Directionally non-rotating electric field therapy delivered through implanted electrodes as a glioblastoma treatment platform: A proof-of-principle study.

Background: While directionally rotating tumor-treating fields (TTF) therapy has garnered considerable clinical interest in recent years, there has been comparatively less focus on directionally non-rotating electric field therapy (dnEFT). Methods: We explored dnEFT generated through customized electrodes as a glioblastoma therapy in in vitro and in vivo preclinical models. The effects of dnEFT on tumor apoptosis and microglia/macrophages in the tumor microenvironment were tested using flow-cytometric and qPCR assays. Results: In vitro, dnEFT generated using a clinical-grade spinal cord stimulator showed antineoplastic activity against independent glioblastoma cell lines. In support of the results obtained using the clinical-grade electrode, dnEFT delivered through a customized, 2-electrode array induced glioblastoma apoptosis. To characterize this effect in vivo, a custom-designed 4-electrode array was fabricated such that tumor cells can be implanted into murine cerebrum through a center channel equidistant from the electrodes. After implantation with this array and luciferase-expressing murine GL261 glioblastoma cells, mice were randomized to dnEFT or placebo. Relative to placebo-treated mice, dnEFT reduced tumor growth (measured by bioluminescence) and prolonged survival (median survival gain of 6.5 days). Analysis of brain sections following dnEFT showed a notable increase in the accumulation of peritumoral macrophage/microglia with increased expression of M1 genes (IFNγ, TNFα, and IL-6) and decreased expression of M2 genes (CD206, Arg, and IL-10) relative to placebo-treated tumors. Conclusions: Our results suggest therapeutic potential in glioblastoma for dnEFT delivered through implanted electrodes, supporting the development of a proof-of-principle clinical trial using commercially available deep brain stimulator electrodes.

Cervical alignment in the obese population following posterior cervical fusion for cervical myelopathy.

STUDY DESIGN: Retrospective cohort study OBJECTIVE: The aim of this study was to investigate the effect of body mass index (BMI) on the reoperation rate and cervical sagittal alignment of patients who underwent posterior cervical decompression and fusion for cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Cervical sagittal balance has been correlated with postoperative clinical outcomes. Previous studies have shown worse postoperative sagittal alignment and higher reoperation rates in patients with high BMI undergoing anterior decompression and fusion. Similar evidence for the impact of obesity in postoperative sagittal alignment for patients with (CSM) undergoing posterior cervical decompression and fusion (PCF) is lacking. METHODS: A retrospective analysis of 198 patients who underwent PCF for cervical myelopathy due to degenerative spine disease was performed. Demographics, need for reoperation, and perioperative radiographic parameters were collected. Cervical lordosis (CL), C2-7 sagittal vertical axis (SVA), and T1 slope (T1S) was measured on standing lateral radiographs. Comparative analysis of the patient cohort was performed by stratifying the sample population into three BMI categories (<25, 25-30, ≥30). RESULT: Of the 198 patients that met inclusion criteria, 53 had BMI normal (<25), 65 were overweight (25-30), and 80 were obese (≥30). Mean SVA increased postoperatively in all groups, 4 mm in the normal group, 13 mm in the overweight group, and 13 mm in the obese group (p = 0.003). There was no significant difference in the postoperative change of cervical lordosis or T1 slope between the groups. Multivariate analysis demonstrated fusions involving the cervicothoracic junction and those involving 5 or more levels significantly affected alignment parameters. There were 27 complications requiring reoperation (14%) with no significant differences among the groups stratified by BMI (p = 0.386). CONCLUSIONS: Overweight patients (BMI>25) with CSM undergoing PCF had a greater increase in SVA than normal weight patients while reoperation rates were similar. In addition, preoperative CL increased with increasing BMI, although this trend was not Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation significant and there was not found to be a significant difference between the change in CL from baseline to post-fusion between BMI cohorts. This study further highlights the importance of considering BMI when attempting to optimize sagittal alignment in patients undergoing PCF.

Spinal Cord Stimulation for Visceral Pain: Present Approaches and Future Strategies.

