Overlapping NMDA-R and GFAP Antibody Autoimmune Encephalitis After Nivolumab Therapy

PRACTICAL IMPLICATIONS

The differential diagnosis associated with acute encephalopathy is broad; however, given the increasing frequency with which immunotherapy is being used in the treatment of cancer, consider checkpoint inhibitor-induced autoimmune encephalitis in the appropriate clinical context.

Immunotherapy represents a rapidly expanding area of cancer treatment. Immune checkpoint inhibitors (ICIs), monoclonal antibodies including those targeting cytotoxic T-lymphocyte associated protein 4 or the programmed cell death receptor-1 (PD-1) axis, function by removing inhibitory signals on T-cell activation.¹ Although promoting T-cell mediated tumor lysis, ICIs alter the immune system's regulatory checkpoints that can lead to a host of immune-related adverse events (irAEs).^2,3 Here, we describe a patient treated with nivolumab (Opdivo; Bristol-Myers Squibb, Princeton, NJ) for non–small-cell lung carcinoma (NSCLC) over 2 years who developed overlapping NMDA receptor (NMDA-R) and glial fibrillary acidic protein (GFAP) antibody–associated autoimmune encephalitis (AE).⁴ His hospital course was further complicated by dysautonomia responsive to high-dose steroids.

Case

A 70-year-old man presented to a community hospital with altered mental status and 1 week of fevers. He was being treated for stage III NSCLC with nivolumab (480 mg IV every 4 weeks) beginning 2 years before presentation. Notably, the treatment had been complicated by hypophysitis, requiring daily hydrocortisone therapy. He was treated empirically for meningitis with antibiotics, and ultimately transferred to our tertiary care center.

On admission, he was febrile to 39.4°C, tachycardic (105 beats per minute), and hypotensive (60/40 mm Hg). Although he was lethargic and unable to follow commands, his neurologic examination revealed intact cranial nerves, symmetric antigravity movement in the bilateral upper extremities, withdrawal of lower extremities to noxious stimuli, and 3+ reflexes in the upper and lower extremities with down going toes. He was admitted to the neurointensive care unit for vasopressor management.

Lumbar puncture revealed 42 white blood cells/μL (92% lymphocytes and 8% monocytes), elevated protein (86 mg/dL), elevated oligoclonal bands (5 bands), and an elevated immunoglobulin G index (0.93), but infectious evaluation was negative. EEG showed moderate encephalopathy without seizures. MRI of his brain with gadolinium showed global atrophy, chronic microvascular ischemic changes, and chronic lacunar infarcts, with no evidence of metastases or enhancement. After systemic infectious, metabolic and endocrinologic evaluations were negative, he was started on methylprednisolone, 1,000 mg IV for 5 days for empiric treatment of suspected AE secondary to nivolumab. In addition to near complete resolution of his encephalopathy within 1–2 days of initiation of steroids, his dysautonomia resolved completely. He was discharged home on his prehospitalization dose of hydrocortisone. Ultimately, although a serologic autoimmune panel was negative, the CSF sent to the Mayo Clinic laboratory later revealed positive anti-NMDA-R antibody (cell-based assay, although absent at a 1:2 dilution) and anti-GFAP antibodies (1:128 dilution). Nivolumab was permanently discontinued, and the patient made a complete recovery without further management of his neurologic disease.

Discussion

AE is an ICI-induced irAE that may occur in 0.2% of patients on nivolumab (Table).^4–9 The median reported time to development of AE is 6 weeks, although AE can occur at any point during treatment for unclear reasons, notably 2 years after therapy initiation in our case.¹⁰ Furthermore, although dysautonomia in the setting of NMDA-R encephalitis secondary to nivolumab has rarely been reported, it is common in typical NMDA-R encephalitis.⁵ Patients with GFAP autoantibodies may also develop dysautonomia, although again, it is an uncommon manifestation.¹¹

Table.

Immune Checkpoint Inhibitor–Induced Autoimmune Encephalitis Brief Literature Review

Although antibody overlap is rare in ICI induced AE, it is often reported in non–ICI-induced AE. In our patient, the dual antibodies may serve to indicate a neural autoantibody-mediated process more so than specific pathogenesis, given the lack of typical MRI changes supportive of GFAP astrocytopathy. However, despite being ICI induced, the spinal fluid profile was typical of NMDA-R and GFAP encephalitis, namely lymphocytic pleocytosis, elevated protein, and elevated oligoclonal bands. Curiously then, our patient's phenotype and diagnostic workup demonstrated many of the findings expected in typical autoimmune encephalitis, which serves to inform practicing neurologists of expected CSF profiles when considering ICI-induced AE.

Finally, the mainstay of treatment in ICI-induced AE is corticosteroids. Based on severity, either methylprednisolone, 1,000 mg IV daily for 5–7 days or prednisone, 60–80 mg orally for 1–2 weeks should be used, with an oral prednisone taper over 4–6 weeks. Prompt improvement in mental status within 3–5 days should be observed, with consideration of escalation of therapy to plasmapheresis, intravenous immunoglobulin, or nonsteroid immunosuppressive agents thereafter.^4,12 Natalizumab has also been reported as a potential therapeutic option in the treatment of AE by decreasing leukocyte travel into the CNS without systemic impact.³ Ultimately, neurologists evaluating encephalopathic patients on ICIs should consider autoimmune encephalitis.

Appendix. Authors

Study Funding

No targeted funding reported.

Disclosure

F.A. Ayala, S.C. Dougherty, and W. Swift report no disclosures relevant to the manuscript. D.A. Lapides has served on advisory board for Biohaven Pharmaceuticals. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.