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Table of Contents    
Year : 2021  |  Volume : 69  |  Issue : 1  |  Page : 222-227

Combination Checkpoint Inhibitor-induced Antibody Negative Autoimmune Encephalitis in Non-small Cell Lung Cancer

1 Yale School of Medicine, New Haven, Connecticut, USA
2 Yale School of Medicine, New Haven, Connecticut; Yale-New Haven Hospital, New Haven, Connecticut, USA
3 Jersey Shore University Medical Center, Neptune, New Jersey, USA
4 Yale-New Haven Hospital, New Haven, Connecticut, USA

Date of Submission02-Feb-2019
Date of Decision16-May-2019
Date of Acceptance02-Jun-2019
Date of Web Publication24-Feb-2021

Correspondence Address:
Vinit Singh
Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, CT, 06511
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.310070

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How to cite this article:
Singh V, Zhao CW, Gupta V, Chu Y. Combination Checkpoint Inhibitor-induced Antibody Negative Autoimmune Encephalitis in Non-small Cell Lung Cancer. Neurol India 2021;69:222-7

How to cite this URL:
Singh V, Zhao CW, Gupta V, Chu Y. Combination Checkpoint Inhibitor-induced Antibody Negative Autoimmune Encephalitis in Non-small Cell Lung Cancer. Neurol India [serial online] 2021 [cited 2021 Apr 11];69:222-7. Available from:


Immunotherapy is enriching the primary and alternative treatment option for many cancers. It is already FDA approved for melanoma, small cell and non-small cell lung cancer, renal cell carcinoma, head and neck SCC, and Hodgkin's lymphoma. Checkpoint blockade is one of the critical strategies in immunotherapy. Nivolumab, an anti-PD1 antibody, and ipilimumab, an anti-CTLA4 antibody, are immune checkpoint inhibitors with complementary mechanisms that help T-cells recognize and destroy tumor cells. Recently, combination therapy with nivolumab and ipilimumab was observed to increase the progression-free survival period for patients with high tumor mutational burden.[1] However, by upregulating T-cell function, these checkpoint inhibitors lead to significant immune-related adverse effects (IrAEs), which includes but not limited to diarrhoea, colitis, hepatitis, endocrinopathies, pneumonitis, and pancreatitis.[2] These IrAEs not only lead to patient discomfort and treatment suspension but also sometimes require immunosuppressive agents for symptom control and should be considered by clinicians when making risk-benefit decisions for and with the patients.

Here, we report a case of checkpoint inhibitor-induced autoimmune encephalitis, which is a rare IrAE of nivolumab-ipilimumab combination therapy, occurring in about 1-3% of treated patients.[2] Patients may present with a headache, fever, weakness, tiredness, confusion, memory deficits, sleepiness, hallucinations, seizures, and a stiff neck. Checkpoint inhibitor-induced autoimmune encephalitis is a diagnosis of exclusion and requires a full workup to rule out other causes of encephalopathy,[3] including infective, metabolic, endocrine, and paraneoplastic causes.

As immunotherapy earning approval and becoming increasingly available, the discussion of IrAEs and their treatment options is essential. Immunosuppressive agents such as high dose corticosteroids and immunomodulators such as infliximab and rituximab currently form the mainstay of treatment. In this letter, we are discussing the presentation and diagnosis of checkpoint inhibitor-induced autoimmune encephalitis treated with high dose corticosteroids.

A 72-year-old female with a history of stage 4 invasive adenocarcinoma of lung presented to ED with fatigue, sleepiness, dizziness, and a fever (102.9 F). Her cancer was diagnosed 2 years prior, which was negative for PD-L1 expression. At diagnosis, she had multiple metastases, and MRI brain showed a 2.5 cm left parietal hypo-enhancing anterior pituitary lesion concerning for brain metastasis. She was started on chemotherapy with good response, except for an increase in hyper-metabolism of bony lesions for which she received palliative radiation therapy.

Unfortunately, after 14 months of chemotherapy, MRI showed disease progression. She was started on nivolumab and shifted to a phase 2 study of ipilimumab-nivolumab combination immunotherapy in patients with advanced non-small cell lung cancer resistant to anti-PD-1-axis therapy. After four doses of combination therapy, the patient underwent restaging CT scans and was found to have worsening of metastatic disease, including new liver metastases. She stopped receiving further checkpoint inhibitors, and a blood sample later sent for genetic testing which showed MET amplification. At this point, she was six weeks after her first combination therapy dose. She was started on crizotinib at 250 mg twice daily.

