Sudhakar Tummala

Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma

BACKGROUND Ipilimumab is a novel FDA-approved recombinant human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 and has been used to treat patients with metastatic melanoma. Immune-related neurological adverse effects include inflammatory myopathy, aseptic meningitis, posterior reversible encephalopathy syndrome, Guillain-Barré syndrome, myasthenia gravis-type syndrome, sensorimotor neuropathy, and inflammatory enteric neuropathy. To date, there is no report for ipilimumab-induced chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis (TM), or concurrent myositis and myasthenia gravis-type syndrome. Our objective is to raise early recognition of atypical neurological adverse events and to share our therapeutic approach. METHODS We report 3 cases of metastatic melanoma treated with ipilimumab in which the patients developed CIDP, TM, and concurrent myositis and myasthenia gravis-type syndrome, respectively, at the MD Anderson Cancer Center between July 2012 and June 2013. Patients consented to release of medical information for publication/educational purposes. RESULTS Our 3 cases of metastatic melanoma treated with ipilimumab developed CIDP, TM, and concurrent myositis and myasthenia gravis-type syndrome, respectively. The median time to onset of immune-related adverse events following ipilimumab treatment ranged from 1 to 2 weeks. Ipilimumab was discontinued due to the severe neurological symptoms. Plasmapheresis was initiated in the patients with CIDP and concurrent myositis and myasthenia gravis-type syndrome; high-dose intravenous steroids were given to the patient with TM, and significant clinical response was demonstrated. CONCLUSIONS Ipilimumab could induce a wide spectrum of neurological adverse effects. Our findings support the standard treatment of withholding or discontinuing ipilimumab. Plasmapheresis or high-dose intravenous steroids may be considered as the initial choice of treatment for severe ipilimumab-related neurological adverse events. Improvement of neurological symptoms may be seen within 2 weeks.

Chimeric antigen receptor T-cell therapy — assessment and management of toxicities

Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

Intraoperative magnetic resonance imaging-guided tractography with integrated monopolar subcortical functional mapping for resection of brain tumors. Clinical article.

OBJECT The object of this study was to describe the utility and safety of using a single probe for combined intraoperative navigation and subcortical mapping in an intraoperative MR (iMR) imaging environment during brain tumor resection. METHODS The authors retrospectively reviewed those patients who underwent resection in the iMR imaging environment, as well as functional electrophysiological monitoring with continuous motor evoked potential (MEP) and direct subcortical mapping combined with diffusion tensor imaging tractography. RESULTS As a navigational tool the monopolar probe used was safe and accurate. Positive subcortical fiber MEPs were obtained in 10 (83%) of the 12 cases. In 10 patients in whom subcortical MEPs were recorded, the mean stimulus intensity was 10.4 ± 5.2 mA and the mean distance from the probe tip to the corticospinal tract (CST) was 7.4 ± 4.5 mm. There was a trend toward worsening neurological deficits if the distance to the CST was short, and a small minimum stimulation threshold was recorded indicating close proximity of the CST to the resection margins. Gross-total resection (95%-100% tumor removal) was achieved in 11 cases (92%), whereas 1 patient (8%) had at least a 90% tumor resection. At the end of 3 months, 2 patients (17%) had persistent neurological deficits. CONCLUSIONS The monopolar probe can be safely implemented in an iMR imaging environment both for navigation and stimulation purposes during the resection of intrinsic brain tumors. In this study there was a trend toward worsening neurological deficits if the distance from the probe to the CST was short (< 5 mm) indicating close proximity of the resection cavity to the CST. This technology can be used in the iMR imaging environment as a surgical adjunct to minimize adverse neurological outcomes.

Subcortical injury is an independent predictor of worsening neurological deficits following awake craniotomy procedures.

BACKGROUND Tailored craniotomies for awake procedures limit cortical exposure. Recently we demonstrated that the identification of eloquent areas increased the risk of postoperative deficits. However, it was not clear whether the observed neurological deficits were caused by proximity of functional cortex to the tumor [cortical injury] or subcortical injury. OBJECTIVE We hypothesize that subcortical injury during tumor resection is an important predictor of postoperative neurological deficits compared to cortical injury. METHODS A retrospective review of 214 patients undergoing awake craniotomy was carried out in whom preoperative functional magnetic resonance imaging (fMRI) and cortical mapping (CM) were performed. A radiologist blinded to the clinical data reviewed and graded the postoperative changes on diffusion-weighted MR-imaging (DWI). RESULTS Of the 40 cases who developed new intraoperative neurological deficit, 36 (90%) occurred during subcortical dissection, 3 (7.5%) during both subcortical and cortical dissection, and 1 (2.5%) during cortical dissection. Neurological dysfunction acquired during subcortical dissection was an independent predictor of postoperative deficits both in the immediate postoperative period (P < .001) and at the 3-month follow-up (P < .001). Significant DWI restriction in the subcortical white matter was predictive of neurological deficits both immediately and at 3 months, P = .011 and P < .001, respectively. New or worsening deficits were seen in 38% of patients; however, at 3 months 13% had a mild persistent neurological deficit. CONCLUSION Subcortical injury with significant DWI changes result in postoperative neurological decline despite our efforts to preserve cortical areas of function. This underscores the importance of preserving subcortical fiber tracts during awake craniotomy procedures.

