Parkinsonism and Bilateral Facial Palsy after Chimeric Antigen Receptor T‐Cell Therapy

Multiple myeloma, a plasma cell dyscrasia, is the second most common hematological malignancy.1 Despite advances in therapies, including proteome inhibitors and monoclonal antibodies, multiple myeloma remains largely incurable with high rates of relapse and treatment resistance.2 Chimeric antigen receptor (CAR)-T cell therapy has shown promise in the treatment of multiple myeloma.3 However, its safety profile is not well defined. We present a case of CAR-T cell-induced parkinsonism and facial palsy. A 77-year-old man with essential tremor (ET) presented with acute parkinsonism and bilateral facial paralysis. The patient had a history of IgA-λ multiple myeloma (R-ISS 3) with no known extramedullary involvement. He underwent induction therapy with bortezomib, lenalidomide, and dexamethasone followed by CAR-T cell therapy (cilta-cel). Six days after CAR-T cell infusion, he developed grade 1 cytokine release syndrome (CRS). His neurological symptoms developed 19 days post-infusion. His immune effector cell encephalopathy (ICE) score to screen for immune effector cell-associated neurotoxicity syndrome (ICANS) was 0.4 Neurological exam revealed worsening of the preexisting action tremor, rigidity, and bradykinesia of both arms. Hypophonia, paucity of speech, and evidence of worsening micrographia documented in the days immediately preceding hospital admission were noted (Fig. 1). Patient also had a mild stooped posture, shuffling gait with decreased arm swing amplitude, and postural instability. The patient otherwise did not report any prodromal symptoms of parkinsonism. Concurrently, he presented with facial palsy with diminished ability to raise his eyebrows, close his eyes, and purse his lips, and perioral paresthesia. These symptoms were present bilaterally but more predominant on the right (Video 1). Magnetic resonance imaging (MRI) with gadolinium demonstrated mild microangiopathic changes, unchanged from an MRI 3 months prior (Fig. 2). Cerebrospinal fluid (CSF) analysis showed white blood cells ( 12 × 10 6 / L ) $$ 12\times {10}^6/\mathrm{L}\Big) $$ consisted of 33% lymphocytes, 0.58 g/L protein, and 5 mmol/L glucose. CSF cultures and cytology were negative. The patient started pregabalin 150 mg/day 11 days preceding symptom onset. The patient's symptoms spontaneously improved 2 days after onset. He was treated with a 2-week dexamethasone taper (started 1 day after observed improvement). The symptoms completely resolved 24 days after onset. His symptoms of parkinsonism and facial palsy recurred 46 days post-infusion. Interestingly, this was preceded by reinitiation of pregabalin 100 mg/day 4 days prior. He achieved complete and spontaneous resolution 12 days later (Video 2). CAR-T cell therapy against B-cell maturation antigen (BCMA) is a novel treatment for multiple myeloma. Studies on BCMA-targeted CAR-T cell therapy have shown unprecedented results, achieving partial and complete response rates as high as 95% and 80%, respectively.3 However, CAR-T cell therapy is associated with significant toxicity.5 The most common toxicities include CRS and neurotoxicity. CRS is a systemic inflammatory syndrome associated with fever and end-organ dysfunction.6 In contrast, CAR-T cell-related neurotoxicity, including ICANS, is less well defined. Recognized features of ICANS include confusion, aphasia, apraxia, weakness, or coma, and is typically preceded by CRS.4 Identified risk factors include high-grade CRS, prior ICANS, and high tumor burden.7 However, many patients who present with neurological symptoms do not fit these criteria, have a history of CRS, and have normal ICE scores, which is inconsistent with the literature definition of ICANS.7, 8 To date, several cases of parkinsonism and facial paralysis have been reported in patients receiving BCMA-directed CAR-T cell therapy (Table S1). Significant heterogeneity exists between cases in terms of days to symptom onset, reported symptoms, imaging findings, and response to treatment. However, the majority of cases were reported in men, and all cases of CAR-T cell-associated parkinsonism, except 1, were preceded by high-grade CRS and/or ICANS.8 The underlying pathophysiology of these movement disorders remains unclear, although it appears distinct from Parkinson's disease, with prior reports of negative dopaminergic scans and poor responses to levodopa/carbidopa.8 Prior cases of CAR-T cell-associated parkinsonism found circulating lymphocytes in the CSF, and these individuals may have higher levels of circulating CAR-T cells compared to individuals without neurotoxicity.7 Postmortem analyses in 4 individuals also identified evidence of focal gliosis in the caudate nucleus and basal ganglia.8, 9 We describe a patient presenting with relapsing and remitting parkinsonism and facial palsy following CAR-T cell therapy. Distinctly, this patient did not have a history of high-grade CRS or ICANS. Interestingly, his presentation was temporally associated with pregabalin administration. Although drug-induced parkinsonism is a rare complication of pregabalin, it typically occurs at higher doses (≥300 mg/day), with long-term use, or with renal dysfunction, which was not applicable in this case.10 To the best of our knowledge, there are no reported cases of pregabalin-induced facial palsy. However, it is conceivable that our patient's history of pregabalin use and ET may be potentially predisposing factors. Overall, CAR-T cell-related neurotoxicity remains poorly understood. Our case highlights the need for careful monitoring of neurotoxicity, even in patients without known risk factors. Further studies are needed to delineate the clinical features and biological mechanisms underpinning early and delayed presentations of these adverse neurological presentations. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript preparation: A. Writing of the first draft, B. Review and critique. A.S.W.: 1C, 2A, 2B L.H.: 1C, 2B P.G.: 1C, 2B M.M.: 1C, 2B S.D.B.: 2B A.K.S.: 2B A.F.: 1A, 1B, 1C, 2A, 2B Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. The patient provided written consent to be video-recorded for publication. The authors confirm that they have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interests: This work was supported by the University of Toronto and University Health Network Chair in Neuromodulation (A.F.). The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. Data sharing is not applicable to this article as no new data were created or analyzed in this study. Table S1. Summary of prior case reports on CAR (chimeric antigen receptor)-T cell-associated parkinsonism and facial palsy. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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