Paraneoplastic limbic encephalitis following treatment with single-agent pembrolizumab for advanced gastroesophageal adenocarcinoma
- 1 Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- 2 Department of Neurology, Temple University Health System Inc, Philadelphia, Pennsylvania, USA
- 3 Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
- Correspondence to Dr Benjamin Miron; benjamin.miron@tuhs.temple.edu
Abstract
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.
Background
Cancer immunotherapies have rapidly gained momentum in the last few years marking a new era of cancer therapy.1 Immune checkpoint inhibitors (ICIs) are one class of these immunotherapies, the most notable of which target the cytotoxic T lymphocyte antigen 4 and programmed cell death 1 (PD-1) pathways. Immune checkpoints are responsible for downregulating the T cell response in order to protect the body from autoimmunity; however, this system has been demonstrated as one that can be hijacked by cancer cells in an effort to avoid immune detection.2 ICIs have been trialled and approved in many histological subtypes of cancer and recently in gastrointestinal malignancies as well.3 4 Pembrolizumab, a PD-1 inhibitor, is now specifically approved for the treatment of advanced gastro-oesophageal cancers as monotherapy and in combination with chemotherapy after positive results from the KEYNOTE-059 and KEYNOTE-590 trials.5 6 Nivolumab, another PD-1 inhibitor, is now approved for gastro-oesophageal cancers in the adjuvant setting as a result of CHECKMATE-577.7 ICIs are associated with a side effect profile distinct from cytotoxic chemotherapy in light of their different mechanism of action. These side effects are broadly referred to as immune-related adverse events (irAEs), which can range from mild to severe and affect almost any organ system.5 In Keynote-059, 18% of patients had at least one irAE, with the most common being changes in thyroid function and colitis, which were of primarily low grade and non-fatal. The most common grade 3–5 irAEs reported in the trial were severe skin reactions (1.5%), colitis (1.2%) and pneumonitis (0.8%). One case of encephalitis was reported by the trial, but the rarity of these neurological events limits data on their prevalence.5
Another rare aetiology of neurological symptoms in cancer patients is the paraneoplastic syndrome paraneoplastic limbic encephalitis (PLE). PLE typically presents with cognitive impairment, personality change, short-term memory loss, sleep disturbance and seizures. While about 50% of reports are in association with small cell lung cancer, there are reports of PLE associated with other cancer histologies, including oesophageal carcinoma.8 Antibodies to onconeural proteins can sometimes be detected in the serum or cerebrospinal fluid to assist in diagnosis; however, their absence does not exclude the diagnosis. The most commonly identified antibodies in PLE include anti-LGI1, GABABR, AMPAR, CASPR2, Hu, Ma2 and GAD, which are detected in 50%–60% of patients with PLE.8–10
Herein, we describe the diagnostic evaluation and management of a patient with an unusual presentation of encephalitis while receiving pembrolizumab for the treatment of metastatic gastro-oesophageal adenocarcinoma.
Case presentation
A man in his 70s with a history of non-invasive bladder cancer presented with dysphagia and was ultimately diagnosed with metastatic gastro-oesophageal junction (GEJ) adenocarcinoma with neuroendocrine features, metastatic to the left supraclavicular and retroperitoneal lymph nodes. Molecular profiling was significant for pathogenic TP53 mutation, human epidermal growth factor receptor 2 (HER-2) negative by immunohistochemistry (IHC) and a PDL1 Combined Positive Score of 2. He received treatment with FOLFOX in the first line, followed by ramucirumab and paclitaxel as second-line therapy. On progression, pembrolizumab was started in the third-line setting.
On day 1 of cycle 2 of pembrolizumab, he presented with reports of three episodes of transient left facial paresthesia, the last of which extended to the left upper and lower extremities. He also noted a transient disturbance in the peripheral vision of the left eye; however, none of these symptoms was present at the time of his clinical examination. Pembrolizumab was held, and the patient was sent for urgent imaging evaluation. Brain MRI revealed extensive uniform T2 hyperintensity and insular and anteroinferior temporal cortex and right hippocampus without corresponding abnormal enhancement, haemorrhage or mass effect. These findings remained unchanged on repeat MRI 5 days later (figure 1). Serologies for herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, lyme disease and tuberculosis were all negative. Lumbar puncture was also performed, and CSF cell count, cytology and culture were unremarkable. Paraneoplastic antibody panel was noted to be positive for Ma2/Ta antibodies. Neurology was consulted and recommended initiation of antiseizure therapy with levetiracetam. Prednisone 50 mg was added due to concern for an irAE. After 4 days of steroids, the patient reported improvement of symptoms and endorsed very mild and transient facial paresthesia with decreased frequency. His neurologic symptoms did not resolve completely but were very well controlled with low-dose steroids and levetiracetam.
