LAUSR

Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary and effective treatment of hematological malignancies, in particular diffuse large B-cell lymphoma (DLBCL) [1–3]. Its effectivity, however, comes at the cost of two related but distinct toxicity syndromes. Cytokine release syndrome (CRS) is characterized by fever, hypotension, and hypoxia with onset generally within the first days after CAR T-cell infusion [1]. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in 30–67% of patients and comprises a spectrum from mild encephalopathy symptoms to fatal cerebral edema [2]. Symptoms are heterogeneous, encompassing altered mental status, headache, focal neurological deficits, and seizures [2]. The phenomenological characteristics of tremor after CAR T-cell therapy as well as its functional impact, clinical course and management are largely unknown. We describe four patients in whom ICANS was dominated by persisting tremor. All patients underwent standardized neurological examination by a movement disorders expert. Surface EMG tremor recording and EEG-EMG (corticomuscular)/EMG-EMG (intermuscular) coherence analyses were performed in one case. Patient characteristics regarding DLBCL and CAR T-cell therapy are provided in Supplementary Table 1. Characteristics regarding cortical myoclonic tremor are provided in Table 1. Onset of cortical myoclonic tremor was between one and two weeks after infusion, and coincided with start of CRS in one case opposed to a delay of a few days after ongoing CRS in the other cases. Alternative causes (e.g., metabolic, infectious or structural) were excluded (Table 1). Cortical myoclonic tremor was isolated in one case. In the other three cases, it was accompanied by other signs of ICANS. In these three cases there was improvement within a few days after initiation of high-dose corticosteroids. Other neurological signs of ICANS resolved within a few days, except for slight persistent ataxia in two cases. Cortical myoclonic tremor, however, exacerbated upon discontinuation or dose reduction of corticosteroids in two cases. The cortical myoclonic tremor was formally evaluated between 3 weeks and 3 months after CAR T-cell therapy. It was mainly present in the hands and fingers (polyminimyoclonus), occurred only upon action, and was phenomenologically described as fast, irregular and jerky (Supplementary Videos 1–4). Stimulus sensitivity was present in two patients out of three in whom it was tested. In all patients manual actions were significantly impaired, at least initially. Surface EMG tremor recording and EEG-EMG (corticomuscular)/EMG-EMG (intermuscular) coherence analyses were performed in one case four weeks post-infusion and were consistent with a cortical origin of the myoclonus (Fig. 1) [4]. The cortical myoclonic tremor resolved over the course of one to three months in three patients, and progressively improved until last followup (i.e., death nine months after CAR T-cell therapy) in one patient. In one case, treatment of cortical myoclonic tremor with topiramate and gabapentin was ineffective. We demonstrate that cortical myoclonus is the substrate of tremulous movements following CAR T-cell therapy and can be a dominant and tenacious feature of ICANS. Whereas patients describe the tremulous movements as ‘tremor’, * Bart E. K. S. Swinnen [email protected]