Christopher Dardis

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

Methods: 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. Results: Leptomeningeal spread was present at the time of initial diagnosis in 4 patients. Among 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). Twenty-five 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 < 0.001 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 <90). In a two-variable model incorporating the use any treatment (vs. none) and KPS, the latter 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 ventriculo-peritoneal shunt in place during these injections, which may have reduced its effectiveness. Conclusion: Overall, treatment appears to improve outcomes. We favor maximal treatment, as tolerated, particularly with a KPS of ≥70. Such treatment would typically include radiation to the maximum tolerated dose, concurrent, and adjuvant chemotherapy (preferably with an alkyating agent), in addition to intrathecal treatment.

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.

Acute motor axonal neuropathy in a patient with prolonged CD4 depletion due to HIV: a local variant of macrophage activation syndrome?

Acute inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome is well recognized as a presenting feature of human immunodeficiency virus (HIV) seroconversion and, to a lesser extent, as a complication of HIV infection, particularly immune reconstitution. Acute motor axonal neuropathy (AMAN) is much rarer in this setting. A case is presented of acute motor neuropathy, with features most consistent with AMAN in the setting of congenital HIV and prolonged non-compliance with antiretroviral treatment. The case throws new light on the pathogenesis of this condition. Macrophage activation is proposed as fundamental; the patient was predisposed by HIV as well as the use of granulocyte colony-stimulating factor and AMAN was then precipitated by a bacterial infection.

Whither thiotepa (for patients in the USA)

We wish to highlight the ongoing shortage of thiotepa in the USA so that our colleagues may plan ahead accordingly. We are not aware of similar shortages of this agent affecting other countries. In neuro-oncology, thiotepa is most often used for the treatment of leptomeningeal metastases. It is recommended for this indication in the most recently issued National Comprehensive Cancer Network (NCCN) Guidelines. In the Guidelines, it appears fourth in a list of nine, just below (liposomal) cytarabine and methotrexate [1]. Along with topotecan and etoposide, it is one of only three agents which is indicated by general use (e.g. as opposed to methotrexate where its use is specifically recommended for lymphoma/leukemia and for breast cancer). Like most of the agents on the list, its patent has expired. Thiotepa has been approved by the US Food and Drug Administration (FDA) for:

Abstract CT213: Clinical effects of a ketogenic diet on brain tumor patients: tumor growth and quality of life

Glioblastoma (GB) is the most malignant brain cancer, with few patients surviving beyond 2 years despite treatment including surgical resection, radiation, chemotherapy and new experimental therapies. Improvements in survival require the design of novel therapies that take advantage of phenotypic traits common in tumor cells. One such trait is aberrant metabolism - tumors rely heavily on glucose and glutamine as energy sources and are unable to use other sources of energy. We and others have suggested the exploitation of this through the use of the ketogenic diet (KD), a high fat, low carbohydrate and protein diet (4:1 fat:protein plus carbohydrate) that causes the body to shift metabolically from glucose to ketones as the primary source of energy. In addition to reducing available glucose, in vitro and in vivo preclinical studies have shown that increasing ketones appears to have additional anti-tumor effects, even in the presence of normal glucose levels. We and others have shown that the KD improves survival in mouse models of malignant brain tumors, and we have shown that it potentiates the effects of radiation and chemotherapy in vitro and in vivo. Anecdotal evidence and published case reports suggest that it may also have efficacy in human glioma patients, thus warranting further investigation in a clinical setting. Here, we report results to date from our ongoing, phase I/II single-arm clinical trial of this intervention (clinicaltrials.gov NCT02046187). Patients are eligible to enroll if they have newly diagnosed GB and at least a subtotal surgical resection. The KD is used in addition to standard care (radiation and temozolomide). It is already known to be safe and effective in the treatment of refractory epilepsy. Patients follow a 4:1 ketogenic diet during concurrent radiation and chemotherapy; they then change to a more moderate 1:1 diet during adjuvant chemotherapy. Blood glucose and ketone measurements are recorded daily, with target levels of glucose at ∼70ml/dl and ketones at ∼4mmol/l. To date, our preliminary study suggests that the KD is generally well tolerated and steroid use does not preclude the patient9s ability to reduce glucose levels below 80ml/ml. Overall health and therapy-related quality of life measurements decline from baseline to the end of RT as is typical for patients undergoing radiation therapy, but appears to recover back to baseline over time. This suggests that following the ketogenic diet probably does not adversely affect long-term quality of life. Additional patient followup data will be presented. Citation Format: Leonora Renda, Norissa Honea, Christopher Dardis, Lynn S. Ashby, Adrienne C. Scheck. Clinical effects of a ketogenic diet on brain tumor patients: tumor growth and quality of life. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT213. doi:10.1158/1538-7445.AM2015-CT213

