Prakash Sampath

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.

Outcome in patients with cervical radiculopathy. Prospective, multicenter study with independent clinical review.

STUDY DESIGN The Cervical Spine Research Society study is a prospective, nonrandomized, multicenter investigation of patients with cervical spondylosis and disc disease. In this analysis, only patients who had radiculopathy without myelopathy as the predominant symptom were considered. OBJECTIVES To determine demographics, surgeon treatment practices, and outcomes in patients with symptomatic radiculopathy. SUMMARY OF BACKGROUND DATA Current data on patient demographics and treatment practices of surgeons do not exist. There are no published prospective studies in which outcomes, including pain, function, neurologic symptoms, and ability to perform activities of daily living, are systematically quantified. METHODS Patients were recruited by participating Cervical Spine Research Society surgeons. Demographic, symptomologic, and functional patient data were compiled from surveys of patients and physicians completed at the time of initial examination, and outcomes were assessed from surveys of patients completed after treatment. Data were compiled and statistically analyzed by a blinded third party. RESULTS Of the 503 patients enrolled by 41 CSRS surgeons, 246 (49%) had radiculopathy. Patients had a mean duration of symptoms of 26.7 months (range, 8 weeks to > 352 months) and a mean age of 48.1 +/- 12.42 years; 44.7% were female. Surgery was recommended for 86 (35%) of these patients. Of the 155 patients on whom there were follow-up data, 51 (33%) underwent surgery, whereas 104 (67%) received medical treatment. Surgically treated patients had a significant improvement in pain, neurologic symptoms, functional status, and ability to perform activities of daily living. A significant number of patients who underwent surgery reported persistent excruciating or horrible pain on follow-up (26%). Patients treated medically also had significant improvement in pain and overall functional status. CONCLUSIONS In summary, this study represents the first in-depth, prospective outcome analysis of patients with cervical spondylotic and discogenic radiculopathy.

Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells.

Purpose: Glioblastoma multiforme (GBM) remains highly incurable, with frequent recurrences after standard therapies of maximal surgical resection, radiation, and chemotherapy. To address the need for new treatments, we have undertaken a chimeric antigen receptor (CAR) “designer T cell” (dTc) immunotherapeutic strategy by exploiting interleukin (IL)13 receptor α-2 (IL13Rα2) as a GBM-selective target. Experimental Design: We tested a second-generation IL13 “zetakine” CAR composed of a mutated IL13 extracellular domain linked to intracellular signaling elements of the CD28 costimulatory molecule and CD3ζ. The aim of the mutation (IL13.E13K.R109K) was to enhance selectivity of the CAR for recognition and killing of IL13Rα2+ GBMs while sparing normal cells bearing the composite IL13Rα1/IL4Rα receptor. Results: Our aim was partially realized with improved recognition of tumor and reduced but persisting activity against normal tissue IL13Rα1+ cells by the IL13.E13K.R109K CAR. We show that these IL13 dTcs were efficient in killing IL13Rα2+ glioma cell targets with abundant secretion of cytokines IL2 and IFNγ, and they displayed enhanced tumor-induced expansion versus control unmodified T cells in vitro. In an in vivo test with a human glioma xenograft model, single intracranial injections of IL13 dTc into tumor sites resulted in marked increases in animal survivals. Conclusions: These data raise the possibility of immune targeting of diffusely invasive GBM cells either via dTc infusion into resection cavities to prevent GBM recurrence or via direct stereotactic injection of dTcs to suppress inoperable or recurrent tumors. Systemic administration of these IL13 dTc could be complicated by reaction against normal tissues expressing IL13Ra1. Clin Cancer Res; 18(21); 5949–60. ©2012 AACR.

Spinal epidural abscess: a review of epidemiology, diagnosis, and treatment.

Despite advances in neuroimaging and neurosurgical treatment, spinal epidural abscess (SEA) remains a challenging problem for the practicing physician. Early diagnosis is often elusive, and treatment is delayed. The optimal management of SEA is not clearly defined, and morbidity and mortality remain significant. In this review article, we discuss contemporary issues surrounding SEA. In addition, we shed light on the epidemiology of this potentially devastating disease and outline current diagnostic and therapeutic guidelines. We find the frequency of diagnosis of SEA is increasing. To prevent serious morbidity and mortality, early diagnosis and prompt treatment are essential. Patients who are at high risk for developing such abscesses should have an immediate magnetic resonance scan with contrast enhancement. Surgical drainage and prolonged antibiotic use are the cornerstones of treatment, although selected patients may be treated nonsurgically with very vigilant medical follow-up.