Awake craniotomy for gliomas in a high-field intraoperative magnetic resonance imaging suite: analysis of 42 cases

OBJECTIVES The object of this study was to describe the experience of combining awake craniotomy techniques with high-field (1.5 T) intraoperative MRI (iMRI) for tumors adjacent to eloquent cortex. METHODS From a prospective database the authors obtained and evaluated the records of all patients who had undergone awake craniotomy procedures with cortical and subcortical mapping in the iMRI suite. The integration of these two modalities was assessed with respect to safety, operative times, workflow, extent of resection (EOR), and neurological outcome. RESULTS Between February 2010 and December 2011, 42 awake craniotomy procedures using iMRI were performed in 41 patients for the removal of intraaxial tumors. There were 31 left-sided and 11 right-sided tumors. In half of the cases (21 [50%] of 42), the patient was kept awake for both motor and speech mapping. The mean duration of surgery overall was 7.3 hours (range 4.0-13.9 hours). The median EOR overall was 90%, and gross-total resection (EOR ≥ 95%) was achieved in 17 cases (40.5%). After viewing the first MR images after initial resection, further resection was performed in 17 cases (40.5%); the mean EOR in these cases increased from 56% to 67% after further resection. No deficits were observed preoperatively in 33 cases (78.5%), and worsening neurological deficits were noted immediately after surgery in 11 cases (26.2%). At 1 month after surgery, however, worsened neurological function was observed in only 1 case (2.3%). CONCLUSIONS There was a learning curve with regard to patient positioning and setup times, although it did not adversely affect patient outcomes. Awake craniotomy can be safely performed in a high-field (1.5 T) iMRI suite to maximize tumor resection in eloquent brain areas with an acceptable morbidity profile at 1 month.

Preoperative imaging to predict intraoperative changes in tumor-to-corticospinal tract distance: An analysis of 45 cases using high-field intraoperative magnetic resonance imaging

BACKGROUND Preoperative diffusion tensor imaging (DTI) is used to demonstrate corticospinal tract (CST) position. Intraoperative brain shifts may limit preoperative DTI value, and studies characterizing such shifts are lacking. OBJECTIVE To examine tumor characteristics that could predict intraoperative shift in tumor-to-CST distance using high-field intraoperative magnetic resonance imaging. METHODS We retrospectively evaluated preoperative and intraoperative DTIs, tumor pathology, and imaging characteristics of patients who underwent resection of an intra-axial tumor adjacent to the CST to identify covariates that significantly affected shift in tumor-to-CST distance. For validation, we analyzed data from a separate, 20-patient cohort. RESULTS In the first cohort, the mean intraoperative shift in the tumor-to-CST distance was 3.18 ± 3.58 mm. The mean shift for the 20 patients with contrast and the 5 patients with non-contrast-enhancing tumors was 3.93 ± 3.64 and 0.18 ± 0.18 mm, respectively (P < .001). No association was found between intraoperative shift in tumor-to-CST distance and tumor pathology, tumor volume, edema volume, preoperative tumor-to-CST distance, or extent of resection. According to receiver-operating characteristic analysis, nonenhancement predicted a tumor-to-CST distance shift of ≤ 0.5 mm, with a sensitivity of 100% and a specificity of 75%. We validated these findings using the second cohort. CONCLUSION For nonenhancing intra-axial tumors, preoperative DTI is a reliable method for assessing intraoperative tumor-to-CST distance because of minimal intraoperative shift, a finding that is important in the interpretation of subcortical motor evoked potential to maximize extent of resection and to preserve motor function. In resection of intra-axial enhancing tumors, intraoperative imaging studies are crucial to compensate for brain shift.