Transient Coma Due To Epidural Anesthesia: The Role of Loss of Sensory Input

Patient: Female, 22 Final Diagnosis: Coma due to loss of sensory input Symptoms: Coma Medication: Lidocaine Clinical Procedure: Epidural Specialty: Anesthesiology 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.

A Bayesian approach to the analysis of clinical trial data using logistic regression: example from a randomized placebo-controlled crossover trial of propranolol for migraine prevention

Correspondence: Christopher Dardis Department of Neurology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA Tel +602 406 6262 Fax +602 406 6260 Email christopherdardis@gmail.com Abstract: Bayesian methods enable the “prior” (or informative) beliefs of an audience to be combined with the results of a clinical trial to arrive at a final “posterior” belief. This example concerns previously published data from a double-blind placebo-controlled trial of propranolol to reduce the number of episodes of migraine, where subjects were crossed-over after 3 months of treatment. The informative prior range was supplied by an educated audience (members of our Faculty of Neurology) who were given review papers on propranolol in migraine prophylaxis and placebo responses in migraine trials. We used logistic regression models to try to predict those whose symptoms improved (based on treatment or on the time period under consideration; ie, the first or second 3-month period, or based on both factors considered together). The posterior was generated using the Markov–Chain Monte–Carlo methods. For the original dataset, the Bayesian posteriors tended to be more tightly defined than those with no prior or minimally informative prior beliefs, thus yielding firmer conclusions in light of the trial. When compared with a larger dataset (which was generated from the original, but was arrived at by multiplying the number of observations by 10), the influence of prior beliefs was much less marked, but the posteriors did tend to be marginally more narrowly defined. This finding is in keeping with existing work on Bayesian methods, highlighting their value in aiding interpretation of trials with a small number of observations.

Inclusion Body Myositis: A Case Presenting with Respiratory Failure and Autopsy Findings Leading to the Hypothesis of a Paraneoplastic Cause

Patient: Female, 48 Final Diagnosis: Inclusion body myositis Symptoms: Shortness of breath • weakness Medication: — Clinical Procedure: Biopsy Specialty: Neurology Objective: Rare disease Background: Sporadic inclusion body myositis (IBM) is the most common acquired myopathy seen in adults aged over 50 years, with a prevalence estimated at between 1 and 70 per million. Weakness of the diaphragm with loss of vital capacity is almost universal in IBM. This is almost always asymptomatic. When respiratory complications occur, they are most often due to aspiration. Respiratory failure due to diaphragmatic weakness is exceptionally rare, particularly as the presenting symptom of the disease. It is not currently considered to be a paraneoplastic syndrome. Case Report: Our patient presented with hypercarbic respiratory failure. This is the first such reported case without signs of weakness elsewhere of which we are aware. We suspected IBM based on her history of progressive weakness and findings on electromyography. There was a delay of 5 years in obtaining biopsy for confirmation, during which she presented with recurrent episodes of respiratory failure despite using non-invasive ventilation. An autopsy revealed the presence of papillary thyroid carcinoma with spread to local lymph nodes. On the basis that these co-morbidities are unlikely to have occurred by chance (we estimate 1×10−17), we hypothesize that IBM may be a paraneoplastic condition. We acknowledge that proof would require demonstrating a pathogenic antibody. Conclusions: IBM should be considered in older patients (age >45) presenting with otherwise unexplained respiratory failure. A workup for possible malignancy in this setting appears reasonable.

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.