INTRODUCTION: The introduction of successful neuromodulation strategies for managing chronic visceral pain lag behind what is now treatment of choice in refractory chronic back and extremity pain for many providers in the United States and Europe. Changes in public policy and monetary support to identify nonopioid treatments for chronic pain have sparked interest in alternative options. In this review, we discuss the scope of spinal cord stimulation (SCS) for visceral pain, its limitations, and the potential role for new intradural devices of the type that we are developing in our laboratories, which may be able to overcome existing challenges. METHODS: A review of the available literature relevant to this topic was performed, with particular focus on the pertinent neuroanatomy and uses of spinal cord stimulation systems in the treatment of malignant and nonmalignant gastrointestinal, genitourinary, and chronic pelvic pain. RESULTS: To date, there have been multiple off-label reports testing SCS for refractory gastrointestinal and genitourinary conditions. Though some findings have been favorable for these organs and systems, there is insufficient evidence to make this practice routine. The unique configuration and layout of the pelvic pain pathways may not be ideally treated using traditional SCS implantation techniques, and intradural stimulation may be a viable alternative. CONCLUSIONS: Despite the prevalence of visceral pain, the application of neuromodulation therapies, a standard approach for other painful conditions, has received far too little attention, despite promising outcomes from uncontrolled trials. Detailed descriptions of visceral pain pathways may offer several clues that could be used to implement devices tailored to this unique anatomy.

Risk factors associated with reoperation in posterior cervical fusions: A large-scale retrospective analysis.

OBJECTIVES: To identify risk factors for reoperation in patients who have undergone posterior cervical fusion (PCF). PATIENTS AND METHODS: A retrospective cohort analysis was performed of patients undergoing PCF during a 12-year period at a single institution. Demographic and surgical characteristics were collected from electronic medical records. This study addressed reoperations, from all causes, of PCF. Different strategies, including the addition of anterior fusion, were also compared. RESULTS: Of the 370 patients meeting inclusion criteria there were 44 patients (11.9 %) that required a revision and of those 5 required a second revision. The most common reasons for revision were adjacent segment disease and infection, 13 (3.5 %) and 11 patients (3.0 %), respectively. There was not a higher revision rate (for any cause) for patients who had a subaxial fusion and compared with those that included C2 or those that failed to cross the cervicothoracic junction. Of patients who required reoperation, there was a statistically significant higher fraction of smokers (p =  0.023). CONCLUSION: The risks and benefits of posterior cervical instrumentation and fusion should be thoroughly discussed with patients. This report implicates smoking as a risk factor for all-cause reoperation in patients who have had this PCF and provides surgeons with additional data regarding this complication. When possible, preoperative optimization should include smoking cessation therapy.

Differences and characteristics of symptoms by tumor location, size, and degree of spinal cord compression: a retrospective study on 53 surgically treated, symptomatic spinal meningiomas.

OBJECTIVE: The differences in symptoms of spinal meningiomas have rarely been discussed from the perspective of tumor characteristics. The main purpose of this paper was to define the differences, if any, in symptoms in patients with spinal meningiomas with respect to tumor size, location, and degree of spinal cord compression. The authors also sought the threshold of spinal cord compression that causes motor weakness. METHODS: The authors conducted a retrospective study of 53 cases of spinal meningiomas that were surgically treated from 2013 to 2018. Symptoms related to the tumor were classified as motor weakness, sensory disturbance, pain, and bowel/bladder dysfunction. Based on MR images, tumor location was classified by spinal level and by its attachment to the dura mater. Tumor dimensions were also measured. Occupation ratios of the tumors to the spinal canal and degree of spinal cord flattening were sought from the axial MR images that showed the highest degree of spinal cord compression. RESULTS: Motor weakness and sensory disturbance were significantly more common in thoracic spine meningiomas than in cervical spine meningiomas (p < 0.001 and p = 0.013, respectively), while pain was more common in meningiomas at the craniovertebral junction (p < 0.001). The attachment, height, width, depth, and volume of the tumor showed no significant difference irrespective of the presence or absence of each symptom. In cases of motor weakness and sensory disturbance, occupation ratios and spinal cord flattening ratios were significantly larger. However, these ratios were significantly smaller in the presence of pain. Multivariate logistic regression analysis revealed that occupation ratio independently contributed to motor weakness (OR 1.14, p = 0.035) and pain (OR 0.925, p = 0.034). Receiver operating characteristic curve analysis suggested that occupation ratio with a value of 63.678% is the threshold for the tumor to cause motor weakness. CONCLUSIONS: The study showed the difference in clinical presentation of spinal meningiomas by spinal level, occupation ratio, and spinal cord flattening ratio. An occupation ratio of approximately 64% could be utilized as the threshold value of tumor growth to cause motor weakness. Tumor growth in the cervical spine might cause pain symptoms before causing motor weakness. The relationship between the tumor and its symptomatology should be discussed with respect to tumor size relative to the surrounding spinal canal.

