Aaron J. Clark

Proximal junctional kyphosis and failure after spinal deformity surgery: A systematic review of the literature as a background to classification development

Study Design. Systematic review of literature. Objective. To perform a comprehensive English language systematic literature review of proximal junctional kyphosis (PJK) and proximal junctional failure (PJF), concentrating on incidence, risk factors, health related quality of life impact, prevention strategy, and classification systems. Summary of Background Data. PJK and PJF are well described clinical pathologies and are a frequent cause of revision surgery. The development of a PJK classification that correlates with clinical outcomes and guides treatment decisions and possible prevention strategies would be of significant benefit to patients and surgeons. Methods. The phrases “proximal junctional,” “proximal junctional kyphosis,” and “proximal junctional failure” were used as search terms in PubMed for all years up to 2014 to identify all articles that included at least one of these terms. Results. Fifty-three articles were identified overall. Eighteen articles assessed for risk factors. Eight studies specifically reviewed prevention strategies. There were no randomized prospective studies. There were 3 published studies that have attempted to classify PJK. The reported incidence of PJK ranged widely, from 5% to 46% in patients undergoing spinal instrumentation and fusion for adult spinal deformity. It is reported that 66% of PJK occurs within 3 months and 80% within 18 months after surgery. The reported revision rates due to PJK range from 13% to 55%. Modifiable and nonmodifiable risk factors for PJK have been characterized. Conclusion. PJK and PJF affect many patients after long segment instrumentation after the correction of adult spinal deformity. The epidemiology and risk factors for the disease are well defined. A PJK and PJF scoring system may help describe the severity of disease and guide the need for revision surgery. The development and prospective validation of a PJK classification system is important considering the prevalence of the problem and its clinical and economic impact. Level of Evidence: N/A

Impact of bevacizumab chemotherapy on craniotomy wound healing

OBJECT The FDA approval of bevacizumab for recurrent glioblastoma has resulted in its increased use in this patient population. Phase II trials reported 4%-6% impaired wound healing for bevacizumab initiated postoperatively. The effect of preoperative bevacizumab on subsequent craniotomy healing has not been addressed. METHODS The authors retrospectively reviewed the cases of patients who underwent craniotomy for recurrent glioblastoma between 2005 and 2009, evaluating bevacizumab therapy/duration and healing complications (dehiscence, pseudomeningocele, CSF leak, and wound/bone infection). The Wilcoxon rank-sum test and Kruskal-Wallis test were used to compare continuous variables between groups. The Fisher exact test was used to assess for an association between categorical variables, including the comparison of wound-healing complication rates. Logistic regression models were used to estimate odds ratios of wound-healing complications while adjusting for baseline variables. RESULTS Two hundred nine patients underwent a second craniotomy (161 patients) or third craniotomy (48 patients) for recurrent glioblastoma. Twenty-six individuals (12%) developed wound-healing complications. One hundred sixty-eight patients received no bevacizumab, 23 received preoperative bevacizumab, and 18 received postoperative bevacizumab. Significantly more patients receiving preoperative bevacizumab developed healing complications (35%) than non-bevacizumab-treated patients (10.0%, p = 0.004). Postoperative bevacizumab was associated with 6% impaired healing, not significantly different from non-bevacizumab-treated controls (p = 1.0). Preoperative bevacizumab treatment duration (weeks) did not influence healing (OR 0.98, p = 0.55). More healing complications occurred in patients receiving preoperative bevacizumab than in non-bevacizumab-treated controls before the third craniotomy (44% vs 9%, p = 0.03). CONCLUSIONS Although subject to the limitations of a retrospective study, we demonstrate that preoperative bevacizumab treatment resulted in impaired healing after a second and third craniotomy, compared with minimal effect of postoperative bevacizumab. This effect is more striking for the third craniotomy and for a shorter delay between bevacizumab and surgery. These complications should be acknowledged as increased bevacizumab use results in more post-bevacizumab-treated patients in whom surgery for recurrent glioblastoma is considered. Based on these results, the authors recommend performing repeated craniotomy more than 28 days after last administered dose of bevacizumab whenever possible.

