Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

Actual body weight dosing of temozolomide and overall survival in patients with glioblastoma.

BACKGROUND: Adult glioblastoma patients receiving standard radiation therapy and concurrent temozolomide chemotherapy have a median survival of 14.6 months. Based on the pivotal trial data by Stupp et al., temozolomide doses were calculated based on body surface area. However, no details regarding the weight used to calculate body surface area was included in the study. As a result, temozolomide doses have been variable across the province. METHODS: This retrospective chart review was conducted to determine the correlation between dose of first line temozolomide with overall survival. Patients between January 1st, 2009 and December 31st, 2014 who were newly diagnosed, pathology confirmed glioblastoma treated first line with temozolomide within Alberta Health Services were included in the study. Temozolomide doses above and below determined cut points were compared through the Kaplan-Meier method, then assessed using the log-rank test. RESULTS: A cut point of 97.8% of actual body weight calculated body surface area dosing was determined for concurrent phase temozolomide. At doses above this cut point, there was a statistically significant (p = 0.0158) increase of 0.3 years in median overall survival. As for toxicity concerns, there was a statistically significant increase in the proportion of temozolomide dose reductions due to toxicity in patients dosed above the cut point. CONCLUSION: Temozolomide doses at full actual body weight calculated body surface area dosing during the concurrent phase is required to achieve a similar median OS as seen in the pivotal trial by Stupp et al.

Population based analysis ependymoma patients in Alberta from 1975 to 2007.

BACKGROUND: Ependymomas are rare tumors of the central nervous system whose management is controversial. This population-based study of adults and children with ependymoma aims to (1) identify clinical and treatment-related factors that impact survival and (2) determine if postoperative radiotherapy (RT) can improve survival of patients with subtotal resection (STR) to levels similar to patients who had gross total resection (GTR). METHODS: This retrospective population-based study evaluated 158 patients with ependymoma diagnosed between 1975-2007 in Alberta, Canada. RESULTS: Younger patients (<7 years of age) were more likely to be diagnosed with grade III tumors compared with adults in whom grade I tumors were more common (p=0.003). Adults were more likely to have spinally located tumors compared to young children whose tumors were typically found in the brain. Overall, young children with ependymoma were more likely to die than older children or adults (p=0.001). An equivalent number of patients underwent GTR as compared with STR (48% vs 45%, respectively). Overall, older age, spinal tumor location, lower grade, and GTR were associated with improved progression free survival but only GTR was associated with significant improvement in overall survival. Median survival after STR and RT was 82 months compared with 122 months in patients who had GTR (p=0.0022). CONCLUSIONS: This is the first Canadian population-based analysis of patients with ependymoma including adults and children. Extent of resection appears to be the most important factor determining overall survival. Importantly, the addition of RT to patients initially treated with STR does not improve survival to levels similar to patients receiving GTR.

Phase II trial of concurrent sunitinib, temozolomide, and radiotherapy with adjuvant temozolomide for newly diagnosed MGMT unmethylated glioblastoma.

Background: The overall prognosis of glioblastoma (GBM) remains dismal, particularly for patients with unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In this phase II trial, we tested the combination of the antiangiogenic agent sunitinib with radiotherapy and temozolomide (TMZ) for newly diagnosed unmethylated MGMT GBM patients. Methods: We enrolled 37 patients with unmethylated MGMT promoter GBM, age 18-70, and KPS ≥70. Patients received 12.5 mg of daily sunitinib for 7 days, followed by concurrent chemoradiation plus 12.5 mg sunitinib, then adjuvant TMZ. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), safety, and neutrophil-to-lymphocyte ratio (NLR) biomarker. Results: At a median follow-up time of 15.3 months (range: 3.1-71.3 months), the median PFS was 7.15 months (95% CI: 5.4-10.5) and the 6-month PFS was 54.0%. Median OS was 15.0 months (95% CI: 13.8-19.4) and 2-year OS rate was 17.1%. Patients receiving >3 cycles of adjuvant TMZ, undergoing surgery at progression, and presenting a post-concurrent NLR ≤6 experienced a significant improved OS with hazard ratios of 0.197 (P = .001), 0.46 (P = .049), and 0.38 (P = .021), respectively, on multivariable analysis. Age >65 years predicted for worse OS with hazard ratio of 3.92 (P = .037). Grade ≥3 thrombocytopenia occurred in 22.9%, grade ≥3 neutropenia in 20%, and grade ≥3 thromboembolic events in 14.3% of patients. There were no grade 5 events. Conclusion: Our findings suggest a potential benefit of combining sunitinib with chemoradiation in newly diagnosed GBM patients with unmethylated MGMT status and provide a strong rationale to test this combination in future studies.

