Ipilimumab-Induced Encephalopathy with a Reversible Splenial Lesion

Background Immune checkpoint inhibitors (ICI) are improving prognosis in advanced stage cancers, but also lead to immune-related adverse events (IRAE). IRAEs targeting many organ systems have been reported, but musculoskeletal and rheumatic IRAE have not been well characterized. We systematically reviewed published literature on musculoskeletal and rheumatic IRAE to better understand prevalence and clinical characteristics. Methods Medline and CENTRAL databases were searched for articles reporting rheumatic and musculoskeletal IRAEs secondary to ICI treatment. After screening abstracts and full texts in duplicate, clinical features, prevalence and treatment data were extracted and summarized. Results 1725 unique abstracts were screened; 231 contained original data and were about ICIs and went to full text screening. Fifty-two of these contained information about musculoskeletal or rheumatic IRAEs or about treatment with ICIs in pre-existing autoimmune disease. Of these, 33 were clinical trials, 3 were observational studies, and 16 were case reports or series. Arthralgia prevalence in clinical trials ranged from 1–43%, and myalgia was reported in 2–20%. Arthritis was reported in 5/33 clinical trials, and vasculitis was reported in only 2. One observational study and 3 case reports described patients with pre-existing autoimmune disease treated with ICIs. Case reports included development of inflammatory arthritis, vasculitis, myositis, and lupus nephritis. Conclusions Arthralgia and myalgia have been reported commonly in patients treated with ICIs. The prevalence of rheumatic IRAEs like inflammatory arthritis, vasculitis, and sicca syndrome is less clear from current evidence. There is limited observational and case-level evidence describing ICI use in patients with pre-existing autoimmune disease.

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“…Orbital myositis and encephalopathy with arthralgias were also described in case reports, as shown in Table .…”

Section: Resultsmentioning

confidence: 94%

Rheumatic and Musculoskeletal Immune‐Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature

Cappelli

Gutierrez

Bingham

et al. 2017

Arthritis Care & Research

327

249

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“…We report the case of a 60-year-old man who succumbed to progressive and subacute CNS demyelination that developed while he was receiving nivolumab following ipilimumab for metastatic melanoma. CNS demyelination has never been reported as a side effect of anti-PD-1 therapy, although a case of encephalopathy with a reversible splenial lesion was described in association with ipilimumab treatment (2). As the use of these agents increases, it is important to be aware of this rare but severe potential complication.…”

Section: Introductionmentioning

confidence: 99%

Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma

Maurice

Schneider

Kiehl

et al. 2015

Cancer Immunology Research

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Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell-rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors.

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“…Ipilimumab-associated neurological irAEs span diverse entities including severe meningo-radiculo-neuritis [18], reversible splenial lesions [19, 20], hypophysitis [21], meningitis [21], acute cerebellitis [22], Guillain-Barre syndrome [21, 23], myasthenia gravis [24–27], bilateral phrenic nerve paralysis [28], Bell’s palsy [28], chronic inflammatory demyelinating polyneuropathy (CIDP) [29], transverse myelitis [29], encephalitis [30], necrotic myelopathy [31], and partial motor convulsive status (epilepsia partialis continua) [32]. Herein, we report two cases of ipilimumab-associated neurological irAEs manifesting as meningoencephalomyelitis and AIDP respectively.…”

Section: Discussionmentioning

confidence: 99%

Neurologic immune-related adverse events associated with adjuvant ipilimumab: report of two cases

Garcia¹,

El-Ali²,

Rath³

et al. 2018

j. immunotherapy cancer

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BackgroundPD-1 and CTLA-4 inhibitors are associated with several adverse events including a spectrum of immune-related adverse effects (irAEs). Neurologic irAEs are uncommon occurrences with varied presentations. We describe two separate cases of ipilimumab associated meningoencephalomyelitis and demyelinating polyneuropathy with unusual presentations.Case presentationTwo melanoma patients were treated with ipilimumab in the adjuvant setting. The first patient developed a meningoencephalitis following 3 doses of ipilimumab. MRI imaging of the brain confirmed leptomeningeal enhancement although cerebrospinal fluid (CSF) analyses were negative for malignant cells consistent with meningoencephalomyelitis. Although she initially improved following treatment with steroids and intravenous immunoglobulin, she subsequently relapsed. She was successfully treated with infliximab and made a complete neurological recovery. A second patient developed progressive lower extremity weakness following two doses of ipilimumab. MRI imaging of the spine confirmed diffuse nerve root enhancement consistent with acute inflammatory demyelinating polyneuropathy (AIDP). He was treated with high dose steroids with resolution of neurological symptoms. Both patients remain disease free.ConclusionsNeurological irAEs are uncommon adverse events in the context of CTLA-4 and/or PD-1 inhibitor therapy. Care must be taken to distinguish these from leptomeningeal disease. Early recognition of neurological irAEs is critical for the initiation of specific anti-inflammatory agents to prevent and potentially reverse neurological sequelae.

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Ipilimumab-Induced Encephalopathy with a Reversible Splenial Lesion

Cited by 62 publications

References 16 publications

Rheumatic and Musculoskeletal Immune‐Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature

Rheumatic and Musculoskeletal Immune‐Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature

Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma

Neurologic immune-related adverse events associated with adjuvant ipilimumab: report of two cases

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