Multiinstitutional validation of the University of California at San Francisco low-grade glioma prognostic scoring system: Clinical article

OBJECT Medical and surgical management of low-grade gliomas (LGGs) is complicated by a highly variable clinical course. The authors recently developed a preoperative scoring system to prognosticate outcomes of progression and survival in a cohort of patients treated at a single institution (University of California, San Francisco [UCSF]). The objective of this study was to validate the scoring system in a large patient group drawn from multiple external institutions. METHODS Clinical data from 3 outside institutions (University of Utah, Toronto Western Hospital, and University of California, Los Angeles) were collected for 256 patients (external validation set). Patients were assigned a prognostic score based upon the sum of points assigned to the presence of each of the 4 following factors: 1) location of tumor in presumed eloquent cortex, 2) Karnofsky Performance Scale (KPS) Score <or= 80, 3) age > 50 years, and 4) maximum diameter > 4 cm. A chi-square analysis was used to analyze categorical differences between the institutions; Cox proportional hazard modeling was used to confirm that the individual factors were associated with shorter overall survival (OS) and progression-free survival (PFS); and Kaplan-Meier curves estimated OS and PFS for the score groups. Differences between score groups were analyzed by the log-rank test. RESULTS The median OS duration was 120 months, and there was no significant difference in survival between the institutions. Cox proportional hazard modeling confirmed that the 4 components of the UCSF Low-Grade Glioma Scoring System were associated with lower OS in the external validation set; presumed eloquent location (hazard ratio [HR] 2.04, 95% CI 1.28-2.56), KPS score <or= 80 (HR 5.88, 95% CI 2.44-13.7), age > 50 years (HR 1.82, 95% CI 1.02-3.23), and maximum tumor diameter > 4 cm (HR 2.63, 95% CI 1.58-4.35). The stratification of patients based on scores generated groups (0-4) with statistically different OS and PFS estimates (p < 0.0001, log-rank test). Lastly, the UCSF patient group (construction set) was combined with the external validation set (total of 537 patients) and analyzed for OS and PFS. For all patients, the 5-year survival probability was 0.79; the 5-year cumulative OS probabilities stratified by score group were: score of 0, 0.98; score of 1, 0.90; score of 2, 0.81; score of 3, 0.53; and score of 4, 0.46. CONCLUSIONS The UCSF scoring system accurately predicted OS and PFS in an external large, multiinstitutional population of patients with LGGs. The strengths of this system include ease of use and ability to be applied preoperatively, with the eventual goal of aiding in the design of individualized treatment plans for patients with LGG at diagnosis.

Immunocompetent murine models for the study of glioblastoma immunotherapy

Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches.

Neurosurgical management and prognosis of patients with glioblastoma that progresses during bevacizumab treatment.

BACKGROUND: The management and prognosis of glioblastoma patients after Stupp protocol treatment and progression during bevacizumab (BV) treatment remain undefined. OBJECTIVE: We compared the morbidity and survival of patients whose glioblastomas progressed during BV treatment requiring craniotomy with those of patients not treated with BV. METHODS: We retrospectively reviewed patients who underwent craniotomy for recurrent glioblastoma from 2005 to 2009. Patients operated on for progression during BV (preoperative BV) were compared with patients receiving no BV or receiving BV after surgery (postoperative BV). Patients receiving BV preoperatively were compared with those patients whose gliobastoma progressed on BV treatment but were not operated on (no surgery). RESULTS: There were 23 preoperative BV patients, 135 no BV patients, 16 postoperative BV patients, and 25 no surgery patients. Patients receiving BV preoperatively had a worse postoperative overall survival rate (hazard ratio, 3.1; P < .001) and worse postoperative progression-free survival rate (hazard ratio, 3.4, P < .001) than patients not receiving BV. Patients receiving BV preoperatively had a higher perioperative morbidity rate (44%) than patients not receiving preoperative BV (21%) (P = 0.02). Survival after diagnosis was comparable between groups (86-93 weeks, P = .9), consistent with glioblastomas developing BV evasion being not intrinsically more aggressive, but possibly BV evasion conferring a uniquely poor prognosis. No surgery patients had a shorter overall survival after progression during BV treatment compared with preoperative BV patients (hazard ratio, 3.6, P < .001). CONCLUSION: Patients whose glioblastomas progress while receiving BV leading to craniotomy exhibit shorter postoperative survival and more perioperative morbidity than patients not treated with BV. Although there may be benefits to surgical debulking, the decision to pursue repeat surgery in patients in whom BV treatment failed must be balanced against the increased risk of perioperative complications.

Surgical Outcomes for Minimally Invasive vs Open Transforaminal Lumbar Interbody Fusion: An Updated Systematic Review and Meta-analysis.