An analysis of image texture, tumor location, and MGMT promoter methylation in glioblastoma using magnetic resonance imaging.

In glioblastoma (GBM), promoter methylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT) is associated with benefit from chemotherapy. Correlations between MGMT promoter methylation and visually assessed imaging features on magnetic resonance (MR) have been reported suggesting that noninvasive detection of MGMT methylation status might be possible. Our study assessed whether MGMT methylation status in GBM could be predicted using MR imaging. We conducted a retrospective analysis of MR images in patients with newly diagnosed GBM. Tumor texture was assessed by two methods. First, we analyzed texture by expert consensus describing the tumor borders, presence or absence of cysts, pattern of enhancement, and appearance of tumor signal in T2-weighted images. Then, we applied space-frequency texture analysis based on the S-transform. Tumor location within the brain was determined using automatized image registration and segmentation techniques. Their association with MGMT methylation was analyzed. We confirmed that ring enhancement assessed visually is significantly associated with unmethylated MGMT promoter status (P=0.006). Texture features on T2-weighted images assessed by the space-frequency analysis were significantly different between methylated and unmethylated cases (P<0.05). However, blinded classification of MGMT promoter methylation status reached an accuracy of only 71%. There were no significant differences in the locations of methylated and unmethylated GBM tumors. Our results provide further evidence that individual MR features are associated with MGMT methylation but better algorithms for predicting methylation status are needed. The relevance of this study lies on the application of novel techniques for the analysis of anatomical MR images of patients with GBM allowing the evaluation of subtleties not seen by an observer and facilitating the standardization of the methods, decreasing the potential for interobserver bias.

Systematic review of the clinical spectrum of CASPR2 antibody syndrome.

BACKGROUND: Contactin-associated protein-like 2 (CASPR2) autoantibody disease has a variable clinical phenotype. We present a case report and performed a systematic review of the literature to summarize: (1) the clinical phenotype of patients with CASPR2 antibodies, (2) the findings in neurological investigations, and (3) the associated neuroimaging findings. METHODS: A chart review was performed for the case report. A systematic review of the medical literature was performed from first available to June 13, 2018. Abstracts were screened, and full-text peer-reviewed publications for novel patients with CASPR2 positivity in serum or cerebrospinal fluid (CSF) were included. Selected publications were reviewed, and relevant information was collated. Data were analyzed to determine overall frequency for demographic information, clinical presentations, and investigation findings. RESULTS: Our patient was a previously healthy 61-year-old male with both serum and CSF CASPR2 antibodies who presented with limbic encephalitis and refractory epilepsy. He was successfully treated with immunosuppression. For our systematic review, we identified 667 patients from 106 studies. Sixty-nine percent were male. Median age was 54 years (IQR 39-65.5). Median disease duration was 12 months (IQR 5.6-20). Reported overall clinical syndromes were: autoimmune encephalitis [69/134 (51.5%)], limbic encephalitis [106/274 (38.7%)], peripheral nerve hyperexcitability [72/191 (37.7%)], Morvan syndrome [57/251 (22.7%)], and cerebellar syndrome [24/163 (14.7%)]. Patients had positive serum [642/642 (100%)] and CSF [87/173 (50.3%)] CASPR2 antibodies. MRI was reported as abnormal in 159/299 patients (53.1%), and the most common abnormalities were encephalitis or T2 hyperintensities in the medial temporal lobes, or hippocampal atrophy, mesial temporal sclerosis, or hippocampal sclerosis. FDG-PET was abnormal in 30/35 patients (85.7%), and the most common abnormality was temporomesial hypometabolism. The most commonly associated condition was myasthenia gravis (38 cases). Thymoma occurred in 76/348 patients (21.8%). Non-thymoma malignancies were uncommon [42/397 (10.6%)]. CONCLUSIONS: Most patients have autoimmune or limbic encephalitis and corresponding abnormalities on neuroimaging. Other presentations include peripheral nerve hyperexcitability or Morvan syndromes, cerebellar syndromes, behavioral and cognitive changes, and more rarely movement disorders. The most commonly associated malignancy was thymoma and suggests a role for thymoma screening in CASPR2-related diseases.

