Pembrolizumab-related systemic myositis involving ocular and hindneck muscles resembling myasthenic gravis: a case report

A 78-year-old man with urinary cancer was consulted to neurological service and referred to the neurological ward presenting with generalized weakness. He was diagnosed with renal, pelvis, and ureter cancer with multiple metastasis of lymph nodes 2 years before consultation. The patient’s tumor worsened, despite three courses of methotrexate, vinblastine, adriamycin and cisplatin, with three courses of gemcitabine and cisplatin. After chemotherapy, pembrolizumab was administered for the enlargement of lymph nodes. Serum levels of CK were increased to 817 U/L (normal range 57–240) at the second course of pembrolizumab, and, in the following several weeks, he presented with bilateral ptosis (Fig. 1a), restriction of eye movements (Fig. 1b), dropped head and lower extremities, without daily fluctuation. Deep tendon reflexes were diminished with left lateral femoral weakness. His blood examination showed elevated serum levels of CK 7765 U/L and aldolase 91.8 U/L (normal range < 6.0 U/L). Anti-PM-Scl 75 and anti-signal recognition particle (SRP) antibodies were positive, but no other myositis specific autoantibodies, including Jo-1, ARS, MDA5, TiF1γ, Mi-2, Ku, PL-7, PL-10, OJ, EJ, or MG-related antibodies, including AChR and muscle specific kinase (MuSK) were observed. Repetitive nerve stimulation test (RST) revealed no significant decrement in any muscles tested. Needle electromyography revealed low amplitude polyphasic motor unit potentials with early recruitment in right biceps brachii and vastus lateralis. Fibrillation potentials, increased insertional irritability and repetitive discharges were also found, suggesting inflammatory myopathy. Hyperintense signal and enhancement on short T2 inversion recovery (STIR) was observed for both sides of the orbicularis oculi, brachial and femoral muscles (Fig. 1c–f). The patient presented with omnidirectional eye movement restriction and MRI revealed inflammatory changes in each orbital oculi muscle so that gaze restrictions were inferred to be related to ocular myositis. Evidence of inflammation in limbs by MRI indicated the weakness in neck extensor and lower extremities resulting in a manual muscle testing (MMT) score of 4 were caused by myositis. There were no signs indicating heart dysfunction, such as heart failure and arrhythmia. Edorophonium test was negative. Pembrolizumab-related myositis was suspected, and administration of intravenous methylprednisolone (IVMP) following plasma exchange (PE) ameliorated CK levels to 984 U/L and inhibited the progression of clinical symptoms. However, the patient died due to a worsening metastasis of cancer. The patient’s family declined an autopsy.

A-72-year old female with lung cancer was consulted to neurological service presenting with back pain and elevated serum CK. She was diagnosed with lung cancer with multiple metastasis of the lymph nodes and brain, 6 months before consultation. After stereotactic radiotherapy for brain metastasis, she received pembrolizumab for the enlargement of a lymph node. Serum levels of CK increased to 1817 U/L after the second course of pembrolizumab and she presented with back pain, right-sided ptosis, restricted eye movements (Fig. 2a, b) and weakness of her neck extensors and flexors. Her blood examination showed elevated serum levels of CK 1844 U/L and aldolase was elevated to 18.2 U/L. Myositis specific autoantibodies including Jo-1, ARS, MDA5, TiF1γ, Mi-2, Ku, PL-7, PL-10, OJ, EJ, HMGCR, SRP and myasthenic gravis related antibodies including anti AChR and MuSK antibody were negative. She had no signs indicating heart dysfunction and electrocardiogram revealed no specific abnormal findings. EMG revealed myogenic change with acute denervation in the right biceps brachii and trapezius without waning in the orbicularis oculi muscle. Hyperintense signal and enhancement on STIR was observed in both sides of the orbicularis oculi muscle, posterior cervical muscles, brachial and femoral muscle (Fig. 2c, d, e). Although her symptoms were insignificant, MRI showed diffuse inflammatory changes. Muscle biopsy showed muscle fiber necrosis and regeneration with sparse inflammatory infiltration, indicating she had immune-mediated necrotizing myopathy (Fig. 2f, g). Edorophonium test was negative and there was not daily fluctuation. Thus, she was diagnosed with myositis due to pembrolizumab. Her clinical symptoms including ptosis, eye movement restriction and serum CK levels were ameliorated (Fig. 2a) soon after the administration of IVMP. She was discharged and received oral PSL 0.5 mg/kg/day and tapering thereafter.