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Multiple Cranial Neuropathies From Nivolumab in a Patient With Metastatic Hepatocellular Carcinoma

      To the Editor:
      Nivolumab is a checkpoint inhibitor immunotherapy with multiple clinical indications. Based on encouraging activity from a phase 1/2 single-arm study,
      • El-Khoueiry A.B.
      • Sangro B.
      • Yau T.
      • et al.
      Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet.
      nivolumab now has accelerated approval for use as second-line therapy for advanced hepatocellular carcinoma.
      US Food and Drug Administration
      FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib [news release]. US Food and Drug Administration website.
      A phase 3 confirmatory study comparing nivolumab with sorafenib is ongoing.
      Bristol-Myers Squibb
      A Randomized, Multi-center Phase III Study of Nivolumab Versus Sorafenib as First-Line Treatment in Patients With Advanced Hepatocellular Carcinoma (CheckMate 459: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 459). ClinicalTrials.gov Identifier: NCT02576509. ClinicalTrials.gov website.
      As the use of nivolumab increases, it is important to be aware of potential immune-related adverse effects, including the rare subset of neurotoxicities. To date, nivolumab has been linked to cases of encephalitis, acute and chronic immune demyelinating polyneuropathy, myasthenic syndromes, and myositis.
      • Touat M.
      • Talmasov D.
      • Ricard D.
      • Psimaras D.
      Neurological toxicities associated with immune-checkpoint inhibitors.
      We report a case of nivolumab-induced multiple cranial neuropathies.

      Report of Case

      Our patient, a 64-year-old man with a history of metastatic hepatocellular carcinoma from hepatitis C, was treated with off-label nivolumab, 3 mg/kg, every 2 weeks.
      • El-Khoueiry A.B.
      • Sangro B.
      • Yau T.
      • et al.
      Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet.
      There had been progression of disease despite various therapies, including transarterial chemoembolization, sorafenib, and a blinded study medication as part of a placebo-controlled trial evaluating tivantinib.
      Daiichi Sankyo, Inc
      A Phase 3, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects With MET Diagnostic-High Inoperable Hepatocellular Carcinoma Treated With One Prior Systemic Therapy. ClinicalTrials.gov Identifier: NCT0175576. ClinicalTrials.gov website.
      After receiving 4 doses of nivolumab, the patient gradually developed slurred speech, difficulty swallowing, abnormal extraocular movements, and left-sided facial droop over the course of a few weeks. He had lost 6.75 kg. At this point, he was treated empirically with dexamethasone, 20 mg/d, for a potential drug adverse effect and had a percutaneous endoscopic gastrostomy tube placed for enteral nutrition.
      Two weeks later, the patient had worsening of symptoms, with severe bilateral facial droop, bilateral internuclear ophthalmoplegia, left-sided ptosis, severe dysarthria, and an impaired gag reflex, consistent with dysfunction in bilateral cranial nerves III, VII, X, and XII. He was hospitalized and intubated shortly thereafter due to inability to protect his airway. Lumbar puncture specimens yielded negative results on cytologic examination, comprehensive infectious studies, and paraneoplastic antibody tests. Magnetic resonance imaging of the brain with contrast medium revealed faint enhancement of left cranial nerve III consistent with inflammation (Figure).
      Figure thumbnail gr1
      FigureCoronal T1-weighted magnetic resonance imaging of the brain with contrast medium shows enhancement of left cranial nerve III (arrow).
      The patient was diagnosed with nivolumab-induced multiple cranial neuropathies. He was treated with simultaneous intravenous methylprednisolone, 1 g/d for 5 days, and plasma exchange for 7 days. On hospital day 8, he was extubated and had improvement in extraocular movements. Because of persistent left-sided facial droop, dysarthria, and dysphagia, he was also treated with a 5-day course of intravenous immunoglobulin, 2 g/kg daily. Four months after hospitalization, he had nearly complete recovery with his only deficits being a mild left-sided facial droop and left hemifacial spasm. The dysphagia, dysarthria, and ptosis had fully resolved, and his percutaneous endoscopic gastrostomy tube was removed.

      Discussion

      Despite the rarity of neurotoxicity secondary to checkpoint inhibitor therapies, it must be considered in all patients with previous exposure who present with a new neurologic deficit. Immune-related neurotoxicity remains a diagnosis of exclusion; it requires ruling out brain metastases, infection, and paraneoplastic syndromes. However, a timely diagnosis is crucial. As illustrated by our case, nivolumab-induced neurotoxicity can be both life-threatening and reversible with the appropriate treatment. Although the exact mechanism of nivolumab-induced cranial neuropathy is unknown, this case suggests that treatment with corticosteroids alone may be insufficient, at least in severe cases, and that the addition of plasmapheresis and intravenous immunoglobulin can lead to sustained recovery.

      References

        • El-Khoueiry A.B.
        • Sangro B.
        • Yau T.
        • et al.
        Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet.
        2017. 2017; 389: 2492-2502
        • US Food and Drug Administration
        FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib [news release]. US Food and Drug Administration website.
        (Updated September 25, 2017. Accessed October 24, 2017)
        • Bristol-Myers Squibb
        A Randomized, Multi-center Phase III Study of Nivolumab Versus Sorafenib as First-Line Treatment in Patients With Advanced Hepatocellular Carcinoma (CheckMate 459: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 459). ClinicalTrials.gov Identifier: NCT02576509. ClinicalTrials.gov website.
        • Touat M.
        • Talmasov D.
        • Ricard D.
        • Psimaras D.
        Neurological toxicities associated with immune-checkpoint inhibitors.
        Curr Opin Neurol. 2017; 30: 659-668
        • Daiichi Sankyo, Inc
        A Phase 3, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects With MET Diagnostic-High Inoperable Hepatocellular Carcinoma Treated With One Prior Systemic Therapy. ClinicalTrials.gov Identifier: NCT0175576. ClinicalTrials.gov website.
        https://clinicaltrials.gov/ct2/show/NCT01755767
        Date accessed: November 20, 2017