Population-based study of pseudoprogression after chemoradiotherapy in GBM.

INTRODUCTION: Chemoradiotherapy followed by monthly temozolomide (TMZ) is the standard of care for patients with glioblastoma multiforme (GBM). Case reports have identified GBM patients who experienced transient radiological deterioration after concurrent chemoradiotherapy which stabilized or resolved after additional cycles of adjuvant TMZ, a phenomenon known as radiographic pseudoprogression. Little is known about the natural history of radiographic pseudoprogression. METHODS: We retrospectively evaluated the incidence of radiographic pseudoprogression in a population-based cohort of GBM patients and determined its relationship with outcome and MGMT promoter methylation status. RESULTS: Out of 43 evaluable patients, 25 (58%) exhibited radiographic progression on the first MRI after concurrent treatment. Twenty of these went on to receive adjuvant TMZ, and subsequent investigation demonstrated radiographic pseudoprogression in 10 cases (50%). Median survival (MS) was better in patients with pseudoprogression (MS 14.5 months) compared to those with true radiologic progression (MS 9.1 months, p=0.025). The MS of patients with pseudoprogression was similar to those who stabilized/responded during concurrent treatment (p=0.31). Neither the extent of the initial resection nor dexamethasone dosing was associated with pseudoprogression. CONCLUSIONS: These data suggest that physicians should continue adjuvant TMZ in GBM patients when early MRI scans show evidence of progression following concurrent chemoradiotherapy, as up to 50% of these patients will experience radiologic stability or improvement in subsequent treatment cycles.

The worldwide incidence and prevalence of primary brain tumors: a systematic review and meta-analysis.

BACKGROUND: Primary brain tumors are a heterogeneous group of benign and malignant tumors arising from the brain parenchyma and its surrounding structures. The epidemiology of these tumors is poorly understood. The aim of our study is to systematically review the latest literature on the incidence and prevalence of primary brain tumors. METHODS: The systematic review and meta-analysis were conducted according to a predetermined protocol and established guidelines. Only studies reporting on data from 1985 onward were included. Articles were included if they met the following criteria: (i) original research, (ii) population based, (iii) reported an incidence or prevalence estimate of primary brain tumors. RESULTS: From the 53 eligible studies overall, 38 were included in the meta-analysis. A random-effects model found the overall incidence rate of all brain tumors to be 10.82 (95% CI: 8.63-13.56) per 100 000 person-years. The incidence proportion estimates were heterogeneous, even among the same tumor subtypes, and ranged from 0.051 per 100 000 (germ cell tumors) to 25.48 per 100 000 (all brain tumors). There were insufficient data to conduct a meta-analysis of the prevalence of primary brain tumors. CONCLUSIONS: There is a need for more accurate and comparable incidence and prevalence estimates of primary brain tumors across the world. A standardized approach to the study of the epidemiology of these tumors is needed to better understand the burden of brain tumors and the possible geographical variations in their incidence.

A feasibility study to assess the integration of a pharmacist into neurooncology clinic.

OBJECTIVE: A multidisciplinary approach is increasingly used in NeuroOncology clinics. Although this model has several advantages, patients report feeling overwhelmed by the complexity of their treatment protocol and staff feel rushed because each provider must evaluate the patient within the limited clinic hours. We hypothesized that the presence of a pharmacist in clinic could address these concerns by (1) reviewing all treatment protocols and side-effect management with patients, (2) being available to address questions outside of clinic and (3) answering staff related medication questions. METHODS: The pharmacist met with consenting patients at the initial clinic visit and followed up by telephone two additional times. The pharmacist was available to answer questions outside of clinic hours. Surveys were developed and given to patient and staff to evaluate their experience. RESULTS: Over 4 months, 13 patients were enrolled. The pharmacist interacted with each patient an average of 9 times with 55% of interactions occurring outside scheduled visits and two-thirds of pharmacist interventions directly involving patient care. A total of 85% of patients and staff responded to the evaluation survey and 90% of respondents indicated that the pharmacist should remain part of the NeuroOncology team. Patients reported less stress related to their treatment and clinical staff experienced improved clinical efficiency directly as a result of the presence of the pharmacist. CONCLUSION: Based on these results, a clinical pharmacist should become a permanent member of the outpatient NeuroOncology clinic.

Predicting MGMT methylation status of glioblastomas from MRI texture.

