Successful Management of Immune-Mediated Myelitis in a Renal Cancer Patient: A Case Report Open Access

Immune checkpoint inhibitors (ICIs) have significantly advanced cancer therapy by enhancing T-cell-mediated immune responses against tumor cells through the blockade of inhibitory pathways such as CTLA-4, PD-1, and PD-L1 [1]. While these agents have improved survival outcomes in various malignancies, their use is associated with immune-related adverse events (irAEs) due to nonspecific activation of the immune system. Neurological irAEs, although rare, are of particular concern because of their potential severity and risk of long-term morbidity [2]. Among these, immune-mediated myelitis is an exceptionally rare but serious complication characterized by inflammation of the spinal cord, which can lead to significant neurological deficits. Early recognition and prompt management are essential to mitigate these risks [3]. In this case report, we describe a patient with metastatic renal cell carcinoma who developed multiple irAEs, including immune-mediated myelitis, during combination immunotherapy with anti-PD-1 and anti-CTLA-4. The patient was successfully treated with high-dose corticosteroids, highlighting the importance of timely intervention and multidisciplinary management in such cases.

A 54-year-old Caucasian white male was diagnosed in September 2021 with intermediate-risk, high-grade clear cell renal carcinoma, presenting with metastatic lung disease. In November 2021, a left radical nephrectomy was performed due to a symptomatic primary tumor and nonthreatening visceral disease. In January 2022, the patient began first-line treatment with a combination of nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) every 3 weeks for four cycles, followed by nivolumab monotherapy.

In April 2022, after completing four cycles of nivolumab and ipilimumab, a follow-up CT scan showed a partial response in the lung metastases. Laboratory tests revealed cortisol levels of <0.2 μg/dL, TSH at 0.4 mUI/L, and T4 at 0.57 nmol/L. With suspected immune-related hypophysitis grade 1, a cranial magnetic resonance imaging (MRI) was performed, which showed an enlargement of the pituitary gland within the sella turcica, confirming the diagnosis.

A consultation with the endocrinology department confirmed the diagnosis of grade 1 hypophysitis with grade 2 adrenal insufficiency and grade 2 central hypothyroidism secondary to immunotherapy. The patient was started on replacement therapy with hydrocortisone 60 mg/24 h and levothyroxine 100 μg/24 h and continued treatment with nivolumab at 480 mg every 28 days.

In August 2022, after four cycles of nivolumab, the patient presented with right eyelid ptosis and weakness in the fingers of his right hand. A cranial MRI revealed a significant reduction in the size of the sellar lesion. Tests for anti-acetylcholine receptor antibodies and anti-muscle-specific kinase antibodies were negative, and an electromyography was performed, ruling out myasthenia gravis and Eaton-Lambert syndrome. The results were compatible with moderate chronic axonal sensorimotor polyneuropathy without evidence of an acute process and signs of reinnervation, so nivolumab treatment was continued. A timeline of the patient’s clinical events is illustrated in Figure 1.

In December 2022, after seven cycles of nivolumab, the patient was admitted with back pain and band-like dysesthesia from T4 to T10, without motor deficits. A full spinal MRI showed involvement of the cervicothoracic spinal cord, raising suspicion of immune-mediated myelitis (Fig. 2). Focal areas of myelitis in the spinal cord, extending longitudinally from C7 to T3 at the cervicothoracic level can be seen. A subtle contrast enhancement is also observed in the periphery of the spinal cord from C4 to T3 at the cervical level.

Neurology consultation led to a lumbar puncture, which showed negative results for oligoclonal bands and cytology. The findings were consistent with a diagnosis of immune-mediated myelitis grade 3 secondary to immunotherapy toxicity, and nivolumab was discontinued. The patient was treated with 1 gram of methylprednisolone every 24 h for 5 days, with clinical improvement. He was then placed on a tapering corticosteroid regimen with oral prednisone, which was finally discontinued in May 2023 without recurrence of symptoms.

The patient remained under clinical follow-up until April 2023, when pulmonary disease progression was detected. At that time, treatment with pazopanib 800 mg daily was initiated. Since then, the patient has maintained a partial response to the therapy, which is ongoing to date. The CARE Checklist has been completed this case report and is attached as online supplementary material at https://doi.org/10.1159/000543929.

We presented a patient with metastatic renal cell carcinoma who developed multiple irAEs, including hypophysitis, adrenal insufficiency, hypothyroidism, and notably, immune-mediated myelitis related to dual ICI therapy. After initiating high-dose corticosteroid therapy, the patient showed significant improvement in neurological symptoms without recurrence following corticosteroid tapering. This allowed for the initiation of second-line anticancer treatment, to which the patient responded favorably. This case demonstrates the successful management of severe immunotherapy-related side effects and adds valuable insights to the limited literature on immune-mediated myelitis.

