Importance Encephalitis is a severe immune-related adverse event secondary to treatment with immune checkpoint inhibitors (ICIs). The spectrum of ICI-induced encephalitis (ICI-iE) ranges from disease that resolves fully to lethal forms. Moreover, ICIs may unmask a paraneoplastic encephalitis. To our knowledge, the factors associated with ICI-iE prognosis are unknown. Objectives To evaluate the presentation of ICI-iE and to identify features helpful in assessing outcomes. Evidence Review This systematic review pooled case series from the published literature (n = 77) and medical records from 1 center (n = 5) to assess the association between the form of ICI-iE presentation and its prognosis. Eligibility criteria included references identified by searches of PubMed and Web of Knowledge databases in the English literature from June 2000 (first patient dose of ipilimumab) to April 17, 2020, that examined patients with encephalitis with presumed autoimmune etiologic features induced by ICIs. Information regarding clinical, cerebrospinal fluid, and neuroimaging (magnetic resonance imaging) features, as well as treatment given, were extracted. Findings A total of 82 patients (52 men [63%]; median age, 61.0 years [interquartile range, 52.5-70.0 years]) were included. Most patients presented with focal syndromes (39 [48%]) or meningoencephalitis (36 [44%]). Seven patients (9%) had nonclassifiable ICI-iE. Neuronal autoantibodies were detected in 23 patients with focal syndromes and 1 patient with nonclassifiable ICI-iE. Most autoantibodies were onconeuronal (17 of 24 [71%]), targeting intracellular antigens. Patients without a focal syndrome or with a negative-antibody focal syndrome had a good prognosis (49 of 55 [89%]). Among patients with autoantibodies, those with anti–glutamic acid decarboxylase or anticell surface responded to treatment and had a favorable prognosis (100%). However, patients with other autoantibodies had poor outcomes (17 of 24 [71%]). Antineuronal autoantibodies (13 of 24 [54%] vs 5 of 41 [12%];P  Conclusions and Relevance Immune checkpoint inhibitors may induce mainly 2 different encephalitic syndromes: a focal limbic or extralimbic encephalitis and a meningoencephalitis. Immune checkpoint inhibitor–induced encephalitis is associated with an overall favorable outcome, with a low rate of fatal events. An undetected preexisting paraneoplastic encephalitic syndrome may be triggered by ICIs, and this type of syndrome has the worst outcome among all the different types of ICI-induced encephalitis syndromes. Clinical presentation and systematic measurement of autoantibodies will be a helpful guide for the therapeutic strategy and for counseling regarding prognosis.

https://jamanetwork.com/journals/jamaneurology/articlepdf/2777621/jamaneurology_velasco_2021_rv_210001_1624467410.9432.pdf

Encephalitis Induced by Immune Checkpoint Inhibitors: A Systematic Review.

Since the first Immune Checkpoint Inhibitor was developed, tumor immunotherapy has entered a new era, and the response rate and survival rate of many cancers have also been improved. Despite the success of immune checkpoint inhibitors, resistance limits the number of patients who can achieve a lasting response, and immune-related adverse events complicate treatment. The mechanism of immune-related adverse events (irAEs) is unclear. We summarize and discuss the mechanisms of action of immune checkpoint inhibitors, the different types of immune-related adverse events and their possible mechanisms, and describe possible strategies and targets for prevention and therapeutic interventions to mitigate them.

/pdf/immune-related-adverse-events-of-immune-checkpoint-25agi34w.pdf

Immune-related adverse events of immune checkpoint inhibitors: a review

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.

Neurological Syndromes Associated with Anti-GAD Antibodies

Paraneoplastic neurological syndromes are more commonly seen with malignancies such as small cell lung cancer, thymoma, gynecological malignancies, and breast cancer as well as seminoma. With the introduction of immune checkpoint inhibitor (ICI) cancer immunotherapy we see an increase of autoimmune neurological complications in patients with malignancies not traditionally associated with paraneoplastic neurological syndromes, such as melanoma and renal cell carcinoma. Immune checkpoint inhibitors enhance antitumor immune responses resulting often in immune-related adverse effects that can affect any organ, including the central and peripheral nervous system, neuromuscular junction and muscle. Neurological complications are rare; neuromuscular complications are more common than central nervous system ones but multifocal neurological presentations are often encountered. The vast majority of neurological complications appear within 3 months of ICI initiation, but have been described even after ICI cessation. Neural autoantibody testing reveals autoantibodies in approximately half of the patients with CNS complications. Early suspicion and diagnosis is critical to avoid worsening and improve outcomes. Therapeutic strategies depend on the severity of the symptoms and initially typically involve discontinuation of ICI and high dose steroids. Further immunosuppression might be necessary. Outcomes are dependent on patient's characteristics and clinical presentations.

/pdf/paraneoplastic-neurological-syndromes-and-beyond-emerging-1ttqw075ue.pdf

Paraneoplastic Neurological Syndromes and Beyond Emerging With the Introduction of Immune Checkpoint Inhibitor Cancer Immunotherapy.

OBJECTIVE: To determine the clinical and laboratory features of immune checkpoint inhibitor (ICPI)-associated autoimmune encephalitis (ICPI-AIE), an increasingly recognized adverse event with ICPI treatment. METHODS. We searched PubMed, The Cochrane Library and Embase for ICPI-AIE cases from the first description in 2015 until 01/2020 using standard bibliographic measures including PRISMA guidelines and pre-registration with PROSPERO (CRD42019139838). RESULTS. Thirty-nine studies met inclusion criteria, resulting in 54 ICPI-AIE patients (mean age 58.6 years; 43% females). Common cancers included melanoma (30%) and non-small cell lung cancer (30%). Brain metastases were found in 16 patients (30%). The most frequent ICPI was nivolumab (61%). Onset of ICPI-AIE occurred after a median of 3.5 treatment cycles, but very early and late presentations were common. Non-limbic AIE was roughly twice as frequent as limbic AIE (p CONCLUSIONS. ICPI-AIE consists of a heterogenous group of conditions. Neurologists will likely encounter ICPI-AIE more often in the future, but important unresolved questions include the exact pathophysiological mechanisms, the epidemiology and the best treatment approaches associated with ICPI-AIE.

Autoimmune Encephalitis Related to Cancer Treatment With Immune Checkpoint Inhibitors: A Systematic Review.

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.

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

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.

/pdf/rituximab-for-immune-checkpoint-inhibitor-myasthenia-gravis-1jbibhfgza.pdf

Rituximab for Immune Checkpoint Inhibitor Myasthenia Gravis

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.

https://journals.sagepub.com/doi/pdf/10.1177/1179554920978024

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

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

Rituximab for Immune Checkpoint Inhibitor Myasthenia Gravis

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