In glioblastoma (GBM), promoter methylation of the DNA repair gene MGMT is associated with benefit from chemotherapy. Because MGMT promoter methylation status can not be determined in all cases, a surrogate for the methylation status would be a useful clinical tool. Correlation between methylation status and magnetic resonance imaging features has been reported suggesting that non-invasive MGMT promoter methylation status detection is possible. In this work, a retrospective analysis of T2, FLAIR and T1-post contrast MR images in patients with newly diagnosed GBM is performed using L1-regularized neural networks. Tumor texture, assessed quantitatively was utilized for predicting the MGMT promoter methylation status of a GBM in 59 patients. The texture features were extracted using a space-frequency texture analysis based on the S-transform and utilized by a neural network to predict the methylation status of a GBM. Blinded classification of MGMT promoter methylation status reached an average accuracy of 87.7%, indicating that the proposed technique is accurate enough for clinical use.

Methylation status of MGMT gene promoter in meningiomas.

Meningiomas are usually cured by surgical resection. However, approximately 10% are characterized by more aggressive clinical behavior and higher risk of recurrence. Typically, recurrent meningiomas require further surgical resection followed, in some cases, by radiotherapy. To date, no chemotherapeutic agent has proven to be effective in either preventing or treating recurrence. The alkylating chemotherapeutic agent, Temozolomide (TMZ) has shown to increase overall survival in patients with glioblastoma (GBM) but its effectiveness for other types of brain tumor is less known. The clinical benefit of TMZ seems to be limited to those GBM tumors with promoter methylation of the MGMT gene. In this study, we assessed if a biologic rationale exists to support the use of TMZ as a treatment for meningiomas by assessing the MGMT promoter methylation status in these tumors using methylation specific PCR. We investigated the MGMT promoter methylation status in 36 tumors (32 newly diagnosed; 4 recurrent). Histologically, the majority were grade I. Patients were primarily female (64%) with a mean age of 52. None of the meningiomas in our series showed MGMT gene promoter methylation. Based on these data, we conclude that there is no biological rational to suggest that TMZ might have significant anti-meningioma activity.

An analysis of image texture, tumor location, and MGMT promoter methylation in glioblastoma using magnetic resonance imaging

In glioblastoma (GBM), promoter methylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT) is associated with benefit from chemotherapy. Correlations between MGMT promoter methylation and visually assessed imaging features on magnetic resonance (MR) have been reported suggesting that noninvasive detection of MGMT methylation status might be possible. Our study assessed whether MGMT methylation status in GBM could be predicted using MR imaging. We conducted a retrospective analysis of MR images in patients with newly diagnosed GBM. Tumor texture was assessed by two methods. First, we analyzed texture by expert consensus describing the tumor borders, presence or absence of cysts, pattern of enhancement, and appearance of tumor signal in T2-weighted images. Then, we applied space-frequency texture analysis based on the S-transform. Tumor location within the brain was determined using automatized image registration and segmentation techniques. Their association with MGMT methylation was analyzed. We confirmed that ring enhancement assessed visually is significantly associated with unmethylated MGMT promoter status (P=0.006). Texture features on T2-weighted images assessed by the space-frequency analysis were significantly different between methylated and unmethylated cases (P<0.05). However, blinded classification of MGMT promoter methylation status reached an accuracy of only 71%. There were no significant differences in the locations of methylated and unmethylated GBM tumors. Our results provide further evidence that individual MR features are associated with MGMT methylation but better algorithms for predicting methylation status are needed. The relevance of this study lies on the application of novel techniques for the analysis of anatomical MR images of patients with GBM allowing the evaluation of subtleties not seen by an observer and facilitating the standardization of the methods, decreasing the potential for interobserver bias(AU)

Predicting MGMT methylation status of glioblastomas from MRI texture

In glioblastoma (GBM), promoter methylation of the DNA repair gene MGMT is associated with benefit from chemotherapy. Because MGMT promoter methylation status can not be determined in all cases, a surrogate for the methylation status would be a useful clinical tool. Correlation between methylation status and magnetic resonance imaging features has been reported suggesting that non-invasive MGMT promoter methylation status detection is possible. In this work, a retrospective analysis of T2, FLAIR and T1-post contrast MR images in patients with newly diagnosed GBM is performed using L1-regularized neural networks. Tumor texture, assessed quantitatively was utilized for predicting the MGMT promoter methylation status of a GBM in 59 patients. The texture features were extracted using a space-frequency texture analysis based on the S-transform and utilized by a neural network to predict the methylation status of a GBM. Blinded classification of MGMT promoter methylation status reached an average accuracy of 87.7%, indicating that the proposed technique is accurate enough for clinical use(AU)

