LAUSR

Immune checkpoint inhibitors are increasingly used in cancer treatment and have a significant impact on survival [1]. Pembrolizumab is a recombinant monoclonal antibody that blocks the programmed death-1 (PD-1) receptor, which is an inhibitor of T-cell activation, and thereby can promote the immune response against the tumor [2]. The increased immune response can also induce auto-immune side effects [3]. For the first time, we report a case of Susac’s syndrome induced by pembrolizumab. A 55-year-old woman was diagnosed with stage IV nonsmall cell lung cancer (NSCLC) with metastases in the adrenal gland, bones and brain. The primary tumor was thyroid transcription factor-1 (TTF-1) positive and tested negative for oncogenic drivers, including epidermal growth factor receptor (EGFR), B-Raf proto-oncogene serine/threonine kinase (BRAF), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) and KRAS proto-oncogene GTPase (KRAS). Oncogenic drivers are possible therapeutic targets if present. The tumor proportion score for programmed death ligand 1 (PD-L1), the ligand that stimulates the PD-1 receptor, was ≥ 50%. Patients with higher levels of PD-L1 expression have better response rates to PD-1/PD-L1 directed immunotherapy [4]. She was treated with one cycle of pembrolizumab and after three weeks, she developed cholangitis. The cholangitis was confirmed by a liver biopsy and diagnosed as an immune-related adverse event (irAE). Pembrolizumab was discontinued and she was treated with oral prednisone 1 mg/ kg/day. Radiological response evaluation 3 months after the first pembrolizumab cycle revealed a partial response. Five months after the first pembrolizumab cycle, she presented with disorientation in time, amnesia, dysphasia and behavioral changes (subacute encephalopathy). At neurological examination, she had no focal neurological deficits and no signs of epilepsy such as myoclonic jerks, nystagmus or tonic clonic motor manifestations. A brain MRI revealed multiple linear and punctiform T2 hyperintense white matter lesions with subtle enhancement on T1-weighted postgadolinium MRI (Fig. 1). No abnormalities were observed in the corpus callosum. Cerebrospinal fluid (CSF) showed no biochemical abnormalities, negative cytology and immunoflow cytometry. Based on the clinical symptoms and the MRI abnormalities, there was a high suspicion of an immune-related cerebral vasculitis. Prednisone was increased to 2 mg/kg/day and tacrolimus (0.1 mg/kg/day) was added. After 1 week of treatment, she almost completely recovered. However, 1 week later, she developed tinnitus and audiometry showed a bilateral hearing loss of 80 dB. A second CSF analysis showed an elevated total protein level of 1.36 g/l. The diagnosis Susac’s syndrome was considered because of the hearing loss, earlier encephalopathy and MRI findings. Although she did not complain of visual symptoms, ophthalmological evaluation, consisting of fundoscopy, revealed signs of retinal branch ischemia and perivascular sheating suspect for vasculitis. In addition to the prednisone and tacrolimus, oral mycophenolate 2000 mg/day was started. The hearing loss did not recover. Six months later, she showed progression of the lung tumor and new brain metastases. This is the first case description of Susac’s syndrome as neurological irAE due to anti-PD1 treatment. Neurological irAEs are rare and occur in 1–5% of patients treated with immune checkpoint inhibitors. Most irAEs occur within 2–12 weeks after start of immune checkpoint inhibitors; however, irAEs have even been described after 1 year of * M. De Groot [email protected]