Aseptic meningitis is a rare immune-related adverse event (irAE), which occurs during treatment with immune checkpoint inhibitors (ICIs). This condition has non-specific symptoms and exhibits no clear signs on magnetic resonance imaging (MRI). There are only a few reports of aseptic meningitis caused by pembrolizumab treatment for non-small cell lung cancer (NSCLC). The present study includes a report of such a case and a review of the related literature. A 67-year-old Japanese man received first-line pembrolizumab treatment for NSCLC and subsequently developed severe nausea and vomiting. No significant findings were observed following a computed tomography (CT) scan, MRI of the brain and upper gastrointestinal tract, or upper gastrointestinal endoscopy. Cerebrospinal fluid analysis revealed lymphocyte infiltration and elevation of the IgG index, without indications of metastasis or infection, which suggested the presence of aseptic meningitis. The symptoms immediately improved following prednisolone treatment, and aseptic meningitis was diagnosed as an irAE related to pembrolizumab treatment. Given that aseptic meningitis can cause non-specific symptoms, including headache and nausea, the possibility of an irAE should be considered in patients with non-specific symptoms who are receiving ICIs, and a cerebrospinal fluid examination should be performed.
Immune checkpoint inhibitors (ICIs) are used to treat various malignant tumors, including lung cancer (
In August 2018, a 67-year-old Japanese man with a history of asthma and chronic obstructive pulmonary disease was referred to our hospital due to chest pain. Chest radiography revealed linear opacity in the right middle lung field (
Oxycodone hydrochloride hydrate tablet (10 mg/day) was administered for the chest pain that was caused by the pleural lesions, and γ-knife irradiation was performed for the two metastatic brain lesions. Six days later, the patient started treatment using pembrolizumab (200 mg, once every 3 weeks). However, on day 2 after starting pembrolizumab treatment, the patient developed persistent nausea and was admitted to our department on day 5 to identify the cause of the nausea. A physical examination showed no fever, Kernig's sign, Brudzinski's sign and a stiff neck, other than tachycardia, and no altered mental status. Blood tests revealed a slight increase in C-reactive protein (CRP) concentration (0.74 mg/dl), but no other abnormalities in electrolyte concentrations or endocrine function were observed. Contrast-enhanced abdominal CT showed only a slight thickening of the stomach wall and contrast effects, without other new findings, and upper gastrointestinal endoscopy showed no obstructive or bleeding lesions, only atrophic gastritis, which was insufficient to identify the cause of the nausea. The nausea was therefore attributed to the opioid treatment, and opioid rotation (from oxycodone hydrochloride hydrate tablet 30 mg/day to fentanyl continuous infusion 0.6 mg/day) was performed. The nausea appeared to improve by day 9 after starting pembrolizumab treatment, but subsequently worsened on day 15. Brain contrast-enhanced MRI revealed no tumor progression, no occurrence of new tumors and no subcranial enhancement, suggesting meningitis (
Treatment with immune checkpoint inhibitors (ICIs) can be used for various types of cancer, including renal cell carcinoma, melanoma, head and neck cancers, urothelial carcinoma and Hodgkin lymphoma (
Head jolt sign, Kernig's sign, Brudzinski's sign and stiff neck are well-known signs of meningitis, although only 29% of cases of aseptic meningitis involve these symptoms (
To distinguish between cancerous and aseptic meningitis as an irAE is challenging. The sensitivity of CSF puncture for cancerous meningitis is 50-60% for a single dose and 80% for multiple doses (
Several reports have described ipilimumab-induced meningitis, which may be associated with the drug's affinity for the cranial nervous system. Indeed, ipilimumab frequently induces hypophysitis, which is thought to be caused by the expression of CTLA-4 in the anterior pituitary cells and a resulting type II hypersensitivity (
The main treatment for neurological irAEs involves immunosuppression, with prednisone or methylprednisolone being recommended for CTCAE grade 3 or higher meningitis (
A prospective cohort study of 43 patients with advanced NSCLC revealed that patients with irAEs after nivolumab treatment had a higher objective response rate (37 vs. 17%) and longer median progression-free survival (6.4 vs. 1.5 months) (
While repeat treatment using ICIs may be an effective strategy for cases of aseptic meningitis as an irAE, it is associated with a risk of meningitis relapse (
In conclusion, the present study reported a case of nausea and vomiting that was ultimately diagnosed as aseptic meningitis, as an irAE related to pembrolizumab treatment. Although there are a few reports of meningitis as an irAE, this condition may be underdiagnosed due to its non-specific symptoms. The majority of patients will experience a good response to steroid treatment, and a good response rate for ICIs has been observed in patients with irAEs. A CSF examination is required to diagnose aseptic meningitis as an irAE, which may be supported based on lymphocytic inflammation findings, such as elevated lymphocyte or ADA values. Since there are few reports of aseptic meningitis after ICIs for lung cancer, an accumulation of further case reports is desired to discern whether re-administration of ICIs is acceptable.