5 days later, she felt tired and slept all day, then sustained a fall which brought her to the ED. At this point, she was seven weeks from her last nivolumab-ipilimumab dose and 4 days after her previous crizotinib dose. On admission, she had fatigue, sleepiness, dizziness, and a fever of 102.9 F. She has increased leukocytes, procalcitonin was within the normal range, and creatinine was 1.6 mg/dl, up from a baseline of 0.9 mg/dl. Blood culture, urine culture, and respiratory viral DFA were negative. CXR did not suggest pneumonia. She was started on empirical vancomycin, ciprofloxacin, and metronidazole. CT chest/abdomen/pelvis was ordered and showed no acute changes from baseline. CT head showed no sign of acute hemorrhage, infarct, or mass effect.

On hospital day 2, she had a fall while passing urine with a sudden drop in BP. On the morning of hospital day four, she became confused and had impaired attention, hallucinations, and confabulations. Due to her altered mental status, CSF study and MRI head were performed. CSF showed lymphocyte predominance pleocytosis, normal glucose, and very high protein levels (>180 mg/dl). Given the clinical presentation and CSF findings, the neuro-oncology consult was taken. Their differential included infective encephalitis, autoimmune encephalitis, checkpoint-inhibitor induced autoimmune encephalitis, and paraneoplastic syndrome. They recommended an EEG to rule out non-convulsive seizures. EEG showed mild to moderate generalized slowing.

Interestingly, her MRI was positive for acute demyelination with restricted diffusion in the inferior right cerebellar hemisphere [Figure 1]a, enhancement within the left corona radiata and left supramarginal gyrus. Also, abnormal FLAIR signals were seen within the right temporal lobe [Figure 1]b, bilateral thalami [Figure 1]c, cerebellar hemispheres, and midbrain [Figure 1]d, with faint linear enhancements along the left cerebellar hemisphere, suggesting an acute inflammatory process.
Figure 1: MRI Brain showing (a) Restricted diffusion in the inferior right cerebellar hemisphere consistent with demyelination; abnormal FLAIR signals consistent with acute inflammatory process seen within (b) Right temporal lobe; (c) Bilateral Thalami; (d) Midbrain

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Considering the clinical scenario and investigation findings, we highly suspected the possibility of autoimmune encephalitis due to recent treatment with checkpoint inhibitors ipilimumab and nivolumab and advised initiation of high dose methylprednisolone. The infectious disease team was initially hesitant to start steroids until infectious causes were ruled out, but on discussion, agreed that the risk of harm with steroids was outweighed by the need for timely treatment of potential immune-mediated encephalitis. The patient was started on 1g methylprednisolone for 5 days, followed by a steroid taper over two weeks, with an appropriate clinical response. Meanwhile, CSF culture was negative for bacterial infection, and PCR for HSV, EBV, VZV, CMV, HHV-6, and West Nile, along with Cryptococcus antigen, were all negative. Her CSF and serum studies were negative for the autoimmune encephalitis panel, which included NMDA receptor, AMPA receptor, GABA receptor, anti-glial, and amphiphysin antibodies. She was back to her mental baseline and discharged on hospital day 12 and resumed crizotinib 10 days after discharge. At the time of writing this report and one month after returning to her crizotinib therapy, she was admitted for pulmonary embolism and undergoing treatment for the same.

Immune checkpoints are a regulator of the immune system and modulate the time and place of immune reactions. Cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and Program cell death protein-1 (PD-1) are well-characterized checkpoint regulatory.[4],[5] It regulates T-cell function by controlling the amplitude of immunological activation, thus protecting cells from T-cell induced auto immunogenicity.

