Pembrolizumab-Induced Isolated Cranial Neuropathy: A Rare Case Report and Review of Literature

Introduction: Anti-PD1 agents are widely used in the treatment of solid tumors. This has prompted the recognition of a class of immune-related adverse events (irAEs), due to the activation of autoimmune T-cells. Pembrolizumab is an anti-PD1 agent, which has been related to an increased risk of various neurological irAE (n-irAEs). Here, we present a rare case of pembrolizumab-induced neuropathy of cranial nerves. Case Report: A 72-year-old patient was diagnosed with a lung adenocarcinoma in February 2018 (EGFR–, ALK–, and PDL1 90%). According to the molecular profile, pembrolizumab was started. After three administrations, the patient developed facial paresis, ptosis, ophthalmoplegia, and dysphonia. As brain metastases and paraneoplastic markers were excluded, a drug-related disorder was suspected and pembrolizumab was discontinued. A nerve conduction study and electromyography excluded signs of neuropathy and myopathy at four limbs, and repetitive nerve stimulation was negative. However, altered blink reflex and nerve facial conduction were consistent with an acute neuropathy of the cranial district. Thus, the patient was treated with two cycles of intravenous immunoglobulins (IVIg), which rapidly allowed improvement of both symptoms and neurophysiological parameters. However, the patient died in October 2018 for a progression of lung tumor. Discussion: Only 16 cases of pembrolizumab-related neuropathies have been described so far. Our case is of particular interest for the isolated involvement of cranial nerves and the prompt response to IVIg. Conclusion: N-irAEs are insidious conditions that require solid knowledge of onco-immunotherapy complications: it is mandatory not to delay any treatment that would potentially modify the course of a neurological complication.


INTRODUCTION
Pembrolizumab (an anti-PD1 agent) may favorably impact the outcome of melanoma and non-small cell lung carcinoma (NSMLC) (1,2). By promoting the activation of T-cells, pembrolizumab fosters the immune response against tumor. However, it may also increase the risk of autoimmune reactions, known as immune-related adverse events (irAEs). Various neurological irAEs (n-irAEs) have been associated with pembrolizumab: in clinical trials with checkpoint inhibitors, 6.3% of patients on pembrolizumab presented n-irAEs of any type and grade (3). The peripheral nervous system is more likely to be involved than the central nervous system (4). In a recent systematic review focused on pembrolizumabinduced neuromuscular disorders (5), 14 (36%), 13 (33%), 9 (23%), and 3 (8%) of 39 patients on pembrolizumab were reported to develop myopathy, myasthenia gravis, neuropathy, or overlapping disorders, respectively.
Here, we describe a patient who developed a rare acute neuropathy of cranial nerves from pembrolizumab.

CASE REPORT
In February 2018, a 72-year-old man was diagnosed with an adenocarcinoma of the lung (EGFR-, ALK-, and PDL1 amplificated in 90% of the cells). A total-body CT scan and an FDG-PET ruled out the presence of metastases at presentation. Based on the molecular profile, pembrolizumab was started. After three cycles (June 2018), the patient developed fatigue, dizziness, mild bilateral facial palsy (grade III of the House-Brackmann scale), bilateral ptosis and ophthalmoplegia, dysphonia, and dysphagia. As the brain and spine MRI with gadolinium excluded the occurrence of metastases, a neuroimmunological drug-related disorder or a paraneoplastic syndrome was considered, and pembrolizumab was stopped. First, we ruled out the presence of neuromuscular junction disorders: both repetitive nerve stimulation (RNS) and specific antibody assays-including anti-acetylcholine receptor (AChR), anti-muscle-specific kinase (MuSK), and P/Q-type VGCC antibodies-were negative. Second, we tested the markers of immune-mediated neuropathy (anti-MAG, anti-GM1/2, anti-GD1a/b, and anti-GQ1b antibodies) and paraneoplastic syndromes (anti-Tr, anti-CV2/CRMP5, anti-amphiphysin, anti-PNMA2/TaMa, anti-GAD65, anti-recoverin, anti-Ri, anti-Yo, anti-Hu, anti-Zic4, anti-SOX1, and anti-titin antibodies), with negative results. Also, creatine kinase was normal (80 IU/l), and cerebrospinal fluid (CSF) did not harbor any inflammatory alterations (being cell count 5/mm 3 and protein concentration 0.32 g/l). Then, we performed nerve conduction studies (NCS) and electromyography (EMG) at the limbs and cranial district: while no signs of neuropathy or myopathy were seen at the extremities, the evidence of slightly decreased amplitude of facial nerve conduction and altered blink reflex (lacking both ipsilateral and contralateral R2 components) suggested a diagnosis of a neuropathy involving the cranial nerves (Tables 1A,B). Therefore, in July 2018, the patient was treated with intravenous immunoglobulins (IVIg: 0.4 g/kg/5 days), with no use of oral glucocorticoids due to the presence of moderate dysphagia. The therapy was well-tolerated and allowed a prompt relief from dizziness, diplopia, and dysphonia and total remission of facial palsy. Also, NCS of the facial nerves and blink reflex showed a rapid improvement, as both ipsilateral and contralateral R2 components were almost completely restored after the first cycle of IVIg (Tables 1A,B). Due to the rapid improvement of symptoms, the employment of intravenous steroids was not needed, but a second cycle of IVIg was administered in August 2018 to consolidate the result. The neurological condition remained stable until October 2018, when the patient died for a progression of the primary tumor.