Not applicable.
All data generated or analyzed during this study are included in this published article.
GI collected the data and wrote the paper. YF treated the patient and revised the article for important intellectual content as the corresponding author. HM and HT treated the patient and provided advice on the paper. KA, KK, YuukiH, RK, TN, KoheiY, YT, YS, TS and KosukeY collected, analyzed and interpreted the clinical data. SK collected, analysed and interpreted the neurological findings and provided advice on the paper. YU, YasushiH and KN analyzed and interpreted the pathological data and provided advice on the paper. MK and AY critically revised the manuscript for important intellectual content. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity (including the collected data) of any part of the work are appropriately investigated and resolved.
This is to certify that the above case report was approved for publication by Tottori University Ethics Review Board (serial no. 22J002).
As the patient was deceased, according to hospital policy, request to publish the case report was published online, and as no contest was made by any family member or other person, the hospital provided approval to proceed with publication of the case study.
The authors declare that they have no competing interests.
Radiography and CT findings. (A) Chest radiography revealed linear opacity in the right middle lung field. (B) Trunk CT revealed multiple thickenings in the right pleura and right pleural effusion. (C) Trunk contrast-enhanced CT revealed a hilar mass shadow with contrast enhancement along the right main bronchus from below the tracheal bifurcation. There were no findings to explain the nausea, despite the slight thickening and contrast enhancement on the stomach wall. CT, computed tomography.
MRI findings. (A and B) Brain contrast-enhanced MRI at diagnosis revealed a metastatic brain tumor in the right frontal lobe and cerebellar hemisphere lesions (white arrows). (C and D) Brain-contrast MRI conducted after admission revealed no signs of encephalitis or meningitis, such as contrast enhancement at the brain and meninges. The existing lesions regressed after γ-knife irradiation, with no subsequent progression (white arrows). MRI, magnetic resonance imaging.
Clinical course. Following pembrolizumab treatment, red papules (CTCAE grade 1) appeared around the extremities. Abnormal laboratory findings included liver enzyme elevation (CTCAE grade 3), as well as decreased TSH and increased T4, which indicated the presence of destructive thyroiditis (CTCAE grade 2). These symptoms were improved after steroid treatment. Dysgeusia (CTCAE grade 1) and gynecomastia (CTCAE grade 1) were also observed during pembrolizumab treatment and persisted following steroid treatment. Bet, betamethasone; PSL, prednisolone; TSH, thyroid stimulating hormone; ALT, alanine aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events.
CT findings. (A) CT prior to pembrolizumab treatment. (B) CT 56 days after treatment showed tumor shrinking and partial response, based on the response evaluation criteria in solid tumors. CT, computed tomography.
Cerebrospinal fluid analysis.
Test | Result | Test | Result | Test | Result |
---|---|---|---|---|---|
Color | Colorless | Total protein (mg/dl) | 80 | Bacteria | Negative |
Turbidity | Clear | Albumin (mg/dl) | 41 | Fungi | Negative |
Total cell count (/µl) | 12 | LDH (U/l) | 22 | Mycobacteria | Negative |
Polynuclear (%) | 8 | Glucose (mg/dl) | 61 | Tb-PCR | Negative |
Mononuclear (%) | 92 | CRP (µg/dl) | <1 | MAC-PCR | Negative |
Open pressure (cmH2O) | 10 | CEA (ng/dl) | <0.8 | Pathology | No malignant cells |
ADA | 3.1 | Lymphocyte infiltration | |||
IgG (mg/dl) | 11.5 | ||||
IgG index | 0.64 |
LDH, lactate dehydrogenase; CRP, C-reactive protein; CEA, carcinoembryonic antigen; ADA, adenosine deaminase; Tb-PCR, PCR assay for tuberculosis; MAC-PCR, PCR assay for the
Reported cases of meningitis as an immune-related adverse event after immune checkpoint inhibitor treatment.