Increased checkpoint activity in the tumor ensures that cancer cells maintain their survivability by adopting immune resistance. This attribute of cancer cells is targeted in checkpoint inhibitor immunotherapy, where antibodies against immune checkpoints are used to inhibit their function. Antibody-mediated checkpoint inhibition increases the immunogenicity of cancer cells and makes them more susceptible to immunogenic killing. As with any other cancer therapy, checkpoint inhibitor therapy comes with its baggage of adverse effects, mainly Immune-related adverse events (IrAE). These adverse effects are the sign of increased immunogenicity after immunotherapy and appear to be an indicator or predictor of the therapeutic effect of immunotherapy on the tumor cells.[2],[6]

Autoimmune encephalitis is a rare IrAE affecting 1-3% of treated patients.[7] This may present mild symptoms of fatigue, fever and weakness to severe symptoms like quadriparesis, dysarthria, amnesia and even death [See [Table 1] and [Table 2]]. The most challenging step in the management of this condition is diagnosing and differentiating it from other causes of encephalitis or encephalopathy. Most reported cases of autoimmune encephalitis after checkpoint inhibitors presented without fever. Interestingly, in our case, the patient had a fever, leucocytosis, and rapid development of the impaired cognitive function, which raised the suspicion for an infective etiology. The patient was worked up for infectious causes and was started on empirical antibiotics. In our literature review, we didn't find any case of autoimmune encephalitis after combination immunotherapy, which presented with fever. There is only one reported case of autoimmune encephalitis with a fever after monotherapy with Nivolumab for progressive clear cell ovarian cancer. The patient recovered after a high dose of steroids and plasmapheresis. The other possibility of the paraneoplastic syndrome was not considered as the symptoms developed over a short period, whereas in paraneoplastic syndrome, symptom progression is subacute or chronic. Negative antibody panel for autoimmune encephalitis proved that assumptions objectively as a paraneoplastic syndrome causing encephalitis are generally antibody positive. The other interesting point in our case was the team-based approach to reaching a treatment decision. The infectious disease team was rightly concerned about infectious causes, which would contraindicate steroid therapy. However, upon receiving MRI and CSF results and after discussion with the neuro-oncology team about risks versus benefits, a decision was made to initiate high dose steroids, which led to clinical improvement[26].
Table 1: Checkpoint inhibitors, clinical presentation and management approach to Checkpoint inhibitor.induced Autoimmune encephalitis

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Table 2: Summary of Patient profile, the checkpoint inhibitors, Clinical symptoms, relevant Investigation findings and management from the case reports and series of Checkpoint inhibitors induced Autoimmune encephalitis; Note - All patient had negative infectious agent investigation and a significant increase in CSF protein with lymphocytic pleocytosis

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A recent position statement by an international working group described clear criteria guiding the clinical, laboratory diagnosis, and categorization of autoimmune encephalitis.[8] The acute onset of symptoms, exclusion of the well-defined syndrome of autoimmune encephalitis, MRI findings suggesting demyelination, CSF pleocytosis and elevated proteins and no clinical outcome was suggesting another probable cause of encephalitis categorize our patient to the “antibody negative but probable autoimmune encephalitis” category. Around half of autoimmune encephalitis cases are antibody negative. Our patient's medication and the relation of symptoms with checkpoint inhibitor combination therapy appropriately led us to categorize the patient as Checkpoint inhibitor-induced Autoimmune encephalitis.

As for treatment for autoimmune encephalitis, our patient responded well to a 5-day course of high dose methylprednisolone followed by a taper over two weeks. The aim of corticosteroid therapy is immunosuppression, thus protecting the brain from the body's heightened immunity. Other agents such as rituximab, infliximab, and natalizumab have been used for the treatment of autoimmune encephalitis. A critical concern with the treatment of IrAE is the effect of immunosuppression on the action of Checkpoint inhibitors against cancer cell. In one case report, it has been suggested that natalizumab would better serve as first-line therapy for autoimmune encephalitis due to its localized action in the CNS without affecting other compartments.[9] This localized immunosuppression will minimally affect the other site of checkpoint inhibition. There are a few studies that suggest that the overall effectiveness of immunotherapy is not compromised by immunosuppression for IrAE treatment.[10],[11] However, further research is needed to understand the relationship between immunosuppressive therapy for IrAE and checkpoint inhibition, specifically elucidating the possible interactions between the two different treatment modalities.

Immune-related adverse effects are a reality for any immunotherapy, targeting cancer cells. Keeping a high grade of suspicion for such adverse effect is of utmost importance. Autoimmune encephalitis is one of such scenarios where the patient can present with overlapping symptoms. Experience of attending physician and team-based approach comes handy in such a situation where along with laboratory findings, knowledge, and experience of diagnosing and handling such cases lead to early intervention and treatment of the patients.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2]


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