Impact of Paraclinical Investigations in the Management of CAR T-Cell-Associated Neurotoxicity: Lessons Learned from Real World Experience
Authors: Mauget Mattéo , Manson Guillaume , Houot Roch 
Published: December 2023

Introduction
International guidelines regarding the management of immune effector cell-associated neurotoxicity syndrome (ICANS) recommend several paraclinical assessments, including MRI, lumbar puncture (LP) and EEG based on ICANS grade. However, the impact of these paraclinical investigations has not yet been evaluated.
Methods
Here, we aimed to analyze the role of MRI, LP and EEG in the management of ICANS in a cohort of real-life patients treated with CAR T-cells at the University Hospital of Rennes, France.
The primary endpoint was to assess the therapeutic modifications induced by each paraclinical investigation. The secondary endpoints were to assess the specific abnormalities and differential diagnoses founded on MRI, LP and EEG. We also performed subgroup analysis for each ICANS grade.
Results
Between August 2018 and January 2023, 190 consecutive patients were treated with CAR T-cells. A total of 91 (48%) patients developed an ICANS including 25 grade 1 (13%), 32 grade 2 (17%), 21 grade 3 (11%) and 12 grade 4 (6%).
MRI was performed in 71 (78%) patients with ICANS. The most common result was a normal MRI, corresponding to 80 % of MRI. One of the most frequent abnormal result was aspecific hypersignal, which occurred in 4 (6%) patients with ICANS. Notably, there was no oedema depicted on MRI, even in the most severe ICANS grade 4. Overall, 3 MRI (4% of all MRI) generated therapeutic modification (Figure 1). Two MRI which described strokes in patients with ICANS grade 3 led to initiation or increase of APT therapy. One patient with ICANS grade 1 received APT as MRI described a stroke event but reclassified as normal a posteriori.
Lumbar puncture was performed in 43 (47%) patients. A high rate of LP was abnormal in our cohort (86%). There were 3 preemptive therapeutic modifications for unconfirmed infection (7%) (Figure 1). Two LP led to probabilistic antivirals introduction (aciclovir) in patient with ICANS grade 1 and 2 because of lymphocytic meningitis. One LP led to probabilistic antifungals introduction (voriconazole) in patient with ICANS grade 3 for a suspected Aspergillus spp. meningitis, which was not confirmed after infectious disease physician's expertise.
Systematic EEG performed in 51 (56%) patients requested without clinical signs of epilepsy were analyzed. Only 18% of EEG were normal (Table 1). The most common finding was encephalopathy in 45% of patients. Notably, 6 EEG (12%) reported seizure or status epilepticus in patients with no abnormal movements. Finally, 8 EEG (16%) led to therapeutic modification in the entire cohort (Figure 1). All EEG which found seizure or status epilepticus led to an increase in AE prophylaxis by levetiracetam or introduction of a new AE (mainly phenytoin).
Discussion
The therapeutic impact varied between paraclinical investigations. On one hand, systematic EEG based on ICANS grade only was often followed by therapeutic modification (16% of cases). On the other hand, systematic LP was never associated with relevant therapeutic modification, even in case of severe ICANS, and this broad LP policy resulted in initiation of antimicrobial agents for unconfirmed infections in three patients (7%).
Moreover, the need for systematic MRI assessment is also questionable, as only 4% of MRI led to a therapeutic modification and no MRI found oedema, which is one of the main concerns of treating physicians managing severe ICANS.
Our study shows that EEG is the paraclinical assessment with the greatest therapeutic impact while MRI and LP appear to have a limited therapeutic impact. Our results emphasize the role of EEG in the current guidelines, but questions the need for systematic MRI and LP, which might be left to the discretion of the treating physician.