Patient no./ Investigators (Refs.) | Age (years) | Sex | Cancer | ICIs | Cycle | Initial symptoms | CSF lymph ocytes | MRI abnormal | Other irAEs | Treatment | Time to resolution | Tumor Response | Re-challenge ICIs |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
#1/Spain |
N/A | N/A | Mela | I+N | 1 | Headache, nausea | + | - | Hepatitis | - | 7 weeks | PR | After 4 weeks |
#2/Spain |
N/A | N/A | Mela | I | 2 | Headache, drowsiness, nausea, vomiting | + | - | - | - | 10 days | SD | - |
#3/Spain |
N/A | N/A | Mela | I | 2 | Delirium | - | - | - | PSL p.o | 8 weeks | PD | - |
#4/Bot |
51 | F | Mela | I | 1 | Headache, fever | + | - | N/A | Dex 8 mg p.o | 2 days | N/A | N/A |
#5/Voskens |
52 | F | Mela | I | 1 | Nausea, vomiting, chills, rash | + | - | N/A | DEX | N/A | PD | - |
#6/Bompaire |
56 | M | Mela | I | 4 | Vertigo, dizziness, cervicalgia, headache | + | Brain-/ spinal+ | Radiculo neuritis | mPSL 1g IV + IVIg | 2 years | CR | - |
#7/Yang |
N/A | N/A | Renal | I | 4 | Headache, photophobia, cranial nerve disorder | + | - | N/A | DEX | <1 month | N/A | N/A |
#8/Takamatsu |
70 | F | Renal | I+N | 2 | Headache, nausea, dizziness | + | - | Isolated ACTH deficiency | PSL 1 mg/kg IV | A few days | CR | 50th day with PSL 10 mg/day |
#9/Takamatsu |
70 | F | Renal | I+N | 3 | Headache, anorexia | + | N/A | Liver dysfunction | PSL 1 mg/kg IV | N/A | CR | - |
#10/Cordes |
58 | M | UC | N | 12 | Fever, chills, malaise, dry cough, headache, bilateral eye pain, right ear pain | + | + | N/A | mPSL 1 mg/kg IV | <3 days | PR | - |
#11/Toyozawa |
71 | F | NSCLC | A | 1 | Fever, consciousness disorder | - | - | N/A | mPSL 1 mg/kg IV | 1 day | N/A | - |
#12/Toyozawa |
55 | M | NSCLC Ade | A | 1 | Fever, consciousness disorder | - | - | N/A | mPSL 1 mg/kg IV | 4 days | N/A | - |
#13/Toyozawa |
50 | M | NSCLC Ade | A | 1 | Fever, neck and legs pain, consciousnesss disorder | + | + | N/A | mPSL 1 mg/kg IV | 2 days | N/A | - |
#14/Lima |
55 | M | NSCLC Ade | P | 11 | Bilateral throbbing, frontal headache | + | - | Hepatitis | Dex 10 mg IV | 1 day | CR | - |
#15/Present case | 67 | M | NSCLC Ade | P | 1 | Nausea, vomiting | + | - | Hepatitis, dysgeusia, gynecomastia thyroid dysfunction | PSL 1 mg/kg IV | 3 days | PR | - |
ICIs, immune checkpoint inhibitors; CSF, cerebrospinal fluid; MRI abnormal means contrast effect of meninges or brain parenchyma; N/A, not available; M, male; F, female; Mela, melanoma; Renal, renal cell carcinoma; UC, urothelial carcinoma; NSCLC, non-small cell lung cancer; Ade, adenocarcinoma; I, ipilimumab; N, nivolumab; P, pembrolizumab; IV, intravenous; p.o, per os; PSL, prednisolone; DEX, dexamethasone; IVIg, intravenous immunoglobulin; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.