Subacute CNS Demyelination After Treatment With Immune Checkpoint Inhibitors

PRACTICAL IMPLICATIONS

In a patient who develops neurologic symptoms while taking immune checkpoint inhibitors such as pembrolizumab, do consider CNS demyelination as a differential diagnosis.

Immune checkpoints are molecules on the surface of leucocytes which modulate the amplitude of immune responses. Monoclonal antibodies blocking these molecules are known as immune checkpoint inhibitors (ICIs) and have been shown to unleash antitumor immunity and mediate durable cancer regressions. ICIs include ipilimumab, which blocks the cytotoxic T-lymphocyte antigen-4, nivolumab and pembrolizumab which are against the programmed cell death protein 1 (PD-1).¹ The clinical use of these ICIs has led to significantly improved survival in patients with a variety of solid malignancies including melanoma.

ICIs have been associated with a number of immune-related adverse effects (irAEs) which are mainly due to the upregulation of T-cell activity and the consequential disruption of immune tolerance. Common irAEs include colitis, pneumonitis, hepatitis, rash, and endocrinopathies. These irAEs are normally responsive to immunosuppression with corticosteroid therapy or with other immunosuppressive agents such as infliximab; therefore, early recognition and treatment of neurologic irAEs is essential to prevent patient morbidity and mortality.

Here, we report a case of CNS demyelination associated with pembrolizumab. Although CNS demyelination after ipilimumab treatment has been well-documented,² cases documenting an inflammatory demyelinating disease during treatment with pembrolizumab are rare. The molecular mechanisms underlying this process are not yet elucidated; however, it is believed that the blockade of the PD-1 signal unleashes high-affinity autoreactive T cells which infiltrate the CNS and lead to demyelination and axonal degeneration.²

Case

A 38-year-old woman who was diagnosed with a 1.9-mm nonulcerated BRAF positive right thigh melanoma which was initially treated by excision. Because of a positive sentinel lymph node biopsy, she had completion lymphadenectomy. She later developed a right upper arm superficial spreading melanoma which was excised with no evidence of residual malignancy. She had a recurrence of the melanoma in her right groin scar 9 months later that was again excised with clear margins. Three months later, she had progressive disease with new lesions in the right upper leg and right pulmonary hilum. She was started on systemic treatment with a combination of ipilimumab and nivolumab, but unfortunately developed acute colitis after cycle 1 requiring methylprednisolone, infliximab, and mycophenolate. She was subsequently started on dabrafenib and trametinib; however, these were stopped after 4 months because of disease progression.

Pembrolizumab was started, and she had stable disease for 13 months. After cycle 15 of pembrolizumab in April 2018, she began to notice discomfort on the extremes of vision with flashing lights. Ocular examination showed mild anterior inflammation and papilledema in both eyes. An MRI brain in May 2018 showed a new right frontal lobe white matter lesion (Figure 1). There was no high signal on T1 as is expected with melanin, and it did not enhance after contrast administration. No mass effect was observed. Morphologically, it was long and located in the periventricular white matter. She was treated for ICI-induced uveitis. Pembrolizumab was discontinued, and she was started on a 1-month reducing regime of dexamethasone 0.1% eye drops and 30 mg prednisolone. Her vision normalized on corticosteroid treatment, and she was restarted on pembrolizumab 2 months later.

Figure 1. Comparison of MRI FLAIR Sequence Images From March 2018 to May 2018.

Comparing MRI FLAIR sequence image in March 2018 (A) to MRI FLAIR sequence image in May 2018 (B); there is an emergence of a new right frontal lobe white matter lesion. This was not enhancing on the contrast enhanced sequence (C). It was a long, periventricular lesion demonstrating no mass effect. FLAIR = fluid-attenuated inversion recovery.

In March 2019, she started to experience dizziness, an unsteady gait and word finding difficulties. An MRI brain at this time demonstrated a much greater burden of periventricular white matter lesions in both cerebral hemispheres oriented perpendicular to the axis of the ventricles along the pericallosal borders (Figure 2). Further lesions in the subcortical white matter were also evident. These findings were suspicious of demyelinating disease. She was managed with 500 mg of pulsed methylprednisolone for 5 days, and she had full resolution of her symptoms. Given her quick response to treatment, no further investigations were performed.

Figure 2. Serial Improvement in White Matter Disease With Steroid Treatment.

(A.a) Axial FLAIR sequence image in March 2019 demonstrating a deterioration of the right frontal lobe lesion and emergence of bilateral, symmetrical white matter abnormalities. (A.b) Sagittal T2 image of the right hemisphere shows the confluent and pericallosal distribution of the signal abnormality. No high signal on T1 weighted imaging and no enhancement after contrast administration observed as before. (B.a, B.b) In May 2019, two months after steroid treatment commencement, the burden of white matter disease demonstrates mild improvement. (C.a, C.b) In September 2019, images from the same location demonstrates further serial improvement. FLAIR = fluid-attenuated inversion recovery.

Follow-up repeat MRI brain scans 2 months later and subsequent time points showed improved appearances with a reducing burden of demyelinating lesions. The decision was made for pembrolizumab to be permanently discontinued because of her demyelinating disease until surveillance PET-CT showed disease progression. Before the treatment with ICIs, the patient had no neurologic symptoms. Furthermore, this patient had no family history of demyelinating disease.

Discussion

This case describes an example of CNS demyelination during treatment with a PD-1 inhibitor in a patient with metastatic melanoma. As previously described, the temporal relationship between the clinical manifestations of CNS inflammation and the use of a PD-1 inhibitor strengthen the case for pembrolizumab-induced CNS demyelination. An important observation is that CNS inflammation responded well to corticosteroid therapy. This case highlights the importance of close monitoring of patients on ICIs and prompt diagnosis and management of immune-related adverse events. More specifically, this case also illustrates that the presence of clinical or subclinical CNS inflammation should not be a contraindication to life-threatening metastatic melanoma.

Appendix. Authors

Study Funding

No targeted funding reported.

Disclosure

The authors report no disclosures relevant to the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.