Mononeuritis multiplex following immune checkpoint inhibitors in malignant pleural mesothelioma

Abstract

Introduction: Mononeuritis multiplex is frequently related to vasculitic neuropathy and has been reported only sporadically as an adverse event of immune checkpoint inhibitors.

Methods: Case series of three patients with mononeuritis multiplex-all with mesothelioma-identified in the databases of two French clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; OncoNeuroTox, Paris; January 2015-October 2022) set up to collect and investigate n-irAEs on a nationwide level.

Results: Three patients (male; median age 86 years; range 72-88 years) had pleural mesothelioma and received 10, 4, and 6 cycles, respectively, of first-line nivolumab plus ipilimumab combined therapy. In patient 1, the neurological symptoms involved the median nerves, and in the other two patients, there was a more diffuse distribution; the symptoms were severe (common terminology criteria for adverse events, CTCAE grade 3) in all patients. Nerve conduction studies indicated mononeuritis multiplex in all patients. Peripheral nerve biopsy demonstrated necrotizing vasculitis in patients 1 and 3 and marked IgA deposition without inflammatory lesions in patient 2. Immune checkpoint inhibitors were permanently withdrawn, and corticosteroids were administered to all patients, leading to complete symptom regression (CTCAE grade 0, patient 2) or partial improvement (CTCAE grade 2, patients 1 and 3). During steroid tapering, patient 1 experienced symptom recurrence and spreading to other nerve territories (CTCAE grade 3); he improved 3 months after rituximab and cyclophosphamide administration.

Discussion: We report the occurrence of mononeuritis multiplex, a very rare adverse event of immune checkpoint inhibitors, in the three patients with mesothelioma. Clinicians must be aware of this severe, yet treatable adverse event.

Keywords: immune checkpoint inhibitor; mononeuritis multiplex; n-irAEs; nerve vasculitis; neurological immune-related adverse events; neurological toxicity; vasculitic neuropathy.

Figure 1

Clinical, ultrasonography, and electrophysiological findings in patient 1. (A) The patient was asked to clench his fists. Note the impaired thumb opposition and index flexion on both sides (arrows). (B) Nerve conduction study (day 28 from clinical onset) of the left median nerve on musculus abductor pollicis brevis, with distal stimulation at the wrist, and proximal stimulation at the elbow (200 μV/div, 5 ms/div): very low distal amplitude (0.1 mV), with normal distal latency (3.6 ms) and normal motor conduction velocity at 53.1 m/s. On the right side, the muscle was unexcitable even by the maximum output of nerve stimulation. (C) Myography of left muscle flexor carpi radialis (day 28 from clinical onset) at rest: positive sharp waves (++) in the muscle (50 μV/div, 20 ms/div). (D) Myography of left muscle flexor carpi radialis (day 28 from clinical onset) at effort (1 mV/div, 20 ms/div): severely impaired motor unit recruitment, while a motor unit is firing at 30 Hz. (E) Ultrasonography: normal cross-sectional area (0.08 cm²) of the right median nerve (N < 0.10 cm²), at forearm (1/3 distal; letter A in white, with a green circle for the epinerve). Hyperechogenicity of right flexor digitorum profundus suggesting denervation (star). (F) Purpuric lesions of the medial aspect of the right foot. μV, microvolt; mV, millivolt; ms, milisecond, m/s, meter/second; Div, division; and Hz, Hertz.

Figure 2

Histological findings. (A) Sural nerve biopsy (hematoxylin–phloxine–saffron) in patient 1 showing endocapillary mononuclear inflammatory infiltrates (arrow) with fibrinoid necrosis (arrowhead). (B) Sural nerve biopsy (indirect immunofluorescence) in patient 2 demonstrating marked endoneurial IgA deposition (green fluorescence). (C) Superficial fibular nerve biopsy in patient 3 showing mononuclear inflammatory infiltrate surrounding one endoneural small vessel (arrow). (D) Fibularis brevis muscle biopsy in patient 3 showing a mononuclear inflammatory infiltrate associated with thrombosis and fibrinoid necrosis of a medium caliber vessel (arrow).