ABSTRACT
A 69‐year‐old man who was a former plumber with a history of occupational asbestos exposure was diagnosed with unresectable pleural mesothelioma. Six months after initiation of combination therapy with ipilimumab and nivolumab, he presented with an altered level of consciousness and extrapyramidal symptoms and was diagnosed with immune‐related encephalitis. Although high‐dose corticosteroid therapy and intravenous immunoglobulin led to partial improvement in his level of consciousness, the response was limited. Immune‐related encephalitis is rare, especially in association with pleural mesothelioma. Optimal management of the condition needs to be established.
Keywords: asbestos, encephalitis, ipilimumab, magnetic resonance imaging, nivolumab
Immune‐related encephalitis is a rare condition characterized by nonspecific symptoms and often minimal abnormal findings on examination. Optimal management of immune‐related encephalitis needs to be established.
1. Introduction
The introduction of immune checkpoint inhibitors (ICI) has dramatically changed the treatment of unresectable pleural mesothelioma (PM). However, patients may still suffer from adverse events specific to immunotherapy. We report a case of immune‐related encephalitis in a patient with PM.
2. Case Report
A 69‐year‐old man with a history of occupational asbestos exposure as a former plumber visited a local clinic due to dyspnea. He had comorbidities including hypertension and rheumatoid arthritis. He also had a smoking history of 800 pack‐years. He presented with right pleural effusion, and cytological examination including cell block analysis of BAP1 gave the diagnosis of PM. He was referred to our hospital for the treatment and started on combination therapy with ipilimumab (1 mg/kg every 6 weeks) and nivolumab (360 mg/body every 3 weeks).
Six months after the start of the treatment, when the fourth course was administered, he was found with an altered level of consciousness and cognitive disturbance and brought to our hospital. Impairments in memory and orientation, along with action and postural tremors of both upper and lower limbs suggestive of extrapyramidal symptoms, were observed. He was afebrile, and peripheral blood tests showed no evidence of systemic inflammation. Thyroid function was within normal limits.
Neurological examination revealed a Japan Coma Scale (JCS) score of 20, a Glasgow Coma Scale (GCS) score of 11 (E2V3M6), and a Hasegawa's Dementia Scale‐Revised (HDS‐R) score of 6, indicating impairments in memory and orientation. Contrast‐enhanced magnetic resonance imaging (MRI) of the brain demonstrated a hyperintense signal on T2‐weighted imaging and fluid‐attenuated inversion recovery (FLAIR) in the ventral to medial aspect of the left basal temporal lobe, with minimal contrast enhancement (Figure 1). Electroencephalography (EEG) revealed generalized slowing and intermittent spike activity in the left temporal region. Cerebrospinal fluid (CSF) analysis showed no significant pleocytosis, with a cell count of 5/μL, but revealed a mild elevation in protein levels at 61 mg/dL. CSF glucose levels were within the normal range.
FIGURE 1.
Contrast‐enhanced magnetic resonance imaging of the brain demonstrated a hyperintense signal on fluid‐attenuated inversion recovery in the ventral to medial aspect of the left basal temporal lobe.
Based on these findings and the subacute clinical course, autoimmune‐mediated encephalitis as an immune‐related adverse event or herpes simplex virus (HSV) encephalitis was initially suspected. Autoantibody testing including anti‐Hu, anti‐Yo, anti‐Ri, and a paraneoplastic neurological syndrome (PNS) antibody panel including anti‐Ma2 were negative.
Treatment was initiated with methylprednisolone of 1 g for 3 days and acyclovir at 375 mg every 8 h. Acyclovir was discontinued after HSV‐PCR of the CSF revealed negative. After 3 days of high‐dose methylprednisolone, oral prednisolone was started at 1 mg/kg/day and gradually tapered weekly. The patient's consciousness level improved to a JCS score of 3 and GCS score of 14 (E4V4M6), but significant disorientation and altered mental status persisted, with a Mini‐Mental State Examination (MMSE) score of 14. Intravenous immunoglobulin (IVIg) was administered concomitantly at a dose of 15,000 mg/body (352 mg/kg) and his level of consciousness improved to a JCS score of 2, GCS score of 14 (E4V4M6), and MMSE score of 22. However, extrapyramidal symptoms and decreased comprehension persisted, leading to the addition of rituximab at a dose of 500 mg/body (375 mg/m2). The clinical course of the present case including delivered immunotherapy is presented as Figure 2. Although his MMSE score further improved to 26, residual symptoms such as impaired comprehension and delusions remained, leaving him unable to live independently.