Vertebral hemangiomas: Diagnosis and management. A single center experience.

OBJECTIVE: Vertebral hemangiomas (VH) are common benign lesions involving the spine. Owing to the multiplicity of treatments, the management of VH has not always been consistent. In this retrospective review of a single center experience, indications and options available for the treatment of VH are outlined. PATIENTS AND METHODS: This is a retrospective review of 71 cases of VH managed at our institution between 2005 and 2019. Sixty of these cases were managed non-operatively, with 11 cases undergoing operative intervention. Of the 11 cases that underwent surgery, there were 2 cervical cases and 9 in the thoracic spine. Ten cases were symptomatic, and 1 incidental. Three patients presented with localized pain, and the remaining 7 had neurological deficit. Decompression with maximal resection of the hemangioma was undertaken in 10 cases, and vertebroplasty in 1. RESULTS: Of the 60 patients who were managed non-operatively, 13 patients had presented with back/neck pain, with the remaining 47 patients being asymptomatic and diagnosed incidentally. Among the 13 symptomatic patients, all were offered surgical intervention for pain management, but given lack of severity of symptoms, all had opted for conservative approaches of pain control. In the 11 patients who underwent surgery, the preoperative diagnosis of VH was accurate in all but 1 case. There were 2 cervical cases treated with corpectomy. One patient was treated with vertebroplasty, and the remaining 8 with decompression. Radiation was used in 2 cases. Of the 10 patients undergoing decompression, 7 patients had improvement of the neurologic deficit, with resolution of pain in the remaining 3. None of our cases demonstrated deterioration. CONCLUSION: VH are often discovered incidentally during evaluation of spinal pain. Except in rare cases, the diagnosis of VH is made correctly from the radiographic and MRI studies. Observation for the asymptomatic lesion is appropriate. For VH presenting with deficit or intractable pain, decompressive surgery is recommended. Radiation is appropriate in cases of recurrent VH.

Intraoperative Shoulder Traction as Cause of C5 Palsy: Magnetic Resonance Imaging Study.

OBJECTIVE: During surgery, shoulder traction is often used for better fluoroscopic imaging of the lower cervical spine. Traction on the C5 root has been implicated as a potential cause of C5 palsy after cervical spine surgery. Using magnetic resonance imaging, this study was undertaken to determine the impact of upper extremity traction on the C5 root orientation. METHODS: In this study, 5 subjects underwent coronal magnetic resonance imaging of the cervical spine and left brachial plexus. Using a wrist restraint, sequential traction on the left arm with 10, 20, and 30 lb. was applied. Measurements of the angle between the spinal axis and C5 nerve root and the angle between the C5 nerve root and the upper trunk of the brachial plexus were obtained. The measurements were taken by a trained neuroradiologist and analyzed for significance. RESULTS: The angle between the C5 nerve root and the vertical spinal axis remained within 3 and 4 degrees of the mean and was not found to be associated with increased traction weight (P = 0.753). The angle between the C5 root and the upper trunk increased with increasing weight and was found to be statistically significant (P = 0.003). CONCLUSIONS: While the cause of C5 palsy is likely multifactorial, this study provides evidence that, in the awake volunteer, upper extremity traction leads to C5 root and upper trunk tension. These results suggest that shoulder traction in the anesthetized patient could lead to tension of the C5 nerve root and subsequent injury and palsy.

