Updates in the Management of Paraneoplastic Syndrome.

Paraneoplastic neurological syndromes (PNS) are defined as remote neurologic immune-mediated effects triggered by underlying systemic tumors. While recognizing specific syndromes can aid early cancer detection, overutilization of paraneoplastic assays in the absence of a classic syndrome can precipitate overdiagnosis and overtreatment. PNS involve autoantibodies targeting intracellular or extracellular antigens, with variable immunotherapy responses based on antigen type. Diagnosing PNS is challenging, requiring exclusion of other differential diagnoses. New diagnostic criteria classify PNS into high-risk and intermediate-risk phenotypes based on clinical phenotype, neuronal antibodies, and cancer presence. Patients with cell surface antibodies respond better to immunotherapies compared to those with intracellular antigen targets. Understanding PNS syndromes, serological markers, and oncological features guides management, which facilitates initiation of immunosuppression for PNS alongside treatment of the underlying neoplasm, thereby improving neurologic and oncologic outcomes. Initial treatments often include intravenous methylprednisolone, plasma exchange, or intravenous immunoglobulins. Second-line immunosuppressants like rituximab or cyclophosphamide may be necessary if initial treatments fail. Specific therapies vary based on antibody target. Here, we summarize the current approach to the investigation, diagnosis, and treatment of patients with suspected PNS.

A Brain, A Heart, and the Courage: Balancing Benefit and Toxicity of Immunotherapy in Melanoma.

The overall survival of advanced melanoma has improved dramatically. Immunotherapies, specifically checkpoint inhibitors, have played a large role in this improvement. These agents have also shown benefit in the adjuvant setting, are approved for treatment of resected stage II, III, and IV melanoma, and play an evolving role in the neoadjuvant setting. Although generally well tolerated, immune-related adverse events occur and can be severe. Here we focus on some severe and potentially long term toxicities, including cardiovascular and neurologic toxicities. Our understanding of the acute and long-term toxicities of immune checkpoint inhibitors continues to evolve. Oncologists must continue to balance cancer risk and treatment-related toxicities.

Cardiac sarcoidosis: a comprehensive review of risk factors, pathogenesis, diagnosis, clinical manifestations, and treatment strategies.

Cardiac Sarcoidosis (CS) is a deadly consequence of systemic sarcoidosis that inflames all three layers of the heart, especially the myocardium-clinical signs of CS range from asymptomatic disease to abrupt cardiac death. CS generally remains undiagnosed secondary to a lack of definitive diagnostic criteria, a high percentage of false negative results on endomyocardial biopsy, and ill-defining clinical manifestations of the disease. Consequently, there is a lack of evidence-based recommendations for CS, and the present diagnostic and therapeutic management depend on expert opinion. The aetiology, risk factors, clinical symptoms, diagnosis, and therapy of CS will be covered in this review. A particular emphasis will be placed on enhanced cardiovascular imaging and early identification of CS. We review the emerging evidence regarding the use of Electrocardiograms (ECGs), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) imaging of the heart to identify and quantify the extent of myocardial inflammation, as well as to guide the use of immunotherapy and other treatment regimens, such as ablation therapy, device therapy, and heart transplantation, to improve patient outcomes.

Rituximab for Immune Checkpoint Inhibitor Myasthenia Gravis.

The use of immune checkpoint inhibitors (iCPI) in the treatment of multiple cancers has gained prominence due to their high efficacy. However, neurological immune-related adverse events (irAEs) such as myasthenia gravis (MG) have been associated with iCPI therapy. Most of these neurological irAEs are rare, and in many cases, their diagnoses and management can be challenging.  We present a case of a 70-year-old woman with stage IIIC melanoma who developed a new onset of gradually progressive dyspnea, diplopia, and bilateral ptosis following treatment with one cycle of nivolumab and ipilimumab (Nivo+Ipi). She was diagnosed with MG via positive serum acetylcholine receptor (AChR) antibodies. She had developed a severe dyspnea at rest, which was refractory to multiple immune-suppressive therapies including prednisone, pyridostigmine, and intravenous immunoglobulin (IVIG). Subsequently, she was treated with rituximab 375 mg/m2 monthly every four weeks with significant improvement of her symptoms within 48 hours each time. As the implementation of immunotherapy increases in medical practice, irAEs may become more apparent. When first-line therapies are not adequate, other alternative therapies should be explored. This case of MG as an irAE shows that rituximab can provide a potential benefit to treating patients with immunotherapy-induced MG who are refractory to other standard treatments. Prospective studies are needed to further evaluate the efficacy of rituximab in the management of irAEs.

Immunotherapy Induced Myasthenic-Like Syndrome in a Metastatic Melanoma Patient With Amyotrophic Lateral Sclerosis.

Immunotherapy agents such as ipilimumab and nivolumab are immensely effective in the treatment of various malignancies. Despite this, neurologic immune-related sequelae (NIRS) have been observed. Prompt diagnosis and treatment is critical to improve patient outcomes. We present a case of a 63-year-old man with stage IV metastatic melanoma beginning treatment with ipilimumab and nivolumab. Gathered history from the patient showed that he had a 3-year presentation of bradykinesia, shuffling gait, and muscle cramping. After one dose, the patient began to have progressively worsening generalized weakness; after receiving the immunotherapy, there was a rapid decline in his health. In addition to weakness, the patient developed diplopia, impaired single breath count, lingual and upper/lower extremity fasciculations, and brisk reflexes. While the lumbar puncture and myasthenia panel were non-diagnostic, the electromyography (EMG) revealed axonal neuropathy and diffuse denervation/reinnervation changes. Furthermore, a magnetic resonance imaging (MRI) displayed fatty replacement of the tongue with a bright tongue sign. These results pointed to the diagnosis of amyotrophic lateral sclerosis (ALS) superimposed onto myasthenic-like syndrome. The patient was started on various treatments; however, unfortunately he died due to acute hypoxic respiratory failure. This case highlights important considerations that must be taken when using immunotherapy, especially in patients with pre-existing neurological deficits. Furthermore, it shows the importance of early diagnosis as treatment can potentially cure adverse sequelae.

Immune checkpoint inhibitor induced anti-glutamic acid decarboxylase 65 (Anti-GAD 65) limbic encephalitis responsive to intravenous immunoglobulin and plasma exchange.

Immune checkpoint inhibitors have made significant advances in available cancer treatment options towards progression-free and overall survival in cancer patients by potentiating own anti-tumor immune response. Anti-programmed death (PD-1) and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have been increasingly associated with neurologic complications. LE is a rare complication and like many complications secondary to immunotherapy, there is no standard for evaluation and treatment. Anti-GAD65-associated LE has been associated with thymic carcinoma. We describe a patient who presented with progressive memory loss 2 weeks after her third cycle of Ipilimumab and Nivolumab with associated elevated Anti-GAD65 levels. Treatment with IVIG and PLEX led to complete resolution of her symptoms and improvement in her brain imaging and CSF findings.