ICIs targeting PD-1, PD-L1, and CTLA-4 have revolutionized cancer treatment, offering substantial survival benefits across various malignancies. However, their use is associated with irAEs resulting from enhanced immune activation. These adverse events are distinct from those seen with traditional chemotherapy and can affect multiple organ systems. Neurological irAEs occur in approximately 1–5% of patients treated with ICIs, with higher rates observed in those receiving combination therapy [4, 5]. However, some studies have reported slightly higher incidences. For instance, a large analysis of 50,406 cases of immunotherapy-related adverse events found that neurological irAEs accounted for 7.2% (3,619 cases) of all reported events. The most common neurological irAEs in this analysis were neuropathy (2.7%) followed by hypophysitis (1.8%), encephalitis/myelitis (0.9%), myasthenia gravis (0.7%), meningitis (0.4%), and Guillain-Barre syndrome (0.2%). Specifically, 1,985 cases were associated with anti-PD-1 therapy, 372 with anti-PD-L1 inhibitors, 366 with anti-CTLA-4 agents, and 898 with combination ICI therapy [6]. This suggests that the incidence of neurological irAEs may be higher than previously estimated, emphasizing the need for heightened awareness and monitoring for these potentially severe complications as they carry a significant risk of irreversible damage [4, 5].

Immune-mediated myelitis is an exceedingly rare but serious neurological irAE characterized by inflammation of the spinal cord, leading to symptoms such as limb weakness, sensory disturbances, and autonomic dysfunction [7]. Early recognition and prompt management are crucial to prevent irreversible neurological damage. The pathophysiology of immune-mediated myelitis induced by ICIs is believed to involve a breakdown of immune self-tolerance, leading to autoimmune inflammation of the spinal cord [8]. By blocking inhibitory pathways, ICIs enhance T-cell activation, which can result in cross-reactivity against antigens in the central nervous system, including the spinal cord. This aberrant immune response may cause demyelination and neuronal damage. Although the exact mechanisms remain unclear, it is hypothesized that genetic predispositions and pre-existing subclinical autoimmune conditions may increase the susceptibility to such adverse events [8].

Few cases of immune-mediated myelitis have been reported in the literature, emphasizing its rarity but also its significance as a serious neurological irAE. As summarized in Table 1, which includes previously published works on immune-related myelitis, both case reports and case series have documented instances where myelitis developed following treatment with anti-PD-1, anti-PD-L1, anti-CTLA-4 agents, or their combinations.

Chatterton et al. [9] described a case series of 4 patients. One patient with stage IV non-small cell lung cancer treated with pembrolizumab presented a grade 5 myelitis which started with lower back pain, ascending distal numbness and paresthesia, lower limb weakness, and fecal incontinence. The initial therapeutical approach was dexamethasone 8 mg for 7 days followed by 1 g of methylprednisolone for 5 days. The patient had a poor clinical response and IVIG was started for 5 days. There was shown no clinical improvement, and the patient died in the following 3 weeks. Other patient had a stage IV melanoma and started treatment with ipilimumab and nivolumab. After 2 months of starting treatment, he developed distal numbness, paraparesis, and urinary retention and was diagnosed of a grade 4 myelitis. Dexamethasone 8 mg was started followed by IVIG because of no improvement of the symptoms. After the treatment, the outcome was a residual motor and sensory weakness at C7 level. He received nivolumab for further 2 cycles until disease progression. Two patients with diagnosis of stage IIIB and IV melanoma that received treatment with nivolumab and developed grades 2 and 3 myelitis. They started methylprednisolone 1 g for 5 days. One of them presented a completed resolution of the myelitis and the other one needed to receive IVIG for 5 days with no recurrence of the myelitis [9].

Picca et al. [10] reported a case series of 7 patients who presented immune-mediated myelitis. Symptoms were paraparesis (100%), sphincter dysfunction (86%), sensory impairment (71%), and ataxia (43%), and it appeared after a median of 7 cycles of ICIs (range 3–51). A spinal MRI was performed in all of them, and they received high-dose glucocorticoids. Five of them needed a second-line agent and it was started after a median of 20 days from the start of the symptoms. The second-line treatments were plasmapheresis, cyclophosphamide, IVIG, natalizumab, and association of ruxolitinib and tocilizumab. None of them was retreated with ICIs and after a median of 6 months 1 patient died, 1 presented resolution of the symptoms, and 5 patients remained disabled [10].