A feasibility study to assess the integration of a pharmacist into neurooncology clinic

OBJECTIVE:A multidisciplinary approach is increasingly used in NeuroOncology clinics. Although this model has several advantages, patients report feeling overwhelmed by the complexity of their treatment protocol and staff feel rushed because each provider must evaluate the patient within the limited clinic hours. We hypothesized that the presence of a pharmacist in clinic could address these concerns by (1) reviewing all treatment protocols and side-effect management with patients, (2) being available to address questions outside of clinic and (3) answering staff related medication questions.METHODS:The pharmacist met with consenting patients at the initial clinic visit and followed up by telephone two additional times. The pharmacist was available to answer questions outside of clinic hours. Surveys were developed and given to patient and staff to evaluate their experience.RESULTS:Over 4 months, 13 patients were enrolled. The pharmacist interacted with each patient an average of 9 times with 55% of interactions occurring outside scheduled visits and two-thirds of pharmacist interventions directly involving patient care. A total of 85% of patients and staff responded to the evaluation survey and 90% of respondents indicated that the pharmacist should remain part of the NeuroOncology team. Patients reported less stress related to their treatment and clinical staff experienced improved clinical efficiency directly as a result of the presence of the pharmacist.CONCLUSION:Based on these results, a clinical pharmacist should become a permanent member of the outpatient NeuroOncology clinic(AU)

Population-based study of pseudoprogression after chemoradiotherapy in GBM

INTRODUCTION:Chemoradiotherapy followed by monthly temozolomide (TMZ) is the standard of care for patients with glioblastoma multiforme (GBM). Case reports have identified GBM patients who experienced transient radiological deterioration after concurrent chemoradiotherapy which stabilized or resolved after additional cycles of adjuvant TMZ, a phenomenon known as radiographic pseudoprogression. Little is known about the natural history of radiographic pseudoprogression.METHODS:We retrospectively evaluated the incidence of radiographic pseudoprogression in a population-based cohort of GBM patients and determined its relationship with outcome and MGMT promoter methylation status.RESULTS:Out of 43 evaluable patients, 25 (58%) exhibited radiographic progression on the first MRI after concurrent treatment. Twenty of these went on to receive adjuvant TMZ, and subsequent investigation demonstrated radiographic pseudoprogression in 10 cases (50%). Median survival (MS) was better in patients with pseudoprogression (MS 14.5 months) compared to those with true radiologic progression (MS 9.1 months, p=0.025). The MS of patients with pseudoprogression was similar to those who stabilized/responded during concurrent treatment (p=0.31). Neither the extent of the initial resection nor dexamethasone dosing was associated with pseudoprogression.CONCLUSIONS:These data suggest that physicians should continue adjuvant TMZ in GBM patients when early MRI scans show evidence of progression following concurrent chemoradiotherapy, as up to 50% of these patients will experience radiologic stability or improvement in subsequent treatment cycles(AU)

Methylation status of MGMT gene promoter in meningiomas

Meningiomas are usually cured by surgical resection. However, approximately 10% are characterized by more aggressive clinical behavior and higher risk of recurrence. Typically, recurrent meningiomas require further surgical resection followed, in some cases, by radiotherapy. To date, no chemotherapeutic agent has proven to be effective in either preventing or treating recurrence. The alkylating chemotherapeutic agent, Temozolomide (TMZ) has shown to increase overall survival in patients with glioblastoma (GBM) but its effectiveness for other types of brain tumor is less known. The clinical benefit of TMZ seems to be limited to those GBM tumors with promoter methylation of the MGMT gene. In this study, we assessed if a biologic rationale exists to support the use of TMZ as a treatment for meningiomas by assessing the MGMT promoter methylation status in these tumors using methylation specific PCR. We investigated the MGMT promoter methylation status in 36 tumors (32 newly diagnosed; 4 recurrent). Histologically, the majority were grade I. Patients were primarily female (64%) with a mean age of 52. None of the meningiomas in our series showed MGMT gene promoter methylation. Based on these data, we conclude that there is no biological rational to suggest that TMZ might have significant anti-meningioma activity(AU)