Brain MRI showing uniform T2 signal involving the right-sided inferior frontal, insular and anteroinferior temporal cortex and right hippocampus with patent vasculature.
Outpatient EEG performed 8 weeks after initial symptoms (figure 2) showed electrographic seizures in a 40 min EEG that started in the right anterior temporal regions then gradually spread over the right hemisphere. The patient was admitted for continuous EEG monitoring and management of his subclinical seizures, which were now concerning to be secondary to PLE in the setting of positive Ma2/Ta antibodies. On admission, EEG monitoring revealed brief focal seizures of right temporoparietal/centroparietal origin, which occurred two times per hour initially until antiepileptic medications were adequately adjusted. Initially, dosing of levetiracetam was increased to 1000 mg two times/day. However, after 24 hours, EEG monitoring showed continued subclinical seizures and treatment with valproic acid, starting with a loading dose, and methylprednisolone 250 mg intravenous was given for 3 days followed by 30 mg of prednisone daily. Due to incomplete seizure control on hospital day 4, lacosamide and treatment with IVIG 2 g/kg over 5 days were initiated simultaneously and levetiracetam was tapered. Fortunately, the combination of steroids, IVIG, lacosamide and valproic acid was able to achieve control of his seizure activity. The patient was discharged home in stable condition after 8 days with oral antiseizure medications, prednisone and plans for physical and occupational therapy at home. His outpatient seizure regimen included divalproex 250 mg/day, in place of the lacosamide as it was not covered by his insurance, and a prednisone taper. Shortly after discharge, his course was further complicated by a mechanical fall secondary to deconditioning, which resulted in an inoperable pelvic fracture necessitating a lengthy stay in a rehabilitation facility. Remarkably, scans 6 and 11 months after discontinuation of treatment revealed continued radiographic disease control with his primary tumour and lymph nodes all either unchanged or decreased in size. However, despite this ongoing radiographic response and control of seizures, as reflected on subsequent EEG, he continued to experience generalised weakness and a subtle and gradual cognitive decline, which rendered him unable to adequately rehabilitate after pelvic fracture or return to independent living. We suspect that ultimately sequelae from encephalitis contributed to this progressive cognitive decline. As a result, he became progressively more deconditioned and his performance status continued to deteriorate until he eventually expired 14 months after his first dose of pembrolizumab due to complications related to his functional and cognitive decline.
EEG findings. (A) Low amplitude rhythmic theta frequency in R anterior temporal area which evolves into (B) faster alpha frequencies spreading in location over the R hemisphere. (C) Pattern then slows (still counting as evolution) with sharper morphology towards the end.
Discussion
The clinical presentation of this case does not fit the classic presentation of PLE or immunotherapy-related encephalitis, which typically have more severe and acute presentations. Immune-related encephalitis has been documented as presenting most commonly with altered mental status, confusion, aphasia and agitation, while PLE is subacute in onset with rapid progression of short-term memory issues, seizures or other psychiatric symptoms, including behavioural changes, anxiety, depression and psychosis.9 11 The initial clinical concern in this case was for a more common aetiology, such as TIA, cardiovascular accident or brain metastases, due to the isolated neurologic symptom as well as the patient’s active cancer. This case highlights the importance of increased awareness of the potential for neurological immune-related adverse effects as ICIs are approved and adopted for the treatment of cancer.
Neurological irAEs have been documented with the peripheral nervous system being more commonly affected as compared with the central nervous system (CNS). A review by Möhn et al identified 43 case reports documenting CNS complications linked to ICI use, and 27 of these were cases of encephalitis. The other case reports document cerebellitis, myelitis and posterior reversible encephalopathy syndrome causing significant impairment. They found that 72% of these cases were documented in men, and 44.2% of the patients had metastatic melanoma as the indication for receiving ICI therapy.12 One case report describes a metastatic melanoma patient who presented with progressive confusion 12 months after beginning single-agent pembrolizumab. He was documented to have progressively worsening short-term memory loss, difficulty performing regular activities and new obsessions over certain tasks.13 As use of ICIs increases, we are gaining a deeper understanding of the possible range of presentations of neurological irAEs. Our patient did not have significant or progressive neurological findings at the time of initial workup after having received one cycle of pembrolizumab. A case series of six encephalitis cases in patients with advanced melanoma identified a median time to symptom onset of 51.5 days from therapy initiation, with the range being 18–297 days. The presenting symptom for all of these cases was altered mental status.11 While the timeframe does fit for our patient’s timing of symptoms, his presentation with seizures does not fit the classic presentation, especially with his preserved mental status.
