Here, we describe four patients treated with CAR T-cell therapy presenting with a writing disorder, namely paligraphia, as an early manifestation of neurotoxicity. In all cases, paligraphia was followed by a rapid neurological deterioration with frontal predominant encephalopathy that required transfer to ICU for three patients. In previous studies, neurotoxicity was observed with a mean onset of 5 days after infusion, even though it developed within 24 h since reinfusion in a subgroup of patients [7, 11], as we observed in two cases, requiring early management. Despite the use of specific aggressive treatment, one of our cases died from CAR T-cell therapy-related toxicity, while another one because of CAR T-cell therapy failure (disease progression). Accordingly, severe neurotoxicity is a well-known potentially fatal complication of CAR T-cell therapy that is likely antagonized by aggressive early treatment. Thus, clinical or instrumental markers to identify early and reliably patients at higher risk of experiencing severe neurotoxicity is an urgent need in CAR T-cell therapy to ensure close monitoring and prompt interventions without overtreating.
Speech disorders are considered recurrent early findings, even though they are neither specific nor predictive of severity [2, 3, 9]. Conversely, akinetic mutism, a neurological manifestation resulting from frontal-subcortical dysfunction, is quite specific to ICANS, but usually develops over days and it is not always present as in our cases. Agraphia has been previously reported as a neurotoxicity manifestation , yet it has been generally defined as a handwriting impairment. Notably, our cases presented with paligraphia, a writing disorder that has been described anecdotally in literature, mostly in patients with Gilles de la Tourette syndrome  and it has never been reported in ICANS to the best of our knowledge. Paligraphia is defined as a reiterative agraphia characterized by rewriting phrases, words, or letters produced by the patient . Paligraphia occurs mostly in words containing double letters and circular-shaped letters . It is considered as an apraxic disorder and reflects a difficulty in programming or generating the appropriate motor skilled commands for writing production . Dysfunctions of the frontal and dominant parietal lobes are suggested as putative mechanisms . Currently, research on apraxic agraphia, especially paligraphia, is limited by the uncommonness of this phenomenon. Nonetheless, when this feature is accompanied with perseverative behaviours, as in our patients, this is thought to broadly localize to the frontal lobes . Notably, all our patients eventually developed a frontal predominant encephalopathy [3, 4], which was also supported by brain FDG-PET findings in three patients. Taken together, these data suggest that paligraphia may be an early manifestation of frontal lobe dysfunction. Additionally, in our cohort paligraphia was present in three out of four severe ICANS (75%) and only in one out of five mild ICANS (20%), with no cases of death related to neurotoxicity (grade 5) observed among patients who did not present paligraphia. This observation, although not statistically significant, suggests that paligraphia could be more specific to severe ICANS and thus, when present, potentially predicts neurotoxicity severity.
Even though we described only four patients, they were selected from a pool of extensively investigated CAR T-cells infused patients, allowing us to monitor day by day the dynamic evolution of neurotoxicity and to detect paligraphia in most of the observed cases of severe ICANS, suggesting this neurological manifestation may be relatively common in these patients. Serial neurological examinations and the use of specific tools may help in both detection of early writing dysfunction and its monitoring .
Instrumental distinctive findings in ICANS are also currently lacking , , . Brain MRI is usually normal, even though non-specific parenchymal alterations are described, including thalami, brainstem and cerebral white matter oedema, while EEG usually reveals diffuse slowing with frontal abnormalities, as observed in our first patient . More advanced functional studies, such as brain FDG-PET, could be implemented in this setting.
Interestingly, we recently reviewed encephalopathies related to several cytokine storm disorders, including CAR T-cells and COVID-19-associated ones, revealing that electro-clinical frontal lobe dysfunction, among other shared clinical and investigative findings, is a recurrent manifestation across these conditions [17,18,19]. Therefore, we suggested that cytokine-mediated neuroinflammation might represent a common overarching mechanism resulting in encephalopathy and we proposed a unifying term that is cytokine storm-associated encephalopathy (CySE) .