Case Report: Limbic encephalitis following treatment with durvalumab for small-cell lung cancer.

Background: Durvalumab is an immune checkpoint Inhibitor (ICIs) that is used in the treatment of malignant tumors, such as lung cancer and melanoma. ICIs are associated with immune-related adverse events including autoimmune encephalitis, although both paraneoplastic phenomena and ICI treatment may lead to autoimmunity. Case presentation: We describe a 72-year old male patient with small-cell lung cancer, who during adjuvant treatment with Durvalumab developed GABABR1 and GAD65 antibodies and both diabetes and autoimmune limbic encephalitis. Because he was followed prospectively as part of a treatment study, we had access to repeated serum samples and cognitive assessments over time prior to developing encephalitis and diabetes, in addition to later assessments. A high titer of GABABR1 antibodies appeared early, while GAD65 antibodies appeared later with a lower titer in parallel with the development of diabetes. As he subsequently developed clinical signs of encephalitis, verified by EEG and brain MRI, he also had CSF GABABR1 antibodies. Durvalumab was discontinued and steroid treatment with subsequent plasmapheresis were started, resulting in reduction of both CSF and serum antibody levels. Clinical signs of encephalitis gradually improved. Conclusion: This case illustrates the importance of being aware of possible serious autoimmune adverse reactions, including neurological syndromes such as encephalitis, when treating patients with high risk of para-neoplasia with ICIs. In addition, the case shows the development of autoantibodies over time.

Paraneoplastic limbic encephalitis following treatment with single-agent pembrolizumab for advanced gastroesophageal adenocarcinoma.

The use of immune checkpoint inhibitors is increasing in clinical practice. While they have provided significant benefit to many patients, a new category of adverse effects, immune-related adverse effects, has emerged with their use. These effects can range from mild to severe and affect nearly every organ system. A man in his 70swith metastatic gastro-oesophageal junction adenocarcinoma who received one cycle of third-line pembrolizumab presented after three episodes of transient left facial paresthesia, the last of which extended to the left extremities and disturbed peripheral vision of the left eye. He was found to have subclinical seizures and cerebrospinal fluid positive for Ma2/Ta paraneoplastic antibodies, consistent with paraneoplastic limbic encephalitis. We describe an unusual presentation of paraneoplastic limbic encephalitis. This case adds to the limited literature describing the association of paraneoplastic limbic encephalitis and treatment with immune checkpoint inhibitors as well as the observed associations with immune-related adverse events and treatment responses.

Encephalitis Induced by Durvalumab During Treatment of Metastatic Small-Cell Lung Cancer: Illustrative Case and Review of the Literature.

The immune checkpoint inhibitors have improved the standards of care in cancer treatment and have dramatically improved patient prognoses. These new antibodies turned to be an integral part of the standard of care for metastatic small-cell lung cancer. Platinum-based chemotherapy combined with checkpoint inhibitors, resulted in statistically significant improvement of progression free survival and overall survival. Immune checkpoint inhibitors immune-related adverse events have been observed and reported as a consequence of administering these innovative treatment drugs. Neurological immune-related adverse events are rare complications; however, they can be potentially fatal, particularly encephalitis. This report describes a 66-year-old female who received Durvalumab for metastatic small-cell lung cancer. Following 3 cycles of treatment, she developed encephalitis.

Very high-dose methylprednisolone for treatment of nivolumab-induced limbic encephalitis: A case report.

INTRODUCTION: Nivolumab is a programmed death 1 (PD-1) inhibitor approved by the Food and Drug Administration (FDA) for the treatment of eight different cancers including metastatic melanoma. Immune checkpoint blockade may lead to a range of neurologic immune-related adverse events (irAEs) with severity varying from mild to life-threatening, including encephalitis. CASE REPORT: We describe a case of a 68-year-old man who developed alteration in mental status, physical weakness and fatigue after nine cycles of nivolumab 3 mg/kg every two weeks. These symptoms were compatible with a clinical diagnosis of autoimmune limbic encephalitis, although no specific antibodies were detected and the initial MRI was normal. MANAGEMENT AND OUTCOME: The patient received intravenous methylprednisolone 1 g daily for 5 days, which was then converted to a maintenance dose of oral prednisone. The patient made a full clinical recovery but relapsed clinically upon steroid tapering, while hypersignal in the left mesial temporal suggestive of limbic encephalitis was observed on repeated MRI. DISCUSSION: Because of the prevailing usage of nivolumab in many cancer protocols, this case highlights the importance of rapidly recognising neurological impairment in patients treated with nivolumab and of initiating very high doses of corticosteroids.

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.

Anti-Hu-Associated Autoimmune Limbic Encephalitis in a Patient with PD-1 Inhibitor-Responsive Myxoid Chondrosarcoma.