While at first, there was little reason to suspect a rare aetiology such as a paraneoplastic syndrome in the setting of an acute presentation of a focal neurological deficit, the ultimate findings of subclinical status epilepticus and positive Ma2/Ta antibodies strongly suggest a diagnosis of PLE. However, PLE is typically seen in patients with progressive or advancing disease, and treatment of the active cancer can result in neurological improvement.8 About 50%–60% of cases of PLE present with positive paraneoplastic antibodies, which in conjunction with the neurologic symptoms, aid in the diagnosis, as was seen in this case identifying Ma2/Ta antibodies in the CSF. Although Ma2/Ta antibodies are known to be associated with PLE, the lack of progressive oncologic disease in this case challenges the standard diagnosis of PLE. However, ICIs have recently been shown to be associated with increased frequency of anti-Ma2-associated PLE.14 While there is currently limited data to definitively conclude a causal relationship between ICI and PLE, this case could provide support for anti-Ma2 PLE as an irAE and inform future management of this rare side effect.
Interestingly, although our patient did not derive clinical benefit from therapy as a result of PLE, his imaging continued to show a durable radiographic response for over 12 months in spite of receiving only one cycle of pembrolizumab. The Keynote-059 trial that studied single-agent pembrolizumab as third or greater-line therapy in gastric and gastro-oesophageal junction cancer found an objective response rate (ORR) of 11.6% and a median progression-free survival (PFS) of 2 months regardless of PD-1 tumour status. PFS at 6 months was 14.1%, and in those who had PD-1-positive tumours, the ORR was 15.5%.5 Our patient had an exceptional response, far superior to what is expected based on trial data. A review article cites a number of studies, which all demonstrated a significant association between the occurrence of irAEs and ICI efficacy in patients, which further supports the hypothesis that this patient’s PLE was related to ICI therapy given this durable radiographic response.15 However, it is very important to note that despite durable disease control, this patient did not ultimately derive clinical benefit due to what we suspect may have been treatment-related toxicity that contributed to his death.
Unfortunately, both irAEs and PLE have limited treatment options. Current guidelines for management of grade 3 irAEs include suspending the ICI and initiating high-dose corticosteroids, while grade 4 or higher irAEs generally warrant permanent discontinuation. Immunosuppressive therapies such as infliximab can be used in refractory cases.16 Although no controlled studies have been performed regarding management of PLE, patients with PLE are typically treated with steroids, IVIG/plasma exchange and rituximab for symptom stabilisation. However, Ma2 encephalitis has been noted to be uniquely difficult to treat and historically only a third of patients will improve with these measures. PLE associated with immunotherapy is felt to be distinct from autoimmune encephalitis, which tends to be more responsive and reversible with the above treatment options.17 18
This is an unusual presentation of PLE, suspected to be treatment related, in a patient with advanced GEJ adenocarcinoma following a short course of treatment with an ICI associated with a durable radiographic disease control. This case adds to sparse but growing literature describing the association of PLE and treatment with ICI and also the observed associations with certain, often severe, irAEs with good tumour responses. In conclusion, physicians should pay careful attention to the presence of neurologic symptoms among patients receiving ICI and ensure that appropriate evaluation is carried out to address this rare but serious entity.
Learning points
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Neurological symptoms in patients receiving immune checkpoint inhibitors should receive special attention and appropriate evaluation, even when subtle.
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There is sparse but growing literature describing an association between paraneoplastic limbic encephalitis and treatment with immune checkpoint inhibitors, which warrants further investigation.
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Durable disease control has been observed to be associated with significant adverse effects from treatment with immune checkpoint inhibitors in some patients.
Ethics statements
Patient consent for publication
Footnotes
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Twitter @BenMironMD
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Contributors LL and BM were the primary contributors in writing the manuscript. ON and CLK cared for the patient, revised the manuscript and provided additional information on the neurological aspects of the case. ED and BM cared for the patient, revised the manuscript and provided additional insight into the oncological aspects of the case. All authors have read and approved the final manuscript.
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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.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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