Leptomeningeal Metastases in High-Grade Adult Glioma: Development, Diagnosis, Management, and Outcomes in a Series of 34 Patients

Leptomeningeal metastases (LM) in the setting of glioma have often been thought to carry a particularly poor prognosis. We sought to better characterize this phenomenon through a review of patients with glioma seen in our institution over the preceding 10 years. We focus here on 34 cases with LM due to grade III or IV glioma. Over the period in question we estimate a prevalence of almost 4% in those affected by grade IV tumors. Leptomeningeal spread was present at the time of initial diagnosis in 4 patients. In the others, LM occurred at the time of first progression of disease in 17. The median time to development of LM (excluding those where it was present at initial diagnosis) was 16.4 months (95% confidence interval (CI) 8.2-43.9). The median time to further progression of disease following LM was 4.9 months (95% CI 3.1- 6.9). 25 patients were known to have died at the time of writing. Thus median overall survival (OS) was 10.2 months (95% CI 8.8-14.7) following LM. At the time of diagnosis of LM, some form of treatment (chemotherapy and/or radiation vs. no treatment) increased OS (median 11.7 vs. 3.3 months, p\u3c0.001 by log-rank test). Use of radiation therapy (vs. no radiation) also increased OS, although the effect was more modest (7.8 vs. 16.8 months, p=0.07). Higher Karnofsky Performance Status (KPS) at the time of diagnosis of LM was associated with OS (p=0.007, median OS for KPS ‰¥90 19 months vs. 7.8 for KPS \u3c90). In a two-variable model incorporating the use any treatment (vs. none) and KPS, KPS tended to be a more significant predictor of survival (p=0.22 vs. p=0.06 by likelihood-ratio test). This was also true for radiation (vs. none) and KPS (p=0.27 vs. p=0.02). No significant benefit could be demonstrated for the use of chemotherapy considered alone, either systemic or intrathecal. It should be noted that 4 of 9 patients receiving intrathecal chemotherapy had a ventriculoperitoneal shunt in place during these injections, which may have reduced its effectiveness

Biopsy vs. Extensive Resection for First Recurrence of Glioblastoma: Is a Prospective Clinical Trial Warranted?

Background: Glioblastoma is an aggressive and almost universally fatal tumor. The prognosis at the time of recurrence has generally been poor, with overall survival typically in the range of 4-40 weeks. The merits of surgical resection (vs. open biopsy, to confirm recurrence via histology) in addition to conventional adjuvant chemotherapy have been the subject of longstanding debate. We wondered whether it would possible to conduct a trial at our institution to settle this question definitively with Class I evidence. Results: Initially, we had hoped to conduct a randomized, unblinded prospective clinical trial. However on closer inspection it appeared that such an undertaking would pose significant practical challenges. Thus we present our protocol in draft form. In keeping with recommended outcomes for these tumors, the primary endpoint would be median progression free survival. Secondary end points would be: median overall survival (mOS, from time of recurrence) and change in Karnofsky Performance Status over time. Patients would be eligible at the time of first recurrence if they had received conventional treatment until that point and at least 1 month had elapsed since the time of radiation. All patients would be considered potentially eligible for enrollment (unless the decision regarding resection was already clear-cut in view of other factors). Using Cox\u27s proportional hazards model, we estimate that at least 456 patients would be necessary to demonstrate an increase in the hazard ratio to 1.3 for those undergoing biopsy alone. This magnitude of benefit is estimated based on a review of retrospective studies. Discussion: If restricted to our Institution alone, which sees approximately 100-150 new cases of glioblastoma each year, a trial of this nature would be likely to take around 10 years. Furthermore, there may be significant reluctance on the part of patients and physicians to participate. There is also the opportunity cost of excluding patients from other trials to consider. We recognize that the estimate of the magnitude of effect may be conservative. As things stand, we feel that multi-institutional collaboration would almost certainly be required for an undertaking of this kind

Langerhans Cell Histiocytosis in an Adult With Involvement of the Calvarium Cerebral Cortex and Brainstem: Discussion of Pathophysiology and Rationale for the use of Intravenous Immune Globulin

We report a case of Langerhans cell histiocytosis in a 64-year-old male who presented with symptoms and signs of brain involvement, including seizures and hypopituitarism. The diagnosis was confirmed with a biopsy of a lytic skull lesion. The disease affecting the bone showed no sign of progression following a short course of cladribine. Signs of temporal lobe involvement led to an additional biopsy, which showed signs of nonspecific neurodegeneration and which triggered status epilepticus. Lesions noted in the brainstem were typical for the paraneoplastic inflammation reported in this condition. These lesions improved after treatment with cladribine. They remained stable while on treatment with intravenous immune globulin