FIGURE 2.
The clinical course and delivered immunotherapy in the present case. GCS, glasgow coma scale; IVIg, intravenous immunoglobulin; MMSE, mini‐mental state examination.
Follow‐up contrast‐enhanced brain MRI demonstrated lost its contrast enhancement in the ventral to medial left temporal lobe but exhibited scar atrophy, consistent with the clinical symptoms. Corticosteroids were gradually tapered and maintained with oral prednisolone at 7.5 mg/day. The patient received palliative care for PM, which progressed slowly, and died 21 months after the diagnosis of PM and 15 months after the onset of encephalitis.
3. Discussion
Neurological immune‐related adverse events (nirAEs) are rare. Although incidence rates vary among reports, nirAEs associated with ipilimumab plus nivolumab are reported to develop in 0.93% of cases, with encephalitis in 0.159% [1]. Another retrospective single‐center study of ICI‐treated cases reported an incidence rate of encephalitis of 0.55% [2]. Reports of nirAE in PM are quite limited. Encephalitis as a nirAE in the treatment of PM was developed in one case (0.33%) in the CheckMate 743 trial [3], and another case in the IFCT‐1501 MAPS2 trial [4]. In the clinical trial evaluating the combination of platinum, pemetrexed, and pembrolizumab for PM [5], one case of hypophysitis and one case of myelitis were reported, but no cases of irE were observed. Similarly, in real‐world clinical practice, there have been no reports to date of irE associated with pembrolizumab treatment for PM. Concerning the incidence and clinical characteristics of irE according to different ICI regimens, combination therapy of ICIs is expected to increase the risk of severe neurological irAEs. The prevalence of severe neurological irAEs that have a Common Terminology Criteria for Adverse Events grade of 3 or greater was 1.5%, with such severe cases more likely to occur in patients receiving combination therapy [6].
The diagnostic criteria for definite autoimmune encephalitis include: (1) subacute onset (rapid progression within 3 months) of working memory deficits, seizures, or psychiatric symptoms suggestive of limbic system involvement; (2) bilateral brain abnormalities on T2‐weighted FLAIR MRI, predominantly confined to the medial temporal lobes; (3) at least one of the following: CSF pleocytosis (white blood cell count > 5 cells/mm [3]), or EEG showing epileptic or slow‐wave activity involving the temporal lobes; and (4) reasonable exclusion of alternative causes. According to a case series on irE published in 2025 [2], bilateral temporal or multiple T2/FLAIR lesions were typical findings. Lymphocytic pleocytosis in the CSF is likewise reported to be a common finding in irE. In addition, Seki et al. have reported that autoimmune encephalitis typically presents with high signal intensity in the temporal lobe on T2‐weighted MRI and shows lymphocytic infiltration and elevated protein levels in CSF analysis though there were cases that do not exhibit these MRI or CSF findings [7]. Based on these reports, the MRI and CSF findings in the present case were considered to support a diagnosis of irE. According to the autoimmune encephalitis clinical criteria by Graus et al. [8], the presence of bilateral limbic encephalitis is the only MRI finding sufficient to diagnose definite autoimmune encephalitis. Since the hyperintense signal on FLAIR in the ventral to medial aspect was only demonstrated in the left basal temporal lobe in the current case, the diagnosis was considered probable rather than definite as irE.
