A 37-year-old man with newly diagnosed biphasic pleural mesothelioma developed acute neurologic symptoms after receiving four cycles of nivolumab plus ipilimumab. Within one month after ICI exposure he experienced sudden bilateral lower limb weakness, sensory abnormalities, an anterior waist girdle sensation, and loss of autonomous urination. On neurologic examination upper limb strength was normal while lower limb strength was Grade I. Deep sensation was decreased in both lower limbs, superficial sensation deficits were asymmetric, bilateral hyperreflexia and positive Babinski signs were present, and meningeal signs were absent.
The temporal profile, rapid progression, sensory level, and autonomic dysfunction were clinically consistent with a severe spinal cord inflammatory process such as transverse myelitis. Given the recent immune checkpoint inhibitor exposure and imaging and laboratory findings (below), the multidisciplinary team favored a diagnosis of ICI-associated transverse myelitis.
Cerebrospinal fluid (CSF) obtained at symptom onset demonstrated marked inflammatory abnormalities: an opening pressure of 122 mmH2O, yellowish appearance with positive Pandy’s test (3+), pleocytosis (100 × 10^6/L) with lymphocytic predominance, and markedly elevated total protein (5.60 g/L). CSF oligoclonal bands were positive while serum oligoclonal bands were negative. CSF cytology showed no malignant cells.
CSF next-generation sequencing (NGS) detected Epstein–Barr virus reads (57 reads, relative abundance 99.1%), whereas blood NGS was negative. Routine serologic testing was notable for serum anti-Ri IgG positivity at a titer of 1:32. Demyelinating antibodies (anti-AQP4, anti-MOG, anti-GFAP) were negative in both serum and CSF. Other autoantibodies, thyroid function, and serum tumor markers showed no obvious abnormalities.
Initial thoracic spine MRI revealed heterogeneous intramedullary T2 hyperintensity and long-segment intramedullary and meningeal contrast enhancement spanning approximately T2–T10, with irregular spinal cord morphology—findings interpreted as inflammatory myelitis rather than focal metastatic disease.
One month after combined steroid and MMF therapy, follow-up MRI showed partial reduction in the extent and intensity of intramedullary enhancement. However, new cystic or myelomalacic foci were visible within the previously affected cord segments, consistent with potential irreversible parenchymal injury.
A multidisciplinary team (oncology, neurology, radiology) reviewed the case. Arguments against leptomeningeal malignancy included negative CSF cytology and imaging patterns more typical of inflammation. EBV detection in CSF raised the possibility of viral myelitis, although isolated EBV myelitis is uncommon and often involves shorter segments. Serum anti-Ri positivity raised paraneoplastic considerations, though the clinical pattern and timing relative to recent ICI therapy supported dominant immune checkpoint inhibitor–mediated pathology.
The team concluded that a mixed multifactorial etiology could not be excluded, but that ICI-associated TM was the predominant diagnosis guiding treatment.
The patient received IVIg (25 g daily for 5 days) with limited clinical effect. High-dose methylprednisolone pulses (500 mg daily for 5 days) produced partial relief of pain but no meaningful recovery in motor or autonomic function. Subsequent tapering and variable dosing of methylprednisolone and oral prednisone failed to restore significant neurologic function. Persistent sensory, motor, and autonomic deficits plus imaging and inflammatory CSF results met criteria for a steroid-unresponsive course.
Given the inadequate response to first-line measures, mycophenolate mofetil (MMF) 0.5 g twice daily was initiated in combination with methylprednisolone (80 mg daily for 7 days) starting 15 December. Over the next month of combined therapy, the patient demonstrated partial neurologic improvement: bilateral lower limb strength improved from Grade I to Grade II, superficial sensation on the right partially recovered, and the sensory level shifted caudally. Autonomic dysfunction (loss of autonomous urination) and anterior girdle sensation persisted.
Follow-up MRI at one month showed partial reduction of intramedullary enhancement concurrent with MMF plus steroids, though cystic/myelomalacic changes were already apparent, suggesting incomplete reversibility of cord injury. Serum ferritin, elevated during the acute phase, declined during treatment.
No MMF-related gastrointestinal symptoms, marrow suppression, or hepatic or renal dysfunction were reported in the treatment period described.
After stability of neurologic status and control of spinal inflammatory lesions, systemic tumor therapy was resumed. Pemetrexed plus carboplatin chemotherapy was restarted on 29 December and continued alongside maintenance MMF and low-dose prednisone. The patient completed two cycles with close monitoring of neurologic status, blood counts, and organ function; no severe chemotherapy-related adverse events were observed. Tumor evaluation during follow-up showed stable disease with no new lesions or progression.
During the documented treatment period, the patient did not experience MMF-attributed myelosuppression, gastrointestinal intolerance, or hepatic/renal toxicity; steroid adverse effects were mild. The plan included gradual steroid taper guided by neurologic recovery while continuing MMF 0.5 g twice daily as long-term immunosuppression to reduce recurrence risk, with regular thoracic spine MRI and tumor imaging and long-term multidisciplinary follow-up.
This case underscores diagnostic complexity when ICI exposure, CSF EBV reads, and paraneoplastic antibodies coexist. Multidisciplinary assessment attributed predominant causality to ICI-induced immune dysfunction. MMF’s mechanism—IMPDH inhibition with suppression of T and B lymphocyte proliferation and reduced cytokine production—provides a rationale for its use as a second-line immunosuppressant in steroid-unresponsive ICI-associated TM.
The report situates MMF among other second-line options (IVIg, plasmapheresis, cyclophosphamide, rituximab) but notes limited high-quality evidence to define standard therapy. Imaging evidence of cystic or myelomalacic cord change warns that timely, effective immunosuppression remains critical to limit irreversible injury. This observational outcome suggests MMF may contribute to partial clinical and radiologic improvement in some steroid-unresponsive cases, but causality cannot be definitively established from a single case and mixed etiologies may confound interpretation.
Longer-term outcomes, optimal duration of MMF, and comparative effectiveness versus other second-line agents were not reported in this case and remain areas requiring further study.