumbar porcine microinjection procedures between July 2004 and June 2010. This included both non-GLP- and GLP-adherent survival series to validate the safety and accuracy achievable with intraspinal microinjection. During this time, 3 different microinjection platforms, injection stages, and cannula designs were tested. RESULTS: Repetitive technological improvements reduced incision length, decreased procedural complexity, and simplified ventral horn targeting and accuracy. These changes reduced procedural invasiveness and the likelihood of neurological morbidity while improving targeting accuracy. In part as a result of these technological improvements and procedural modifications, we have safely progressed from single unilateral microinjections to multiple bilateral injections without long-term neurological sequelae. CONCLUSION: Technological and procedural refinements have significantly enhanced the capabilities of intraspinal microinjection-based biologics delivery. Reductions in procedural invasiveness and the capability to deliver sequential biological payloads effectively have broadened the flexibility of intraspinal microinjection to a widened array of intrinsic spinal cord pathologies. These advances have laid the groundwork for clinical translation of spinal cord microinjections.

Metastasis infiltration: an investigation of the postoperative brain-tumor interface.

PURPOSE: This study aims to evaluate brain infiltration of metastatic tumor cells past the main tumor resection margin to assess the biological basis for the use of stereotactic radiosurgery treatment of the tumor resection cavity and visualized resection edge or clinical target volume. METHODS AND MATERIALS: Resection margin tissue was obtained after gross total resection of a small group of metastatic lesions from a variety of primary sources. The tissue at the border of the tumor and brain tissue was carefully oriented and processed to evaluate the presence of tumor cells within brain tissue and their distance from the resection margin. RESULTS: Microscopic assessment of the radially oriented tissue samples showed no tumor cells infiltrating the surrounding brain tissue. Among the positive findings were reactive astrocytosis observed on the brain tissue immediately adjacent to the tumor resection bed margin. CONCLUSIONS: The lack of evidence of metastatic tumor cell infiltration into surrounding brain suggests the need to target only a narrow depth of the resection cavity margin to minimize normal tissue injury and prevent treatment size-dependent stereotactic radiosurgery complications.

Cervical multilevel intraspinal stem cell therapy: assessment of surgical risks in Gottingen minipigs.

STUDY DESIGN: Assessment of long-term surgical risks from multiple intraspinal cell injections. OBJECTIVE: To prove that multilevel-targeted cell injection to the spinal cord can be a feasible and safe procedure. SUMMARY OF BACKGROUND DATA: Neural cell transplantation has been proposed as a treatment for a variety of neurologic disorders, including degenerative, ischemic, autoimmune, and traumatic etiologies. Among these diseases, the lack of effective treatment for amyotrophic lateral sclerosis has prompted the search for cell-based neuroprotection or motor neuron-replacement therapies. METHODS: Fifteen female minipigs, divided into 3 experimental groups, underwent either 5 or 10 unilateral injections of neural stem cells or 10 vehicle injections into the C3-C5 segments of the spinal cord, using a device and technique developed for safe and accurate injection into the human spinal cord. All animals received intravenous Tacrolimus (0.025 mg/kg) BID during the course of the study. Sensory and motor functions as well as general morbidity were assessed for 28 days. Full necropsy was performed and spinal cords were analyzed for graft survival. This study was performed under Good Laboratory Practice conditions. RESULTS: Neither mortality nor permanent surgical complications were observed within the 28-day study period. All animals returned to preoperative baseline showing full motor function recovery. Graft survival was demonstrated by immunohistochemistry. CONCLUSION: Clinically acceptable neural progenitor survival, distribution, and density were achieved using the number of injections and surgical techniques specifically developed for this purpose.

A conditioning lesion provides selective protection in a rat model of Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is neurodegenerative disease characterized by muscle weakness and atrophy due to progressive motoneuron loss. The death of motoneuron is preceded by the failure of neuromuscular junctions (NMJs) and axonal retraction. Thus, to develop an effective ALS therapy you must simultaneously preserve motoneuron somas, motor axons and NMJs. A conditioning lesion has the potential to accomplish this since it has been shown to enhance neuronal survival and recovery from trauma in a variety of contexts. METHODOLOGY/PRINCIPAL FINDINGS: To test the effects of a conditioning lesion in a model of familial ALS we administered a tibial nerve crush injury to presymptomatic fALS(G93A) rats. We examined its effects on motor function, motoneuron somas, motor axons, and NMJs. Our experiments revealed a novel paradigm for the conditioning lesion effect. Specifically we found that the motor functional decline in fALS(G93A) rats that received a conditioning lesion was delayed and less severe. These improvements in motor function corresponded to greater motoneuron survival, reduced motor axonopathy, and enhanced NMJ maintenance at disease end-stage. Furthermore, the increased NMJ maintenance was selective for muscle compartments innervated by the most resilient (slow) motoneuron subtypes, but was absent in muscle compartments innervated by the most vulnerable (fast fatigable) motoneuron subtypes. CONCLUSIONS/SIGNIFICANCE: These findings support the development of strategies aimed at mimicking the conditioning lesion effect to treat ALS as well as underlined the importance of considering the heterogeneity of motoneuron sub-types when evaluating prospective ALS therapeutics.