Impact of the Inclusion of C2 in Posterior Cervical Fusions for Cervical Myelopathy on Sagittal Cervical Alignment.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the impact of including C2 in posterior fusions on radiographic parameters of cervical alignment in cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: Despite the use of posterior instrumentation and arthrodesis after cervical laminectomy, loss of lordosis and the development of kyphosis are prevalent. Inadequate cervical lordosis and other measures of sagittal cervical alignment have been shown to correlate with disability, general health scores, and severity of myelopathy. The role of C2 in the posterior tension band, which maintains sagittal alignment, differs from the subaxial spine, as it is the insertion point for erector spinae muscles that play a critical role in maintaining posture. PATIENTS AND METHODS: This study compares the radiographic outcomes of sagittal balance between 2 cohorts of patients who underwent posterior cervical decompression and fusion for cervical myelopathy over a 12-year period at a single institution. Demographic and surgical characteristics were collected using the electronic medical record of patients undergoing posterior cervical fusions (PCF) which included the axis [axial fusion (AF)] and those that were subaxial fusions (SAF). Radiographic measurements included preopertaive and postoperative C2-C7 lordosis (CL), C2-C7 sagittal vertical axis (SVA), and T1 slope (T1S). RESULTS: After review of the electronic medical records, 229 patients were identified as having PCF and decompression for treatment of myelopathy. One hundred sixty-seven patients had AF, whereas 62 had SAF. PCF resulted in loss of CL in both cohorts. Although there was no statistical difference in postoperative CL, there was a significant increase in SVA (P<0.001) and T1S (P<0.001) with AF. CONCLUSIONS: PCF often result in loss of lordosis. When compared with SAF, inclusion of C2 into the fusion construct may result in worsened sagittal balance, increasing the SVA and T1S.

Survival after reoperation for recurrent glioblastoma.

Determining which patients will benefit from reoperation for recurrent glioblastoma remains difficult and the impact of the volume of FLAIR signal hyperintensity is not well known. The primary purpose of this study is to analyze the impact of preoperative volume of FLAIR hyperintensity on prognosis. 37 patients who underwent a reoperation for recurrent glioblastoma after initial gross total resection followed by standard chemoradiation were retrospectively reviewed. Volumetric analysis of preoperative MR images from the initial and second surgery was performed and correlated with clinical data. Survival probabilities were estimated using the Kaplan-Meier method and Cox regression to assess the effect of risk factors on time to reoperation (TTR), progression-free survival (PFS) after reoperation, and overall survival (OS). The volumes of FLAIR signal hyperintensity prior to the initial surgery and reoperation were not associated with prognosis. TTR and OS were significantly affected by the preoperative enhancement volume at the initial surgery, with increasing volumes yielding poorer prognosis. Patients with tumor in critical/eloquent areas were found to have a worse prognosis. Median TTR was 11 months, median PFS after reoperation was 3 months, and OS in patients undergoing a reoperation was 21 months. The results suggest FLAIR signal change seen in patients with glioblastoma does not influence time to reoperation, progression-free survival, or overall survival. These findings suggest the amount of FLAIR signal change should not greatly influence a surgeon's decision to perform a second surgical resection compare to other factors, and when appropriate, aggressive surgical intervention should be considered.

Contemporary Approaches to Preventing and Treating Infections of Novel Intrathecal Neurostimulation Devices.

INTRODUCTION: Contemporary approaches to surgical site infections have evolved significantly over the last several decades in response to the economic pressures of soaring health care costs and increasing patient expectations of safety. Neurosurgeons face multiple unique challenges when striving to avoid as well as manage surgical implant infections. The tissue compartment, organ system, or joint is characterized by biological factors and physical forces that may not be universally relevant. Such implants, once rare, are now routine. Although the prevention, diagnosis, and treatment of surgical site infections involving neural implants has advanced, guidelines are ever changing, and the incidence still exceeds acceptable levels. We assess the impact of these factors on a new class of implantable neuromodulation devices. METHODS: The available evidence along with practice patterns were examined and organized to establish relevant groupings for continuing evaluation and to propose justifiable recommendations for the treatment of infections that might arise in the case of intradural spinal cord stimulators. RESULTS: Few studies in the modern era have systematically evaluated preventive behaviors that were applied to intradural neural implants alone. We anticipate that future efforts will focus even more on the investigation of modifiable factors along a continuum from bacterially repellant implants to weight management. Early diagnosis could offer the best hope for device salvage but to date has been largely understudied. CONCLUSIONS: Historically, prevention is the cornerstone to infection mitigation. However, immediate diagnosis and hardware salvage have not received the attention deserved, and that approach may be especially important for intradural devices.

