Neurological toxicities have been observed in up to 77% of patients treated with CAR-T-cells14, with grade 3–5 in 25–57% of patients6. The underlying pathophysiology of ICANS remains unclear, with possible mechanisms including an inflammatory process triggered by CAR-T-cells, with subsequent secretion of monocyte-derived cytokines like IL-1, IL-6, and GM-CSF, as well as a widespread endothelial activation with increased permeability of the blood-brain barrier (BBB). Studies of CSF from patients who developed severe forms of ICANS showed a 17-fold increase in CD14 + myeloid cells' levels compared to patients with low-grade ICANS. Therefore, ICANS might be the result of systemic inflammation triggered by CAR T-cell infusion and activation, which leads to endothelial activation, BBB disruption, and inflammatory infiltration of central nervous tissues15. The most common neurological symptoms include encephalopathy, tremor, aphasia, and focal weakness14. Expressive aphasia is the most specific first sign of severe neurotoxicity5. We report a case of raised intracranial pressure with cerebral edema in which noninvasive monitoring of intracranial pressure with ONSD serial measurements allowed for rapid identification and initiation of aggressive treatment and monitoring of response with good correlation with invasive EVD-ICP measurements.
A meta-analysis by Cai et al. assessed the incidence and characteristics of fatal toxicity associated with CAR T-cell therapy. After analyzing 19 clinical trials with a total of 890 cases and 33 treatment-related deaths, they found that the most common causes of CAR T-cell therapy-related mortality were CRS (30.3%), nervous system disorders (18.2%) and infections (12%). Other causes included blood, cardiac, respiratory, gastrointestinal and hepatobiliary disorders16. Regarding nervous system involvement, cases of raised intracranial pressure with and without cerebral edema after CAR T-cell therapy have been reported3 and represent the most devastating sequelae of ICANS and the leading cause of neurologic CAR T-cell therapy-associated mortality17.
Prompt recognition of intracranial hypertension after CAR T-cell therapy is necessary to mitigate adverse outcomes. However, assessment of papilledema in patients with encephalopathy using fundoscopy is challenging and, most of the time, inaccurate18. Additionally, obtaining imaging studies such as CT or MRI may be delayed due to logistical reasons and the hemodynamical/neurological stability of the patient, which can create critical delays in the initiation of lifesaving therapeutic interventions.
Moreover, the gold standard assessment of ICP using invasive (lumbar puncture opening pressure) may be contraindicated due to coagulopathy, thrombocytopenia, or clinical instability, and poses a risk of complications such as herniation and bleeding19.
Our case demonstrates sonographic measurement of ONSD as a bedside, noninvasive test is a reliable method to monitor intracranial pressure and ICANS in patients undergoing CAR-T-cell therapy. This tool can be used for effective monitoring of critically ill patients that require early and aggressive management. Bedside ocular ultrasound can be used serially for early detection of increased intracranial pressure after cellular therapy enabling early and aggressive management of cerebral edema which can be a devastating neurologic complication of CAR T-cell therapy.