Utilization of Intraoperative Motor Mapping in Glioma Surgery with High-Field Intraoperative Magnetic Resonance Imaging

Background/Aims: The main goal of glioma surgery is to maximize tumor resection while minimizing neurologic injury. The use of high-field intraoperative magnetic resonance imaging (iMRI) and intraoperative cortical mapping (IOM) together enable the surgeon to increase the extent of tumor resection (EOR) and preserve the neurological function. However, there is insufficient evidence to validate the use of IOM with high-field iMRI. Methods: To study the safety and utility of IOM in a high-field (1.5 T) iMRI suite, we retrospectively studied 38 patients with glioma who underwent surgery with IOM in the iMRI suite. Results: We were able to use IOM in the iMRI suite without any adverse side effects or difficulty. Median EOR was 97%. A new or worsening motor deficit occurred in 14 (37%) patients immediately after the surgery, with 3 (8%) patients exhibiting persistent deficit at 6 months. Conclusion: Our findings suggest that IOM can be successfully used in a high-field MRI environment and can help minimize postoperative motor deficit with a higher EOR.

Simultaneous use of functional tractography, neuronavigation-integrated subcortical white matter stimulation and intraoperative magnetic resonance imaging in glioma surgery: Technical note

The importance of preserving function during glioma surgery cannot be overemphasized. There are a number of techniques utilized including functional MRI, direct electrophysiological monitoring and functional neuronavigation to maximize and safely resect gliomas. The intraoperative MRI is an extremely valuable tool and adds to the neurosurgeon’s armamentarium. Combining these technologies will enhance the safety and efficacy of glioma surgery. This is the first report in the literature where we successfully combine both functional neuronavigation and subcortical stimulation, using a single probe to safely resect a recurrent glioblastoma.

Ifosfamide related encephalopathy: The need for a timely EEG evaluation

BACKGROUND Ifosfamide is an alkylating agent useful in the treatment of a wide range of cancers including sarcomas, lymphoma, gynecologic and testicular cancers. Encephalopathy has been reported in 10-40% of patients receiving high-dose IV ifosfamide. OBJECTIVE To highlight the role of electroencephalogram (EEG) in the early detection and management of ifosfamide related encephalopathy. METHODS Retrospective chart review including clinical data and EEG recordings was done on five patients, admitted to MD Anderson Cancer Center between years 2009 and 2012, who developed ifosfamide related acute encephalopathy. RESULTS All five patients experienced symptoms of encephalopathy soon after (within 12 h-2 days) receiving ifosfamide. Two patients developed generalized convulsions while one patient developed continuous non-convulsive status epilepticus (NCSE) that required ICU admission and intubation. Initial EEG showed epileptiform discharges in three patients; run of triphasic waves in one patient and moderate degree diffuse generalized slowing. Mixed pattern with the presence of both sharps and triphasic waves were also noted. Repeat EEGs within 24_h of symptom onset showed marked improvement that was correlated with clinical improvement. CONCLUSIONS Severity of ifosfamide related encephalopathy correlates with EEG changes. We suggest a timely EEG evaluation for patients receiving ifosfamide who develop features of encephalopathy.

Intraoperative neurophysiologic monitoring with Hoffmann reflex during thoracic spine surgery

The aim of this study was examine the role of Hoffmann reflex (H-reflex) monitoring in identifying intraoperative spinal cord injury and predicting postoperative neurological outcome in patients undergoing thoracic spine surgery. Despite the physiologic basis for the use of H-reflex to monitor spinal motor pathways, there are only a few reports highlighting its application as an intraoperative neuromonitoring tool. We retrospectively reviewed the electronic medical records of 19 consecutive patients who underwent thoracic spine surgery for metastatic thoracic spinal tumors between 2011 and 2013 at the MD Anderson Cancer Center. H-waves and somatosensory evoked potentials (SSEP) were simultaneously monitored in our series consisting of four female and 15 male patients aged 10-71 years. In 10 of 19 patients, bilateral H-waves and SSEP were stable throughout the monitoring. Five of 19 patients had a <50% transient reduction in H-wave amplitude that later returned to baseline. SSEP were absent from baseline throughout surgery in two of 19 patients. In our series, neither general anesthesia nor low dose muscle relaxants interfered with the H-waves. At 3 and 6 month follow-ups, none of the patients exhibited new postoperative neurological deficits. Stable intraoperative H-waves are suggestive of preserved postoperative neurologic outcomes. Intraoperative H-reflex monitoring could be a reasonable alternative especially when motor evoked potentials are unattainable. Given its greater sensitivity to spinal cord ischemia, relatively low cost and ease of acquisition, H-reflex monitoring could be a useful adjunct in during thoracic spine surgeries.