Anterior and Posterior Approaches for Cervical Myelopathy: Clinical and Radiographic Outcomes.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aim of this study was to identify advantages and disadvantages of the anterior and posterior approaches in the treatment of cervical stenosis and myelopathy. SUMMARY OF BACKGROUND DATA: Both anterior and posterior surgical approaches for cervical stenosis and myelopathy have been shown to result in improvement in health-related outcomes. Despite the evidence, controversy remains regarding the best approach to achieve decompression and correct deformity. METHODS: We retrospectively reviewed patients with cervical stenosis and myelopathy who had undergone anterior cervical fusion and instrumentation (n = 38) or posterior cervical laminectomy and instrumentation (n = 51) with at least 6 months of follow-up. Plain radiographs, magnetic resonance imaging, and computed tomography scans, as well as health-related outcomes, including Visual Analog Scale for neck pain, Japanese Orthopedic Association score for myelopathy, Neck Disability Index, and Short Form-36 Health Survey, were collated before surgery and at follow-up (median 12.0 and 12.1 months for anterior and posterior group, respectively). RESULTS: Both anterior and posterior approaches were associated with significant improvements in all studied quality of life parameters with the exception of general health in the anterior group and energy and fatigue in the posterior group. In the anterior group, follow-up assessment revealed a significant increase in C2-7 lordosis. Both approaches were accompanied by significant increases in C2-7 sagittal balance [sagittal vertical axis (SVA)]. There were two complications in the anterior group and nine complications in the posterior group; the incidence of complications between the two groups was not significantly different. CONCLUSION: When the benefits of one approach over the other are not self-evident, the anterior approach is recommended, as it was associated with a shorter hospital stay and more successful restoration of cervical lordosis than posterior surgery. LEVEL OF EVIDENCE: 3.

Durotomy Surrogate and Seals for Intradural Spinal Cord Stimulators: Apparatus and Review of Clinical Methods and Materials.

INTRODUCTION: We are developing a novel intradural spinal cord stimulator for treatment of neuropathic pain and spasticity. A key feature is the means by which it seals the dura mater to prevent leakage of cerebrospinal fluid (CSF). We have built and employed a test rig that enables evaluation of candidate seal materials. METHODS: To guide the design of the test rig, we reviewed the literature on neurosurgical durotomies. The test rig has a mock durotomy slot with a dural substitute serving as the surrogate dura mater and water as the CSF. The primary experimental goal was to evaluate the effectiveness of candidate gasket materials as seals against CSF leakage in an implanted prototype device, at both normal and super-physiologic pressures. A secondary goal was to measure the transmembrane flows in a representative dural substitute material, to establish its baseline aqueous transport properties. RESULTS: The seals prevented leakage of water at the implantation site over periods of ≈ ten days, long enough for the scar tissue to form in the clinical situation. The seals also held at water pressure transients approaching 250 mm Hg. The residual volumetric flux of water through the dura substitute membrane (Durepair®) was δVT /A ≈ 0.24 mm3 /min/cm2 , consistent with expectations for transport through the porous membrane prior to closure and equalization of internal/external pressures. CONCLUSIONS: We have demonstrated the workability of obtaining robust seal against leakage at the implantation site of a novel intradural stimulator using a custom-designed test rig. Extension of the method to in vivo testing in a large animal model will be the next step.

Spinal arachnoid cysts in adults: diagnosis and management. A single-center experience.