Immune Modulation in the Treatment of Amyotrophic Lateral Sclerosis: A Review of Clinical Trials

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Though many molecular and genetic causes are thought to serve as predisposing or disease propagating factors, the underlying pathogenesis of the disease is not known. Recent discoveries have demonstrated the presence of inflammation propagating substrates in the central nervous system of patients afflicted with ALS. Over the past decade, this hypothesis has incited an effort to better understand the role of the immune system in ALS and has led to the trial of several potential immune-modulating therapies. Here, we briefly review advances in the role of such therapies. The clinical trials discussed here are currently ongoing or have been concluded at the time of writing

Atypical Teratoid Rhabdoid Tumor: two Case Reports and an Analysis of Adult Cases With Implications for Pathophysiology and Treatment

We present the first quantitative analysis of atypical teratoid rhabdoid tumors (ATRT) in adults, including two patients from our own institutions. These are of interest as one occurred during pregnancy and one is a long-term survivor. Our review of pathological findings of 50 reported cases of adult ATRT leads us to propose a solely ectodermal origin for the tumor and that epithelial-mesenchymal transition (EMT) is a defining feature. Thus, the term ATRT may be misleading. Our review of clinical findings shows that ATRT tends to originate in mid-line structures adjacent to the CSF, leading to a high rate of leptomeningeal dissemination. Thus, we hypothesize that residual undifferentiated ectoderm in the circumventricular organs, particularly the pituitary and pineal glands, is the most common origin for these tumors. We note that if growth is not arrested soon after diagnosis, or after the first relapse/progression, death is almost universal. While typically rapidly fatal (as in our first case), long-term remission is possible (as in our second). Significant predictors of prognosis were the extent of resection and the use of chemotherapy. Glial differentiation (GFAP staining) was strongly associated with leptomeningeal metastases (chi-squared p = 0.02) and both predicted markedly worse outcomes. Clinical trials including adults are rare. ATRT is primarily a disease of infancy and radiotherapy is generally avoided in those aged less than 3 years old. Treatment options in adults differ from infants in that cranio-spinal irradiation is a viable adjunct to systemic chemotherapy in the adult population. Given the grave prognosis, this combined approach appears reasonable. As effective chemotherapy is likely to cause myelosuppression, we recommend that stem-cell rescue be available locally

Transient Coma Due to Epidural Anesthesia: the Role of Loss of Sensory Input

Objective: Unknown ethiology Background: Epidural anesthesia is the most commonly used method of pain relief during labor in the USA. It is not classically associated with alterations in level of alertness. Coma during the procedure is rare, with a reported incidence of 0.1€“0.3%. Case Report: An otherwise healthy patient experienced almost complete loss of brainstem function following routine epidural anesthesia during delivery. The episode lasted for less than 3 hours and the patient made a full recovery. To our knowledge, this is the most detailed clinical observation to date of this condition. Conclusions: Clinicians should be aware of this rare and potentially serious complication of epidural anesthesia. The case highlights the need for sensory input to maintain alertness through the activity of the ascending reticular activating system

Langerhans Cell Histiocytosis in an Adult with Involvement of the Calvarium, Cerebral Cortex and Brainstem: Discussion of Pathophysiology and Rationale for the Use of Intravenous Immune Globulin

We report a case of Langerhans cell histiocytosis in a 64-year-old male who presented with symptoms and signs of brain involvement, including seizures and hypopituitarism. The diagnosis was confirmed with a biopsy of a lytic skull lesion. The disease affecting the bone showed no sign of progression following a short course of cladribine. Signs of temporal lobe involvement led to an additional biopsy, which showed signs of nonspecific neurodegeneration and which triggered status epilepticus. Lesions noted in the brainstem were typical for the paraneoplastic inflammation reported in this condition. These lesions improved after treatment with cladribine. They remained stable while on treatment with intravenous immune globulin

Immune Modulation in the Treatment of Amyotrophic Lateral Sclerosis: A Review of Clinical Trials

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Though many molecular and genetic causes are thought to serve as predisposing or disease propagating factors, the underlying pathogenesis of the disease is not known. Recent discoveries have demonstrated the presence of inflammation propagating substrates in the central nervous system of patients afflicted with ALS. Over the past decade, this hypothesis has incited an effort to better understand the role of the immune system in ALS and has led to the trial of several potential immune-modulating therapies. Here, we briefly review advances in the role of such therapies. The clinical trials discussed here are currently ongoing or have been concluded at the time of writing