There are other case reports that show untypical presentation of immune-mediated myelitis with uncommon onset of symptoms. For example, Lambert-Cheatham et al. reported a case of transverse myelitis along with neuromyelitis optica and bilateral papillitis induced by pembrolizumab. The onset of symptoms was right eyefloaters and bilateral disc edema in the retinal tomography. The patient also presented mild lower extremity weakness, and the spine MRI showed cervical and thoracic demyelination. Methylprednisolone 1 g for 5 days was started and after 3 months of tapering prednisone, there was a complete resolution of the event [11].

Kim et al. [12] described a patient with hepatocellular carcinoma treated with atezolizumab and bevacizumab who developed transverse myelitis and was successfully managed with 5 sessions of plasmapheresis due to contraindications for corticosteroid use (diabetes mellitus). This patient discontinued ICIs after four cycles because of a septic knee and the particularity of this case is that the onset of the myelitis was 3 months after atezolizumab was discontinued [12]. Similarly, Esechie et al. [13] reported a case of myelitis in a patient with non-small cell lung cancer on maintenance treatment with atezolizumab who did not respond to corticosteroids and required three sessions of plasmapheresis for clinical resolution. The singularity of this case report is that the clinical featuring of the myelitis began the day after the administration of the second dose of the COVID-19 vaccine. The authors suggest that the immunization with the vaccine may have caused a worsening of the existing neuroinflammatory process [13].

As has been seen in the previous described case reports, initial management usually involved high-dose corticosteroids, leading to clinical improvement in many patients. However, some cases experienced symptom recurrence or inadequate response to corticosteroids, necessitating additional immunomodulatory treatments such as plasmapheresis, infliximab, rituximab, or cyclophosphamide, in line with current clinical guidelines [3]. These cases illustrate that while high-dose corticosteroids are the mainstay of initial treatment for immune-mediated myelitis, some patients may require additional or alternative immunosuppressive therapies when corticosteroids are contraindicated or ineffective. The variability in treatment responses underscores the importance of individualized patient management and the need for a multidisciplinary approach to optimize outcomes and prevent irreversible neurological damage.

The occurrence of 1 irAE may predispose patients to additional irAEs, warranting closer follow-up and vigilant monitoring. Studies have shown that patients who develop an initial irAE are at increased risk of experiencing subsequent irAEs [14]. This may be due to a heightened state of immune activation or an underlying predisposition to autoimmunity. In our case, the patient developed an endocrine irAE before presenting with immune-mediated myelitis.

This case underscores the potential severity of immune-mediated myelitis as a rare but serious complication of ICIs in the treatment of metastatic renal cell carcinoma. The successful management of myelitis in this patient, with prompt initiation of high-dose corticosteroids and a carefully monitored taper, highlights the importance of early intervention. Furthermore, the occurrence of 1 irAE may predispose patients to additional irAEs, warranting closer follow-up and vigilant monitoring. A multidisciplinary approach is essential to ensure timely diagnosis, effective management, and the continued success of antineoplastic treatments, even in the face of severe irAEs.

This case report has been conducted in accordance with the ethical principles set forth in the Declaration of Helsinki of the World Medical Association for medical research involving human subjects, as well as with local medical ethics and data protection regulations. The patient was clearly and comprehensibly informed about the purpose of the study, the procedures involved, potential risks and benefits, and the confidentiality of personal information. Written informed consent was obtained for the use of clinical data and medical images for the publication of this case, ensuring that the patient’s personal data were anonymized at all times to protect their privacy. Since this case report does not involve an experimental intervention nor alter the standard care of the patient, ethical approval was waived by the Ethics Committee of Hospital General Universitario de Elche. All sensitive information and patient images have been handled in accordance with international and local data protection regulations. Written informed consent was obtained from the patient for publication of this case report and any accompanying images, with all processes adhering to applicable data protection regulations. All patient data have been de-identified according to European and national privacy standards to ensure confidentiality prior to manuscript submission.

The authors have no conflicts of interest to declare.

The authors declare no funding was obtained or used for this study.

Paula Rodríguez Payá: conceptualization, methodology, investigation, data curation, writing – original draft, and writing – review and editing. Álvaro Muñoz Abad, Beatriz Grau Mirete, Asia Ferrández Arias, and Miguel Borregón Rivilla: conceptualization, methodology, and writing – review and editing. Javier David Benítez Fuentes and Federico J. Vázquez Mazón: conceptualization, supervision, writing – review and editing, and validation.

All data produced or examined during this study are contained within this article and its supplementary material files. Further inquiries can be directed to the corresponding author.