The diagnosis of irE relies on clinical signs, MRI findings, and CSF analysis; however, patients often do not exhibit characteristic findings. Furthermore, the presence of specific autoantibodies necessitates differentiation from PNS. Tada et al. reported a case of anti‐Ma2 antibody‐associated PNS in sarcomatoid PM [9]. More recently, Okten et al. proposed that anti‐Ma2 encephalitis developing during nivolumab plus ipilimumab therapy may represent an ICI‐triggered (or ICI‐unmasked) PNS, rather than a conventional irE [10]. Differential diagnosis of irE from PNS often presents a challenge. Table 1 summarizes the clinical, laboratory, and imaging findings characteristic of irE and PNS. Furthermore, there is another important message that a negative paraneoplastic antibody panel does not exclude PNS. Up to 40%–50% of clinically diagnosed PNS are seronegative, depending on the syndrome and cohort [12]. Autoimmune encephalitis appears as PNS in association with onconeural antibodies against intracellular proteins including anti‐Hu and anti‐Ma2 antibodies. In a previous report, anti‐Ma2 antibodies were detected in seven of 19 patients with autoimmune encephalitis during ICI treatment [13]. In addition, there was a clear association between ICI use and increased diagnosis of anti‐Ma2 antibody‐associated PNS [14]. Based on current knowledge, it is potentially difficult to distinguish between ICI‐induced encephalitis and PNS [7]. In the current case, however, the likelihood of PNS is considered low, given the onset following ICI administration and the absence of relevant autoantibodies. Previous reports indicate that the interval between the initiation of ICI therapy and the onset of irE ranges from a median of 70 days (2 days to 71 weeks) to a median of 62 days (24 h to over 1 year). In the present case, irE occurred 6 months after the start of ICI therapy; it is consistent with these findings [2].
TABLE 1.
Comparison of paraneoplastic encephalitis and ICI‐related encephalitis.
| Paraneoplastic encephalitis | ICI‐related encephalitis | |
|---|---|---|
| Primary lesion sites | Cerebellum, Brainstem, Limbic system, Spinal cord, Dorsal root ganglia, Myenteric plexuses | Limbic system (medial temporal lobe) |
| MRI findings | FLAIR and T2 signal abnormalities involving the hippocampus and amygdala | FLAIR hyperintensity with contrast enhancement |
| Onset | Develop before the presence of the underlying cancer is detected in ~70% of patients. Subacute onset in weeks to months | Develop following ICI treatment. Acute to subacute onset within days to a few weeks |
| CSF | Lymphocytic pleocytosis | Lymphocytic pleocytosis |
| Antibody | Hu, Yo, Ma2 and so forth | Hu, Ma2, GAD65, GFAP, NMDAR etc. |
| Response to treatment | Rarely resolves with immunosuppressive therapy | Responsive to steroids, IVIg, plasma exchange |
| Reference | [11] | [2] |
Abbreviations: CSF, cerebrospinal fluid; FLAIR, fluid‐attenuated inversion recovery; GAD, glutamic acid decarboxylase; GFAP, glial fibrillary acidic protein; ICI, immune checkpoint inhibitor; IVIg, intravenous immunoglobulin; MRI, magnetic resonance imaging; NMDAR, N‐methyl‐D‐aspartate receptor.
Treatment of irE in the current case was administered according to autoimmune encephalitis. Therapeutic algorithm for autoimmune encephalitis is demonstrated in the best practice recommendations summary for acute management of autoimmune encephalitis [15]. In brief, once infection is ruled out based on basic CSF results and if biopsy for primary CNS lymphoma or neurosarcoidosis is not a consideration, acute immunotherapy with high‐dose corticosteroids should be started. If there is no clinical, radiological, or electrophysiological improvement by the end of the initial treatment cycle, IVIg or plasma exchange should be added. Rituximab can be considered in known or highly suspected antibody‐mediated autoimmunity, and cyclophosphamide can also be considered in known or highly suspected cell‐mediated autoimmunity. The current case demonstrated slight improvement in the level of consciousness, but the therapeutic effect was limited.
In conclusion, irE is a rare condition characterized by nonspecific symptoms and often minimal abnormal findings on examinations. The optimal management for irE should be established.
Author Contributions
Fumie Onishi, Naofumi Hara, Moeko Ota, Kiriko Onishi, Yusuke Fujioka, and Hisaaki Tanaka contributed to Conceptualization, Investigation, and Writing‐Original draft preparation. Nobukazu Fujimoto contributed to Investigation and Supervision.
Consent
The authors declare that written informed consent was obtained for the publication of this manuscript and accompanying images and attest that the form used to obtain consent from the patient's bereaved family complies with the journal's requirements as outlined in the author guidelines.
Conflicts of Interest
N.F. received honoraria from Ono Pharmaceutical. Other authors declare no conflicts of interest.
Onishi F., Hara N., Ota M., et al., “Immune‐Related Encephalitis in a Patient With Pleural Mesothelioma: Case Report,” Respirology Case Reports 14, no. 9 (2026): e70748, 10.1002/rcr2.70748.
Associate Editor: Motoko Tachihara
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.