Discussion
Our main finding is that language dysfunction after CAR-T cell therapy is associated with generalised EEG abnormalities such as GRDA and GPDs as seen on LTM studies. Patients most commonly developed language dysfunction between 4 and 14 days post CAR-T cell infusion, consistent with the literature.6 The language dysfunction seen included acute onset expressive dysphasia or aphasia. Fifty per cent of patients presented with acute onset aphasia and developed mutism, which has previously been reported.7
All patients had EEG abnormalities at the time of clinical identification of expressive dysphasia or aphasia. Four (22%) patients had isolated focal EEG abnormalities, with three (17%) having epileptiform discharges over the frontotemporal regions. None of the patients with focal epileptiform discharges were reported to have clinical seizures. Most patients (78%) had an EEG signature which was profoundly slowed with GRDA at symptom onset. These generalised changes were identified during LTM (mean duration 106 hours±14) but not in patients undergoing 30 min EEG recording. Six of the patients with this EEG signature were identified as having convulsive seizures. Runs of GPDs or GRDAs may be on the ictal–interictal continuum concerning for electrographic seizures, consistent with the literature.6 All patients identified to have GRDA or GPDs went on to develop encephalopathy (severe NTX grade 3–4). Studies have demonstrated a strong relationship between seizure activity and GPDs, thus those seen in our study may well be ictal; however, the relationship between GRDA and seizures is less clear.8 9 The ACNS guidelines state that any pattern of evolving activity (>4 Hz) can be regarded as ictal5; however, the significance of slower rhythmic activity such as GRDA remains uncertain.9 Patients with GPDs were treated with antiepileptic medications including levetiracetam and many demonstrated neurological improvement thereafter, suggesting that these were epileptiform discharges. GPDs or GRDA in the setting of encephalopathy may be mediated by both cortical or subcortical dysfunction, including T-cell mediated toxicity or cytokine-mediated disruption of the thalamocortical network.4 10 11
Little is known regarding EEG findings in CAR-T patients. However, a recent case series demonstrated the presence of GPDs in four patients on LTM in this context, including one patient with acute onset aphasia as the presenting symptom.4
Two of the patients in our study had a second and delayed presentation of expressive dysphasia: at 90 and 210 days post infusion, both of which were related to a disease relapse. Both recurrent episodes were clinically similar in their presentation with initial word-finding difficulty, progressing to encephalopathy. In the case presenting at 90 days, the repeat LTM showed prolonged periods of 1–2 Hz GPDs consistent with non-convulsive status epilepticus as in the initial study. This patient was loaded with levetiracetam and intravenous benzodiazepine and made an electroclinical recovery within 48 hours. Brain MRI revealed a subtle right superior parietal lobule lesion possibly contributing to the language dysfunction and EEG findings. In the second case of delayed language alteration at 210 days, LTM identified GRDA, similar to the initial EEG.
In selected cases, NTX has been described months after CAR T-cell infusion.3 At 1 year post infusion, 70% of our cohort made good clinical progress. Unfortunately, 30% of our cohort died within 30 days of CAR-T cell therapy, a third of whom had severe NTX grade 3–4 with encephalopathy and GPDs on the EEG at the time of death. As such, GPDs appeared to be associated with worse outcomes.
Most patients had normal cranial brain MR imaging despite marked neurological decline, suggesting a functional rather than structural underlying mechanism.12
Limitations of our study include the retrospective nature of our study, and the initiation of EEG recordings after onset of language dysfunction, although all patients were monitored within 4 hours of clinical identification of language dysfunction. Inter-rater variability also may remain an issue in relation to clinical identification of language dysfunction in a uniform and timely manner. It may be that those described as having acute onset marked dysphasia or aphasia, in fact had milder symptoms several hours earlier. Additionally, it is possible that cortical/subcortical dysfunction had already generalised by the time EEG recording was initiated without identifying a focal onset of EEG abnormality. Moreover, some patients may have had (asymptomatic) EEG abnormalities at baseline prior to CAR-T cell treatment, which cannot be ruled out given the design of our study. LTM had a mean duration of 106 hours which was limited due to resources. Ideally, monitoring would be for the entire duration of clinical symptoms.
It remains unclear why areas of expressive language function are exquisitely vulnerable in the setting of CAR-T mediated NTX. However, 78% (n=14) of our cohort demonstrated more generalised EEG changes, supporting the notion that cortical dysfunction may be a more global than focal phenomenon.10–12
LTM for patients undergoing CAR-T therapy from time of infusion (ideally prior to onset of NTX until resolution of NTX, resource permitting) should be considered to better characterise the temporal and spatial patterns of cortical dysfunction in this vulnerable patient population and guide appropriate management such as initiation of steroids or antiepileptic drugs. A repeat EEG study could be considered if there is a clinical deterioration or symptom recurrence. Ninety-five per cent of patients with language dysfunction at presentation went on to develop grade 3–4 NTX and this presentation may therefore predict more profound NTX. Given that language dysfunction and EEG findings may represent an early finding in CAR-T cell therapy-related NTX, EEG monitoring is emerging as a useful tool in monitoring patients undergoing CAR-T cell therapy.