BACKGROUND Minimally invasive transforaminal lumbar interbody fusion (TLIF)-or MI-TLIF-has been increasing in prevalence compared with open TLIF (O-TLIF) procedures. The use of MI-TLIF is an evolving technique with conflicting reports in the literature about outcomes. OBJECTIVE To investigate the impact of MI-TLIF in comparison with O-TLIF for early and late outcomes by using the Visual Analog Scale for back pain (VAS-back) and the Oswestry Disability Index (ODI). Secondary end points include blood loss, operative time, radiation exposure, length of stay, fusion rates, and complications between the 2 procedures. METHODS During August 2014, a systematic literature search was performed identifying 987 articles. Of these, 30 met inclusion criteria. A random-effects meta-analysis was performed by using both pooled and subset analyses based on study type. RESULTS Our meta-analysis demonstrated that MI-TLIF reduced blood loss (P < .001), length of stay (P < .001), and complications (P = .001) but increased radiation exposure (P < .001). No differences were found in fusion rate (P = .61) and operative time (P = .34). A decrease in late VAS-back scores was demonstrated for MI TLIF (P < .001), but no differences were found in early VAS-back, early ODI, and late ODI. CONCLUSION MI-TLIF is associated with reduced blood loss, decreased length of stay, decreased complication rates, and increased radiation exposure. The rates of fusion and operative time are similar between MI-TLIF and O-TLIF. Differences in long-term outcomes in MI-TLIF vs O-TLIF are inconclusive and require more research, particularly in the form of large, multi-institutional prospective randomized controlled trials. ABBREVIATIONS CI, confidence intervalMCID, minimal clinically important differenceMI-TLIF, minimally invasive transforaminal lumbar interbody fusionODI, Oswestry Disability IndexO-TLIF, open transforaminal lumbar interbody fusionVAS, Visual Analog Scale.

Treatment-related morbidity and the management of pediatric craniopharyngioma: a systematic review.

OBJECT Craniopharyngiomas are benign tumors but their close anatomical relationship with critical neurological, endocrine, and vascular structures makes gross-total resection (GTR) with minimal morbidity difficult to achieve. Currently, there is controversy regarding the extent, timing, and modality of treatment for pediatric craniopharyngioma. METHODS The authors performed a systematic review of the published literature on pediatric craniopharyngioma to determine patterns of clinical practice and the reported outcomes of standard treatment strategies. This yielded 109 studies, which contained data describing extent of resection for a total of 531 patients. Differences in outcome were examined based upon extent of resection and choice of radiation treatment. RESULTS Gross-total resection was associated with increased rates of new endocrine dysfunction (OR 5.4, p < 0.001), panhypopituitarism (OR 7.8, p = 0.006), and new neurological deficits (OR 9.9, p = 0.03) compared with biopsy procedures. Subtotal resection (STR) was not associated with an increased rate of new neurological deficits. Gross-total was associated with increased rates of diabetes insipidus (OR 7.7, p = 0.05) compared with the combination of STR and radiotherapy (RT). The addition of RT to STR was associated with increased rates of panhypopituitarism (OR 9.9, p = 0.01) but otherwise similar rates of morbidities. CONCLUSIONS Although subject to the limitations of a literature review, this report suggests that GTR is associated with increased rates of endocrinopathies compared with STR + RT, and this should be considered when planning goals of surgery.

Tuberculoma of the central nervous system

Tuberculosis is among the oldest and most devastating infectious diseases worldwide. Nearly one third of the worlds population has active or latent disease, resulting in 1.5 million deaths annually. Central nervous system involvement, while rare, is the most severe form of tuberculosis. Manifestations include tuberculoma and tuberculous meningitis, with the majority of cases occurring in children and immunocompromised patients. Despite advancements in imaging and laboratory diagnostics, tuberculomas of the central nervous system remain a diagnostic challenge due to their insidious nature and nonspecific findings. On imaging studies tuberculous meningitis is characterized by diffuse basal enhancement, but tuberculomas may be indistinguishable from neoplasms. Early diagnosis is imperative, since clinical outcomes are largely dependent on timely treatment. Stereotactic biopsy with histopathological analysis can provide a definitive diagnosis, but is only recommended when non-invasive methods are inconclusive. Standard medical treatment includes rifampicin, isoniazid, pyrazinamide, and streptomycin or ethambutol. In cases of drug resistance, revision of the treatment regimen with second-line agents is recommended over the addition of a single drug to the first-line regimen. Advances in genomics have identified virulent strains of tuberculosis and are improving our understanding of host susceptibility. Neurosurgical referral is advised for patients with elevated intracranial pressure, seizures, or brain or spinal cord compression. This review synthesizes pertinent findings in the literature surrounding central nervous system tuberculoma in an effort to highlight recent advances in pathophysiology, diagnosis, and treatment.

