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Abstract
Immune checkpoint inhibitors have transformed the treatment of advanced malignancy, while increasing the risk of immune-related adverse events. A 56-year-old woman who had received nivolumab for stage 4 renal cell carcinoma subsequently developed altered behaviour, memory deficits and worsening of previously stable epilepsy. MR scan of the brain showed bilateral FLAIR (fluid-attenuated inversion recovery) hyperintensity of the mesial temporal lobes, and there were anti-Ma2 antibodies in both serum and cerebrospinal fluid. She was treated with corticosteroids but developed further clinical relapses requiring immunoglobulin and rituximab. The immune-related adverse events relating to immune checkpoint inhibitors are an emerging challenge for the neurologist. Some cases are refractory and require serial immunosuppression.
- immune checkpoint inhibitor
- anti-PD1
- encephalitis
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Introduction
Immune checkpoint inhibitor therapy has significantly changed the management of many advanced cancers. T cell-mediated tumour cell death is potentiated by inhibition of cytotoxic T lymphocyte-associated protein 4, programmed cell death protein 1 (PD1), programmed death-ligand 1 or a combination of all three.1 Inhibition of these antigens potentially precipitates new autoimmunity in patients. There are numerous well-described immune-related adverse events of immunotherapy, including hyperthyroidism and hypothyroidism, pneumonitis, colitis, hypophysitis, and hepatitis.1 2 Neurological immune-related adverse events account for <1% of all such adverse events, and limbic encephalitis occurs in 0.1%–0.2% of patients receiving immune checkpoint inhibitor therapy.1 3 Nivolumab is an anti-PD1 antibody approved for use in metastatic melanoma, renal cell carcinoma and small cell lung cancer.
Case report
A 56-year-old woman with previous metastatic renal cell carcinoma presented with haemoptysis; she was diagnosed with stage 4 (T3aN1M1) renal cell cancer with a large pulmonary hilar metastasis. She had a history of childhood-onset epilepsy well controlled on levetiracetam 500 mg twice daily, and also of hypertension and obesity. She underwent cytoreductive nephrectomy and resection of the hilar mass and received chemotherapy initially with a tyrosine kinase inhibitor, poziotinib. Following a mixed response radiologically, this was switched after 9 months to an anti-PD1 checkpoint inhibitor, nivolumab, 240 mg every 2 weeks for 12 weeks. CT scan of the thorax, abdomen and pelvis showed a marked improvement in tumour burden. However, 18 days after her last treatment, she developed worsening seizure control, new onset of memory loss, behavioural and personality changes, and a left internuclear ophthalmoplegia. This coincided with a new onset of diabetes mellitus.
MR scan of the brain showed multiple areas of increased T2 fluid-attenuated inversion recovery signal intensity in the temporal lobes, frontal lobes, brainstem, including bilateral limbic structures and left temporal cortex (figure 1). A serum autoantibody screen was positive for antiglutamate acid decarboxylase antibodies, 1577 U/mL (range 0–5), and anti-Ma2 antibodies. Cerebrospinal fluid (CSF) analysis was acellular but with a protein of 4.0 g/L (0.15–0.45) and with positive CSF anti-Ma2 antibodies.
MR scan of the brain (axial T2 fluid-attenuated inversion recovery) showing bilateral limbic hyperintensity, with involvement of the left frontal lobe and right inferior temporal lobe.
We diagnosed multifocal autoimmune encephalitis relating to immune checkpoint inhibitor treatment. We stopped the nivolumab and gave high-dose intravenous methylprednisolone for 5 days (converting to oral prednisolone starting at 60 mg), followed by a 5-day course of intravenous immunoglobulin, and started immunosuppression with mycophenolate mofetil 1000 mg twice daily. We treated her diabetes with metformin. Interval MR scan of the brain showed resolving limbic inflammation with near-total resolution of the cortical and brainstem areas of hyperintensity. Her memory impairment gradually improved over 8 weeks and her personality returned to baseline. Her serum antiglutamate acid decarboxylase antibodies during this convalescent period fell to 352 U/mL. However, her serum C peptide concentration was elevated at 6017 pmol/L (and varied between 370 and 1470 pmol/L), so we could not confirm a diagnosis of autoimmune diabetes. She was discharged with a slow tapering course of oral corticosteroids. Five weeks after discharge, with the prednisolone tapered to 20 mg daily, her symptoms recurred, with increasing confusion and somnolence. Repeat MR imaging showed persistent signal change in the medial temporal lobes. She received a second course of intravenous immunoglobulin, and the oral prednisolone was increased back to 60 mg, with improvement in her symptoms. Six weeks later, with the prednisolone tapered to 25 mg daily, there was a further relapse with worsening cognition and drowsiness. Repeat MR scan of the brain showed more extensive limbic encephalitis. She improved only modestly with rituximab, with persisting significant cognitive and behavioural problems.
