Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy

Abstract

Background Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma, but can also cause symptomatic or life‐threatening immune‐related adverse events, including encephalitis. Epididymitis and orchitis are rare complications of these therapies. Case Presentation We describe herein a patient with metastatic melanoma who developed epididymo‐orchitis followed by encephalitis while receiving pembrolizumab. The patient developed testicular pain and fever after his third dose of pembrolizumab; ultrasound evaluation demonstrated bilateral epididymo‐orchitis. He then developed headaches, fever, and altered mental status over the next week and was admitted to the hospital. Lumbar puncture revealed inflammatory changes consistent with meningoencephalitis; he did not improve with broad‐spectrum antibiotics, and an extensive workup for infectious etiologies, including cerebrospinal fluid testing using a clinical metagenomic next‐generation sequencing assay, was negative. He received high‐dose steroids for suspected autoimmune encephalitis, and both his orchitis and meningoencephalitis improved rapidly after one dose. He fully recovered after a 5‐week taper of oral steroids. Discussion Here, we report a case of epididymo‐orchitis complicating immune checkpoint inhibitor therapy. This patient subsequently developed severe encephalitis but rapidly improved with steroids. Clinicians should be aware of rare complications of these agents. Key Points Epididymo‐orchitis is a rare and potentially life‐threatening complication of anti‐programmed death protein 1 (anti‐PD‐1) therapy. For patients on anti‐PD‐1 therapy who develop either epididymo‐orchitis or epididymitis without clear infectious cause, immune‐related adverse events should be considered in the differential diagnosis. If severe, epididymo‐orchitis related to anti‐PD‐1 therapy may be treated with high‐dose corticosteroids.

Neurological immune‐related adverse events associated with immune checkpoint inhibitors: A review of the literature

“…We searched PubMed for irEncephalitis (including meningoencephalitis, encephalomyelitis, and cerebellitis) cases and identified 60 patients (Tables 1 and S1), 22,32‐73 35 (58.3%) of which were males. The median onset age was 60 years (interquartile range, IQR: 53‐69; range: 19‐83).…”

Autoimmune Encephalitis Related to Cancer Treatment with Immune Checkpoint Inhibitors: Systematic Review

“…We divided patients in the following (partly overlapping) subgroups: With brain metastases (BM+) (N=16) 11,13,17,23,28,31,33,35,45,47,38,41,42,44,46 , without brain metastases (BM-) (N=38) 10,12,24–27,29–32,34,36,14,37,39,40,42,43,45,46,48,15,16,18–22 , with limbic AIE (N=16) 14,18,46,47,19,22,26,27,34,36,39,42 and extra-limbic AIE (N=38) 10,11,23–26,28–33,12,35,37,38,40–42,44–46,48,13,15–17,20–22 . Limbic AIE were determined according to criteria for AIE by Graus et al 7 One patient had bitemporal FLAIR lesions and anti-Ma2 antibodies present in CSF, but the clinical presentation was not consistent with involvement of the limbic system, there were no CSF pleocytosis or EEG activity suggestive of temporal involvement, and this patient was therefore labelled as having extra-limbic AIE.…”

“…Following application of the AIE criteria proposed by Graus et al, 7 23 patients 11,17,32,33,35,37,38,40,44,46,20–23,28–31 fulfilled the criteria for possible AIE; 16 patients 14,18,43,46,47,19,22,26,27,34,36,39,42 , including the one in Figure 1, criteria for limbic AIE; two patients 31,41 criteria for definite anti-NMDA AIE; two patients 10,45 criteria for probable auto-antibody negative AIE, one patient 16 criteria for Hashimoto’s encephalopathy (aka. steroid responsive encephalopathy associated with autoimmune thyroiditis, SREAT); and one patient 48 met criteria for definite acute disseminated encephalomyelitis (ADEM).…”

Sustained remission of Lynch syndrome‐associated metastatic adrenocortical carcinoma following checkpoint inhibitor therapy‐associated multiorgan autoimmunity

“…Whilst common endocrinopathies such as autoimmune thyroid disease, diabetes and hypophysitis are well documented, orchitis is rare and only reported in 2 previous cases who both experienced scrotal pain after checkpoint inhibition for melanoma 5 . The acute onset of primary hypogonadism in our patient with previously normal testosterone concentrations was consistent with immunotherapy-related autoimmune orchitis.…”