CAR t-cell therapy in BOlogNa-NEUrotoxicity TReatment and Assessment in Lymphoma (CARBON-NEUTRAL): proposed protocol and results from an Italian study.

OBJECTIVE: To investigate neurotoxicity clinical and instrumental features, incidence, risk factors, and early and long-term prognosis in lymphoma patients who received CAR T-cell therapy. METHODS: In this prospective study, consecutive refractory B-cell non-Hodgkin lymphoma patients who received CAR T-cell therapy were included. Patients were comprehensively evaluated (neurological examination, EEG, brain MRI, and neuropsychological test) before and after (two and twelve months) CAR T-cells. From the day of CAR T-cells infusion, patients underwent daily neurological examinations to monitor the development of neurotoxicity. RESULTS: Forty-six patients were included in the study. The median age was 56.5 years, and 13 (28%) were females. Seventeen patients (37%) developed neurotoxicity, characterized by encephalopathy frequently associated with language disturbances (65%) and frontal lobe dysfunction (65%). EEG and brain FDG-PET findings also supported a predominant frontal lobe involvement. The median time at onset and duration were five and eight days, respectively. Baseline EEG abnormalities predicted ICANS development in the multivariable analysis (OR 4.771; CI 1.081-21.048; p = 0.039). Notably, CRS was invariably present before or concomitant with neurotoxicity, and all patients who exhibited severe CRS (grade ≥ 3) developed neurotoxicity. Serum inflammatory markers were significantly higher in patients who developed neurotoxicity. A complete neurological resolution following corticosteroids and anti-cytokines monoclonal antibodies was reached in all patients treated, except for one patient developing a fatal fulminant cerebral edema. All surviving patients completed the 1-year follow-up, and no long-term neurotoxicity was observed. CONCLUSIONS: In the first prospective Italian real-life study, we presented novel clinical and investigative insights into ICANS diagnosis, predictive factors, and prognosis.

Cognitive Rehabilitation and Transcranial Direct Current Stimulation in a Patient with Posterior Cortical Atrophy: An fMRI Study.

BACKGROUND Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that accounts for 5% of the atypical presentation of Alzheimer disease (AD). To date, only a few studies have explored the effect of non-pharmacological treatment in PCA patients and no studies have evaluated the efficacy of transcranial direct current stimulation (tDCS) in this disorder. CASE REPORT A 58-year-old PCA patient underwent a cognitive rehabilitation treatment followed by 2 cycles of tDCS stimulation. The effects of both treatments were monitored over time with a standardized task-based fMRI protocol and with a neuropsychological assessment. Improvements in cognitive abilities, increased fMRI activation in the dorsolateral prefrontal cortex, and deactivation of the default mode network during the Stroop test performance were detected after each session treatment. CONCLUSIONS This combined approach lead to both cognitive improvements and neurophysiological adaptive changes, however, further studies on a larger cohort are needed to confirm these preliminary results.

Late onset bipolar disorder due to a lacunar state.

OBJECTIVE: To describe a patient with a new onset bipolar disorder (BD) type II, secondary to a lacunar state. BACKGROUND: Poststroke BD is rare and mainly associated with lesion in the prefrontal-striatal-thalamic circuit. MATERIALS AND METHODS: A 51-year-old woman came to our attention for a mood disorder of recent onset. At 49, she had suffered acute left-sided limb weakness that improved spontaneously four days later. Arterial hypertension was subsequently diagnosed. After 6 months, she began to suffer from alternating brief periods of expansive and elevated mood with longer periods of depressed mood, with a suicide attempt. We performed extensive laboratory and instrumental investigations, as well as, psychiatric consultation, and a cognitive assessment, which was repeated 9 months later. RESULTS: Brain magnetic resonance disclosed leukoaraiosis and a lacunar state of the basal ganglia. Transcranial Doppler showed a patent foramen ovale. A psychiatric consultation led to the diagnosis of BP type II. Neuropsychological evaluation detected deficits in attention/executive functions, verbal fluency, and memory. Nine months later, after specific psychiatric therapy, the psychiatric symptoms were remarkably improved. CONCLUSION: Our case sheds light on the role of the basal ganglia in mood disorders and the importance of ruling out brain injury in late onset BP.

Minimal hepatic encephalopathy: follow-up 10 years after successful liver transplantation.

BACKGROUND: The long-term effect of liver transplantation (LT) on cognitive functions and the complete reversibility of minimal hepatic encephalopathy are poorly documented. Much evidence indicates that spatial attention improves starting from the immediate period after LT. However, at least in the first 2 years, some cognitive defects seem to persist to some degree, especially for supramodal nonverbal cognitive functions. The aim of this study is to investigate (i) whether the improvements observed in the perioperative period fluctuate or remain stable 10 years after LT and (ii) whether the functions that have been found defective also improve. METHODS: We called patients previously included in a prospective study (Mattarozzi et al., Arch Neurol 2004; 61: 242) for a further neuropsychological evaluation. We compared the cognitive evaluation after 7 to 10 years with previous data gathered 6 and 18 months after LT. RESULTS: The improvements obtained in the first 2 years after transplantation remain stable during the 7 to 10 years thereafter, especially for visuospatial attention, F(12,96) 1.70; P=0.04 and selective attention, F(6,66) 3.51; P=0.005. Furthermore, these findings also seem to suggest an improvement in supramodal cognitive functions, such as spatial planning intelligence, measured by the Elithorn Maze Test, F(3,33) 7.42; P=0.002. Verbal short-term memory, F(3,33) 3.69; P=0.038, and visuospatial short-term memory, F(6,64) 2.97; P=0.013, show a more fluctuating trend over time. CONCLUSIONS: Despite the risk of surgery, the neurotoxicity of immunosuppression therapy, and the effects of aging and related comorbidities, our data indicate that LT is able to significantly improve patients' cognitive functions in the long term.