A systematic review of treatment outcomes in pediatric patients with intracranial ependymomas

OBJECT Ependymoma is the third most common primary brain tumor in children. Tumors are classified according to the WHO pathological grading system. Prior studies have shown high levels of variability in patient outcomes within and across pathological grades. The authors reviewed the results from the published literature on intracranial ependymomas in children to describe clinical outcomes as they relate to treatment modality, associated mortality, and associated progression-free survival (PFS). METHODS A search of English language peer-reviewed articles describing patients 18 years of age or younger with intracranial ependymomas yielded data on 182 patients. These patients had undergone treatment for ependymoma with 1 of 5 modalities: 1) gross-total resection (GTR), 2) GTR as well as external beam radiation therapy (EBRT), 3) subtotal resection (STR), 4) STR as well as EBRT, or 5) radiosurgery. Mortality and outcome data were analyzed for time to tumor progression in patients treated with 1 of these 5 treatment modalities. RESULTS Of these 182 patients, 69% had supratentorial ependymomas and 31% presented with infratentorial lesions. Regardless of tumor location or pathological grade, STR was associated with the highest rates of mortality. In contrast, GTR was associated with the lowest rates of mortality, the best overall survival, and the longest PFS. Children with WHO Grade II ependymomas had lower mortality rates when treated more aggressively with GTR. However, patients with WHO Grade III tumors had slightly better survival outcomes after a less aggressive surgical debulking (STR+EBRT) when compared with GTR. CONCLUSIONS Mortality, PFS, and overall survival vary in pediatric patients with intracranial ependymomas. Pathological classification, tumor location, and method of treatment play a role in outcomes. In this study, GTR was associated with the best overall and PFS rates. Patients with WHO Grade II tumors had better overall survival after GTR+EBRT and better PFS after GTR alone. Patients with WHO Grade III tumors had better overall survival after STR+EBRT. Patients with infratentorial tumors had improved overall survival compared with those with supratentorial tumors. Progression-free survival was best in those patients with infratentorial tumors following STR+EBRT. Consideration of all of these factors is important when counseling families on treatment options.

Intraoperative neuromonitoring with MEPs and prediction of postoperative neurological deficits in patients undergoing surgery for cervical and cervicothoracic myelopathy

OBJECT The use of intraoperative neurophysiological monitoring (IONM) in surgical decompression surgery for myelopathy may assist the surgeon in taking corrective measures to reduce or prevent permanent neurological deficits. We evaluated the efficacy of IONM in cervical and cervicothoracic spondylotic myelopathy (CSM) cases. METHODS The authors retrospectively reviewed 140 cases involving patients who underwent surgery for CSM utilizing IONM during 2011 at the University of California, San Francisco. Data on preoperative clinical variables, intraoperative changes in transcranial motor evoked potentials (MEPs), and postoperative new neurological deficits were collected. Associations between categorical variables were analyzed with the Fisher exact test. RESULTS Of the 140 patients, 16 (11%) had significant intraoperative decreases in MEPs. In 8 of these cases, the MEP signal did not return to baseline values by the end of the operation. There were 8 (6%) postoperative deficits, of which 6 were C-5 palsies and 2 were paraparesis. Six of the patients with postoperative deficits had demonstrated persistent MEP signal change on IONM. There was a significant association between persistent MEP changes and postoperative deficits (p < 0.001). The sensitivity of intraoperative MEP monitoring was 75%, the specificity 98%, the positive predictive value 75%, and the negative predictive value 98%. Due to higher rates of false negatives, the sensitivity decreased to 60% in the subgroup of patients with vascular disease comorbidity. The sensitivity increased to 100% in elderly patients and in patients with preoperative motor deficits. The sensitivity and positive predictive value of deltoid and biceps MEP changes in predicting C-5 palsy were 67% and 67%, respectively. CONCLUSIONS The authors found a correlation between decreased intraoperative MEPs and postoperative new neurological deficits in patients with CSM. Sensitivity varies based on patient comorbidities, age, and preoperative neurological function. Monitoring of MEPs is a useful adjunct for CSM cases, and the authors have developed a checklist to standardize their responses to intraoperative MEP changes.