Combined anterior craniofacial resection for tumors involving the cribriform plate: early postoperative complications and technical considerations.

OBJECTIVECombined craniofacial resection has become the standard approach for malignant tumors involving the cribriform plate and anterior cranial fossa. Despite its widespread application, however, many surgeons agree that the procedure carries a risk of significant morbidity and even mortality. The purpose of this study was to analyze the experience at a single institution to determine the incidence of early postoperative complications encountered after combined craniofacial resection of tumors involving the cribriform plate and to provide information to improve management. METHODSBetween 1987 and 1997, 168 patients underwent combined craniofacial resection at the National Cancer Institute of Milan for tumors involving the cribriform plate. Patient charts, operative notes, follow-up clinic notes, radiographic studies, and pathology reports were analyzed. Morbidity encountered in the first 30 cases was compared with that encountered in the subsequent 138 cases. RESULTSThe most frequently encountered pathological findings were adenocarcinoma (53.6%), squamous cell carcinoma (17%), and esthesioneuroblastoma (9.8%). Eight patients (4.7%) died, 6 of whom were among the first 30 patients to undergo resection. Among patients with fatal complications were three with meningoencephalitis, three with intracranial hemorrhage, and one with myocardial infarction. Fifty patients (29.7%) had nonfatal morbidity; 16 of these patients were among the first 30 patients operated. Transient cerebrospinal fluid leakage was the most frequent adverse effect (9.5%); 12 patients (7.1%) had pneumocephalus, 3 (1.8%) had meningitis, 4 (2.4%) had wound infections, 3 (1.8%) experienced transient impairment of mental status, 3 (1.8%) had transient diplopia, 2 (1.2%) had diabetes insipidus, and 1 (0.6%) had bone flap necrosis. CONCLUSIONWe observed a dramatic decrease in mortality and morbidity in patients who underwent combined craniofacial resection after the first 30 cases in our series. Improvement of specific aspects of surgical technique, such as more refined reconstructive methods and improved prophylactic antibiotic therapy, is at least partly responsible for this favorable trend.

Implantable Slow-Release Chemotherapeutic Polymers for the Treatment of Malignant Brain Tumors.

BACKGROUND: Despite significant advances in neurosurgery, radiation therapy, and chemotherapy, the prognosis for patients with malignant brain tumors remains dismal. In an effort to improve control of local disease, we have developed a biodegradable, controlled-release polymer that is implanted directly at the tumor site. METHODS: The preclinical and clinical development of the polymeric delivery of chemotherapeutic agents for treatment of patients with malignant gliomas is reviewed. RESULTS: Carmustine (BCNU)-impregnated biodegradable polymer is the first new therapy approved by the FDA for patients with gliomas in 23 years. This delivery system provides high local concentration of drug with minimal systemic toxicity and obviates the need for drug to cross the blood-brain barrier. Randomized, multi-institutional, double-blinded, placebo-controlled studies have shown improved survival in patients treated for gliomas both at initial presentation and at recurrence. Several clinical principles have emerged from the use of this polymer system, and further applications are currently being investigated. CONCLUSIONS: Local delivery of therapeutic agents via biodegradable polymers may play an increasing role in patients with brain tumors.

Impact of Temozolomide on Immune Response during Malignant Glioma Chemotherapy

Malignant glioma, or glioblastoma, is the most common and lethal form of brain tumor with a median survival time of 15 months. The established therapeutic regimen includes a tripartite therapy of surgical resection followed by radiation and temozolomide (TMZ) chemotherapy, concurrently with radiation and then as an adjuvant. TMZ, a DNA alkylating agent, is the most successful antiglioma drug and has added several months to the life expectancy of malignant glioma patients. However, TMZ is also responsible for inducing lymphopenia and myelosuppression in malignant glioma patients undergoing chemotherapy. Although TMZ-induced lymphopenia has been attributed to facilitate antitumor vaccination studies by inducing passive immune response, in general lymphopenic conditions have been associated with poor immune surveillance leading to opportunistic infections in glioma patients, as well as disrupting active antiglioma immune response by depleting both T and NK cells. Deletion of O6-methylguanine-DNA-methyltransferase (MGMT) activity, a DNA repair enzyme, by temozolomide has been determined to be the cause of lymphopenia. Drug-resistant mutation of the MGMT protein has been shown to render chemoprotection against TMZ. The immune modulating role of TMZ during glioma chemotherapy and possible mechanisms to establish a strong TMZ-resistant immune response have been discussed.