DISCUSSION
Pembrolizumab-induced acute neuropathy is a rare n-irAE. It is not clear whether the association with other checkpoint inhibitors could drive synergically the onset of the condition. Based on our review of literature, neurological symptoms, such as limb weakness and/or sensory disorders, as well as brainstem and cranial nerve deficits, usually appear soon after the initiation of pembrolizumab and should be carefully investigated in order to rule out differential diagnoses, especially CNS metastases or paraneoplastic syndromes. MRI of the brain and the spine, CSF analysis, neurophysiological studies, and laboratory tests for autoimmune neuropathies and paraneoplastic syndromes are the most useful procedures for the diagnosis. For instance, in cases of polyradiculopathy, MRI of the spine with gadolinium may reveal root enhancement, although this is not a regular finding: in a recent series (16), only two of five cases with facial neuropathies and four of six cases with polyradiculoneuropathy demonstrated gadolinium enhancement of cranial nerves or spinal nerve roots, respectively. CSF may be normal in a minority of cases, whereas Compound muscle action potential (CMAP) amplitude increased to normal values since after the first cycle of therapy. it usually harbors some abnormalities, such as pleocytosis with or without increased protein level (19) or albuminocytologic dissociation; the prevalence and clinical meaning of autoimmune antibodies, which may be common in n-irAE affecting the CNS [as recently reported by Sechi et al. (20)], are not clearly determined so far; finally, although data provided by different authors are heterogeneous, NCS and EMG seem to have a higher sensitivity and specificity than laboratory tests. We described a peculiar case of a lung adenocarcinoma patient who developed an acute neuropathy of cranial nerves from pembrolizumab. Cranial nerve disorders may be observed among patients developing neuropathies from checkpoint inhibitors, as reported by Dubey et al. (16): in this series, seven out of 19 patients with peripheral n-irAEs showed cranial nerve involvement, with or without meningitis, and six had nonlength-dependent polyradiculopathies with or without cranial nerve disorders. However, as far as we know, only five cases of pembrolizumab-induced isolated neuropathy of cranial nerves have been described so far: all those cases are described in melanoma patients (8,18), while only three patients with lung adenocarcinoma have been reported, and none of them presented an exclusive involvement of cranial nerves as in our case. Whether the over-representation of melanoma patients might just reflect the larger employment of pembrolizumab in this tumor or there is a causative correlation should be investigated in further studies. Our patient shares some features with other cases reported in literature: he presented with immune-related neuropathy only after three cycles of pembrolizumab; dismissal of the drug produced clinical benefits; and antibodies of autoimmune neuropathies were not detected by laboratory tests. However, he also presented peculiar features. First, CSF analysis did not show albuminocytologic dissociation or slight pleocytosis, as commonly seen in similar cases; second, he developed a multineuropathy of cranial nerves with no involvement of the extremities; furthermore, he presented with a complex disorder of multiple nerves: in fact, symptoms and signs due to the involvement of the III, IV, VI, VII, IX, and X nerves were all present, and NCS and altered blink reflex confirmed the damage of facial nerves and revealed a subclinical impairment of the trigeminal nerves. Conversely, in other cases of isolated pembrolizumab-derived cranial nerve disorders, patients have been usually reported to have mononeuropathies (mostly facial palsies) or involvement of few cranial nerves (18). Finally, IVIg therapy (not associated to steroids) dramatically impacted the clinical course of the disease, with an improvement of both symptoms and neurophysiological tests since the first cycle: in literature, only two patients were treated with IVIg alone (9, 10), while the most common

CONCLUSION
In case of immune-mediated neuropathy, pembrolizumab should be dismissed immediately. According to our experience, IVIg can be a useful and effective treatment: nevertheless, a combination of steroids and/or plasma exchange should be considered based on clinical severity.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.