Autoimmune encephalitis is an uncommon complication of immune checkpoint inhibitor therapy. This article reports a case of fatal anti-Hu-associated autoimmune limbic encephalitis presenting within 8 weeks following anti-PD1 therapy in a patient with myxoid chondrosarcoma and pre-existing anti-Hu antibodies. Although tumor reduction occurred in response to PD-1 inhibitor therapy, the patient had a rapidly progressive decline in neurologic function despite initial stabilization with immunosuppression. Considering the increasing use of immune checkpoint inhibitors for the treatment of various malignancies, an increase in the occurrence of neurologic adverse events is likely, requiring prompt intervention and enhanced pharmacovigilance in malignancies associated with onconeuronal antibodies.

Risk of cumulative toxicity after complete melanoma response with pembrolizumab.

Pembrolizumab is an approved first-line systemic therapy for unresectable metastatic melanoma. Despite the achievement of complete and durable responses in a small subgroup of patients, it is standard practice that pembrolizumab therapy continues beyond complete response. Nevertheless, the incidence of immune-related toxicities gradually increases with continuing pembrolizumab therapy. We report a case highlighting the occurrence of serious induced immune-related adverse events, which were attributed to pembrolizumab in a patient with metastatic melanoma who obtained a complete response (CR) after receiving pembrolizumab for a total of 6.5 months. Although mild pembrolizumab-related toxicity persists, the patient remains disease-free 5.5 months after discontinuation of pembrolizumab. Accordingly, we believe that cessation of pembrolizumab should be considered in patients who achieve a CR because of the ongoing risk of toxicity with extended pembrolizumab administration.

Limbic encephalitis following immunotherapy against metastatic malignant melanoma.

Novel immunotherapies are increasingly being used to treat malignant melanoma. The use of such agents has been associated with triggering autoimmunity. However, there has been a paucity in reports of limbic encephalitis associated with these immunotherapies. Pembrolizumab, a monoclonal antibody against programmed cell death antigen (PD-1), is currently being trialled in the UK to treat malignant melanoma. We report a unique case of antibody-negative limbic encephalitis presenting 1 year after starting pembrolizumab, in the context of malignant melanoma. The patient presented with progressive cognitive decline. MRI of the brain revealed signal change within the limbic structures. Cerebrospinal fluid studies confirmed evidence of inflammation with raised white cell count and protein. We were able to prevent further progression of symptoms by stopping pembrolizumab and treating the patient instead with steroids. We advocate considering autoimmune neuroinflammation as a differential for neurological disorders presenting in patients receiving PD-1 antagonist treatment and immunotherapy in general.

Multifocal encephalopathy and autoimmune-mediated limbic encephalitis following tocilizumab therapy.

A 63-year-old man with rheumatoid arthritis developed multifocal encephalopathy and limbic encephalitis following therapy with tocilizumab, a humanized anti-interleukin-6 receptor antibody. Anti-glutamate receptor ε2 antibodies were later found to be positive in both the serum and cerebrospinal fluid. This case highlights the possibility of the development of encephalopathy after treatment with tocilizumab, which may also induce autoimmune limbic encephalitis.

Limbic encephalopathy and central vestibulopathy caused by mefloquine: a case report.

Mefloquine is a 4-methanolquinoline anti-malarial that in recent years has fallen out of favor for use as chemoprophylaxis against infection with chloroquine-resistant Plasmodium falciparum malaria owing in part to growing concerns of side effects and potential neurotoxicity. Despite over 20 years of licensed use, the pathophysiological mechanisms underlying mefloquine's neuropsychiatric and physical side effects and the clinical significance of the drug's neurotoxicity have remained poorly understood. In this report, an adverse reaction to mefloquine chemoprophylaxis is described characterized by prodromal symptoms of anxiety with subsequent development of psychosis, short-term memory impairment, confusion and personality change accompanied by complaints of disequilibrium and vertigo, with objective findings of central vestibulopathy. It is posited that these effects represent an idiosyncratic neurotoxic syndrome of progressive limbic encephalopathy and multifocal brainstem injury caused by the drug. This case provides insights into the clinical significance of mefloquine neuronal gap junction blockade and neurotoxicity demonstrated in animal models, points to recommendations for the management of affected patients including diagnostic considerations and appropriate referrals, and highlights critical implications for the continued safe use of the medication.

[Limbic encephalitis up to date].

Limbic encephalitis (LE) refers to an inflammatory disorder involving the hippocampus, amygdala and insular cortex. LE is now regarded as a more frequent disorder than it was previously thought, and the concept of LE has been expanded because of the development of neuroimaging and the increasing recognition of the associated antibodies. We categorized LE into 5 groups. LE caused by virus infection, autoantibody-mediated LE, LE with autoimmune disease, LE associated with drugs and LE during pregnancy. LE having the antibodies against intracellular antigens frequently related to cancer and are resistant to treatment. While, LE with antibodies against cell-membrane antigens, including NMDAR, AMPAR, GABA(B)R, VGKC, tend to respond better to antitumor therapy and immunotherapy.