Discussion
This patient developed a multifocal autoimmune encephalitis, with mesial temporal, cortical and brainstem involvement (as evidenced by the internuclear ophthalmoplegia), associated with anti-Ma2 autoantibodies occurring in the context of immune checkpoint inhibitor therapy. Autoimmunity associated with immunotherapy is an emerging and challenging area of modern neurological practice that will become more important as these medications become more available.4
Anti-Ma2 antibodies are usually associated with testicular tumours but may occur with other malignancies, particularly non-small cell lung cancers.5 The median age when patients are affected is 64 (53–82) years, with neurological symptoms often preceding the cancer diagnosis (62% in one important case series).6
Up to 30% of Ma2-associated paraneoplastic syndromes manifest as classic limbic encephalitis, with memory loss, seizures, irritability and depression. Cognitive decline with diencephalic and brainstem syndromes is also relatively common.6 Diencephalic dysfunction manifests as excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, weight gain, hyperthermia and endocrine abnormalities. Brainstem features, particularly relating to the upper brainstem, are common, including eye movement abnormalities, vertical gaze palsies, opsoclonus, ocular flutter, nystagmus and saccadic gaze pursuit, as well as dysarthria, dysphagia, facial weakness and dystonic jaw closure.6 7 Highly atypical variants occasionally occur, including parkinsonism, ataxia, myelopathy, narcolepsy and chorea.8–10 This patient had an increase in seizures, memory loss and cognitive decline consistent with classic limbic encephalitis. Her internuclear ophthalmoplegia suggested medial longitudinal fasciculus involvement, probably related to the pontine lesion visible on her MR scan. At the time of her first relapse, she had excessive sleepiness and difficulty with arousal.
As in other forms of autoimmune encephalitis, early MR imaging may be normal. Typical lesions comprise T2-weighted and FLAIR hyperintensities in the mesial temporal lobes, thalami, basal ganglia, brainstem and cerebellar peduncles; these may enhance with contrast. CSF is generally abnormal with increased protein and pleocytosis, which is lymphocyte-predominant.
Previous reports of anti-Ma2 autoantibodies in patients receiving nivolumab for renal cell carcinoma have highlighted how immune checkpoint inhibitor treatment may change the epidemiology and natural history of paraneoplastic disorders.11 This is further supported by an apparent increased frequency in the detection of anti-Ma2 antibodies, probably attributable to immune checkpoint inhibitor treatment.7 Autoimmune encephalitis may occur despite successful treatment of the tumour, as in this case. While detecting the autoantibodies can help to characterise the disorder, there have been reported cases of immune checkpoint inhibitor-related autoimmune encephalitis without detected autoantibody. In such cases it is the recognition of the clinical syndrome, its chronological association with therapy, and supportive imaging and CSF findings that enable a diagnosis.12
The management of immune checkpoint inhibitor-related encephalitis is of growing interest. Stopping the precipitating agent and treating with high-dose corticosteroids are recommended but, as in this case, may not arrest the disease. Rituximab and plasma exchange are suggested in refractory cases when there is a detected pathogenic autoantibody.13
This case highlights a potential complication of immune checkpoint inhibitors and the challenge of achieving immunological equilibrium in this situation. Clinicians need to suspect neurological immune checkpoint inhibitor-associated syndromes quickly, as patients may need urgent immunosuppression.
Key points
Immune checkpoint inhibitor treatment is associated with several autoimmune neurological complications and may alter the natural history of these conditions.
A high index of suspicion is necessary for early recognition and treatment of neurological immune related adverse events.
The management of these autoimmune complications includes stopping the immune checkpoint inhibitor and giving high-dose corticosteroids; plasma exchange and rituximab may help in refractory cases.
Footnotes
SL and RJ contributed equally.
Contributors SL and RJ drafted the manuscript. PM and LOD reviewed and edited the manuscript. SB and TJC reviewed, revised and edited the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Next of kin consent obtained.
Provenance and peer review Not commissioned. Externally peer reviewed by Sarosh Irani, Oxford, UK.