Diagnosis and Differential Diagnosis of Neurological Adverse Events during Immune Checkpoint Inhibitor Therapy

Abstract

Therapy with immune checkpoint inhibitors (ICIs) has improved overall survival and cancer-related morbidity of cancer treatment even in cancer entities with poor prognosis. Since the approval of the first ICI, ipilimumab, for treatment of advanced melanoma by the Food and Drug Administration (FDA) in 2011, the spectrum of indications and approved ICIs has grown, rapidly. Up to now, seven different ICIs for more than 20 indications are available. However, their mechanisms of action can lead to immune-related adverse events (irAEs). In particular, neurological irAEs are clinically relevant. Although they are rare, an early and accurate diagnosis is challenging and neurological disease course and sequelae are potentially fatal. Between 08/2017 and 03/2020, 31 patients received ICI treatment at Hannover Medical School and presented with neurological adverse events (N-irAEs). Treated malignancies were metastatic melanoma, bronchial carcinoma, and urothelial cell carcinoma. All patients received comprehensive neurological diagnostics including clinical examination and magnetic resonance imaging (MRI). Cerebrospinal fluid (CSF) analysis was obtained in 21 patients and electroneurography was performed in 22 patients. Although N-irAEs were suspected in all 31 patients, 11 patients had other conditions leading to neurological symptoms including tumor metastases in seven patients and hemorrhagic or ischemic stroke in four patients. In the following, these patients are referred to as the differential diagnosis (DD) group. Patients with N-irAEs suffered from immune mediated neuropathy (9/20), myositis and/or myasthenic syndrome (6/20), or encephalitis/cerebellitis (5/20). Except for cell count, CSF results did not differ between the N-irAEs and the DD group. Symptoms related to N-irAEs are rather unspecific potentially mimicking other tumor-related symptoms such as metastases. Patients with malignancy are predominantly not treated by neurologists. Because of the complexity of neurological symptoms, detailed neurological investigations in specialized institutions are necessary in patients with new neurological symptoms and need to be critically discussed with treating oncologists.

The role of neuromuscular ultrasound in diagnostics of peripheral neuropathies induced by cytostatic agents or immunotherapies

“…To date, there is no effective preventive procedure for CIPN or immune-related neuropathies although interventions regarding dietary recommendations, medication and exercise are currently under investigation [ 32 ]. Early identification and neuromonitoring may lead to sufficient symptom control, more personalized cancer treatment and dose adjustment while avoiding long-term quality of life impairment [ 33 , 34 ]. Moreover, the knowledge of clinical patterns of neurotoxicity is the key for the challenging differentiation between treatment-induced neuropathies, paraproteinemic conditions, leptomeningeal spread mimicking a polyradiculitis as well as “classical” neurological diseases (amyotrophic lateral sclerosis (ALS), multiple sclerosis MS, GBS/CIDP) in cases with atypical clinical presentation.…”

The Flip of the Coin of Personalized Cancer Immunotherapy: A Focused Review on Rare Immune Checkpoint Related Adverse Effects

“…Commonly reported immune relates neurological or neuromuscular toxicities included myasthenia gravis, peripheral neuropathy, multiple sclerosis, Guillain-Barre syndrome, immune-medicated myopathies and encephalitis/meningitis [62,63,[81][82][83]. Early recognition and prompt management of immune related neurotoxicity might prevent severe and/or permanent consequences or uncommonly reported fatalities [84].…”

Evaluation and management of acute high-grade immunotherapy-related neurotoxicity

“…Cranial nerve findings are seen with cavernous sinus, brainstem and cerebellar metastases [ 66 ], and posterior strokes, as well as NirAEs. Ocular CN abnormalities (vision loss, diplopia, ptosis, and pupillary abnormalities) are seen with irAE meningitis and encephalitis, demyelination, cranial neuropathy, MG, and myopathy [ 55 , 66 ].…”

“…Cranial nerve findings are seen with cavernous sinus, brainstem and cerebellar metastases [ 66 ], and posterior strokes, as well as NirAEs. Ocular CN abnormalities (vision loss, diplopia, ptosis, and pupillary abnormalities) are seen with irAE meningitis and encephalitis, demyelination, cranial neuropathy, MG, and myopathy [ 55 , 66 ]. NirAEs that affect the neuromuscular junction (MG) and myopathy may cause ptosis, diplopia, extraocular muscle weakness or incomitant strabismus, which are signs that mimic cranial nerve palsies, but MG and myopathy will present additional symptoms like bulbar palsy and head drop (often preceding limb weakness) [ 55 , 67 ].…”

“…Diagnostic testing recommendations derived from the SITC, ASCO, and NCCN guidelines are designed to help rule out these and unfamiliar conditions like N-PNS [ [17] , [18] , [19] ]. A lack of specific NirAE markers often makes them a diagnosis of exclusion [ 56 , 66 , 80 ].…”