OBJECTIVEAdult spinal arachnoid cysts (SACs) are rare entities of indistinct etiology that present with pain or myelopathy. Diagnosis is made on imaging studies with varying degrees of specificity. In symptomatic cases, the standard treatment involves surgical exploration and relief of neural tissue compression. The aim of this study was to illustrate features of SACs in adults, surgical management, and outcomes.METHODSThe authors searched medical records for all SACs in adults in the 10-year period ending in December 2016. Radiology and pathology reports were reviewed to exclude other spine cystic disorders. Recurrent or previously treated patients were excluded. Demographic variables (age, sex) and clinical presentation (symptoms, duration, history of infection or trauma, and examination findings) were extracted. Radiological features were collected from radiology reports and direct interpretation of imaging studies. Operative reports and media were reviewed to accurately describe the surgical technique. Finally, patient-reported outcomes were collected at every clinic visit using the SF-36.RESULTSThe authors' search identified 22 patients with SACs (mean age at presentation 53.5 years). Seventeen patients were women, representing an almost 3:1 sex distribution. Symptoms comprised back pain (n = 16, 73%), weakness (n = 10, 45%), gait ataxia (n = 11, 50%), and sphincter dysfunction (n = 4, 18%). The mean duration of symptoms was 15 months. Seven patients (32%) exhibited signs of myelopathy. All patients underwent preoperative MRI; in addition, 6 underwent CT myelography. SACs were located in the thoracic spine (n = 17, 77%), and less commonly in the lumbar spine (n = 3, 14%) and cervical/cervicothoracolumbar region (n = 2, 9%). Based on imaging findings, the cysts were interpreted as intradural SACs (n = 11, 50%), extradural SACs (n = 6, 27%), or ventral spinal cord herniation (n = 2, 9%); findings in 3 patients (14%) were inconclusive. Nineteen patients underwent surgical treatment consisting of laminoplasty in addition to cyst resection (n = 13, 68%), ligation of the connecting pedicle (n = 4, 21%), or fenestration/marsupialization (n = 2, 11%). Postoperatively, patients were followed up for an average of 8.2 months (range 2-30 months). Postoperative MRI showed complete resolution of the SAC in 14 of 16 patients. Patient-reported outcomes showed improvement in SF-36 parameters. One patient suffered a delayed wound infection.CONCLUSIONSIn symptomatic patients with imaging findings suggestive of spinal arachnoid cyst, surgical exploration and complete resection is the treatment of choice. Treatment is usually well tolerated, carries low risks, and provides the best chances for optimal recovery.

Management of iatrogenic spinal cerebrospinal fluid leaks: A cohort of 124 patients.

OBJECTIVES: Cerebrospinal fluid leaks are a frequent complication of spinal surgery, with reported rates between 2 and 20%. Management is highly variable and dependent on comorbidities, complexity of the index procedure, and surgeons' experience. Treatment options include primary or delayed repair, with or without spinal drainage. Using a retrospective cohort, the authors aim to identify the appropriate management of iatrogenic spinal cerebrospinal fluid (CSF) leaks. PATIENTS AND METHODS: We queried our institutional database for postoperative spinal CSF leaks between 1/1/2007 and 3/14/2017 using Current Procedural Terminology (CPT) and International Classification of Disease (ICD) codes. Excluded were patients who had primarily intradural procedures such as tethered cord release, tumor resection, and posterior fossa decompression. Information regarding patient demographics, surgical characteristics, and postoperative course was gathered, including whether primary closure (with nonabsorbable suture) was achieved, lumbar drain placement at initial surgery, use of fibrin sealant, number of subsequent explorations, rate of infection, length of stay, and number of hospital admissions. RESULTS: Our cohort consisted of 124 patients who suffered intraoperative iatrogenic CSF leak out of 3965 procedures, for a rate of 3.1%. Primary dural closure (±lumbar drain) was attempted in 64 patients, with successful repair in 47 (73.4%). Lumbar drain placement (±primary closure) was performed in 49, with success in 43 (87.8%). Delayed exploration of the surgical wound was required in 34 patients. Patients in whom primary closure could not be achieved and did not have a lumbar drain placed had a 39.5% reexploration rate. Patients who were treated with delayed exploration had statistically significant increase in length of stay (19.6 vs. 7.8 days), hospital admissions (2.1 vs. 1.0), and infections (15 vs. 0). CONCLUSION: CSF leaks are fraught with complications requiring reexploration for repair in 27.4% of cases. Primary repair of the leak and use of fibrin sealant upon discovery, with consideration of lumbar drain, should be performed whenever possible, as they are associated with shorter hospital stays, fewer hospital admissions, and lower rates of reoperation and infection.