Long-term visual outcome after nonradical microsurgery in patients with parasellar and cavernous sinus meningiomas

OBJECTIVE To determine the long-term visual outcome in patients with parasellar and cavernous sinus meningiomas treated with nonradical surgery. METHODS Retrospective clinical review of 29 patients with parasellar or cavernous sinus meningiomas and visual sensory or ocular motor dysfunction at presentation, all of whom had at least 10 years of follow-up after initial diagnosis and treatment with nonradical surgery. RESULTS Nineteen of 29 patients had a unilateral or bilateral optic neuropathy at presentation, and 7 patients developed a unilateral or bilateral optic neuropathy during a mean follow-up period of 13.6 years. However, 27 (93%) of 29 patients retained vision of 20/40 or better in at least one eye, and 14 patients (48%) retained vision of 20/40 or better in both eyes. New ocular motility deficits developed in 3 (10%) of 29 patients during the follow-up period. CONCLUSION Radical surgery is not required to achieve long-term useful visual function for patients with parasellar or cavernous sinus meningiomas.

Cerebrospinal fluid (vascular endothelial growth factor) and serologic (recoverin) tumor markers for malignant glioma.

BACKGROUND Clinically useful tumor markers have yet to be identified for malignant glioma. We report on two potential novel tumor markers, vascular endothelial growth factor (VEGF) and recoverin (protein A). VEGF is a highly specific endothelial cell activator that induces angiogenesis both in vivo and in vitro. Our study was designed to assess whether VEGF could be measured in the cerebrospinal fluid (CSF) of patients with cerebral neoplasms and used as a marker of particular tumors. We also studied serum recoverin levels in patients with various brain tumors and compared these to controls. Recoverin is a detectable serologic protein that is expressed in patients with cancer-associated retinopathy, a paraneoplastic syndrome. METHODS In the VEGF arm, we used a solid-phase ELISA to determine the levels of VEGF. CSF samples from patients with anaplastic astrocytoma and glioblastoma multiforme (GBM) and with metastatic and nonastrocytic brain tumors were compared with nontumor control samples. In our recoverin study, an immunoenzymetric assay was used to measure the serum recoverin levels patients with glioma and compared with controls. RESULTS In the VEGF arm, 89% of samples with malignant astrocytoma and 27% of nonastrocytoma samples had detectable levels of VEGF. VEGF was not detectable in normal CSF samples. The levels of VEGF were significantly higher in high-grade astrocytomas than in nonastrocytic tumors. Recoverin levels were 10-fold higher in patients with recurrent GBM relative to controls. In patients with low-grade glioma, anaplastic glioma, and GBM with no evidence of recurrence, a 3- to 5-fold increase was observed. CONCLUSIONS VEGF is detectable in CSF and may be a potential marker for differentiating astrocytic from nonastrocytic tumors. Recoverin is detectable in serum and may be a useful glioma tumor marker, especially for recurrent active disease. These markers may have application for tumor diagnosis, surveillance, and treatment response.

Stereotactic radiosurgery for functional disorders

Stereotactic radiosurgery (SRS) with the Gamma Knife and linear accelerator has revolutionized neurosurgery over the past 20 years. The most common indications for radiosurgery today are tumors and arteriovenous malformations of the brain. Functional indications such as treatment of movement disorders or intractable pain only contribute a small percentage of treated patients. Although SRS is the only noninvasive form of treatment for functional disorders, it also has some limitations: neurophysiological confirmation of the target structure is not possible, and one therefore must rely exclusively on anatomical targeting. Furthermore, lesion sizes may vary, and shielding adjacent radiosensitive neural structures may be difficult or impossible. The most common indication for functional SRS is the treatment of trigeminal neuralgia. Radiosurgical treatment for epilepsy and certain psychiatric illnesses is performed in several centers as part of strict research protocols, and radiosurgical pallidotomy or medial thalamotomy is no longer recommended due to the high risk of complications. Radiosurgical ventrolateral thalamotomy for the treatment of tremor in patients with Parkinson disease or multiple sclerosis, as well as in the treatment of essential tremor, may be indicated for a select group of patients with advanced age, significant medical conditions that preclude treatment with open surgery, or patients who must receive anticoagulation therapy. A promising new application of SRS is high-dose radiosurgery delivered to the pituitary stalk. This treatment has already been successfully performed in several centers around the world to treat severe pain in patients with end-stage cancer.