Developmental and epileptic encephalopathies after successful treatment of pediatric ALL: A case series and review of literature

Abstract

Successful treatment of acute lymphoblastic leukemia (ALL) requires multiagent chemotherapy regimens and central nervous system prophylaxis, including intrathecal methotrexate. Although acute symptomatic seizures can occur during ALL treatment, epilepsy is less common. Furthermore, drug resistant epilepsy (DRE) is rare, presenting with two phenotypes: focal epilepsy, such as temporal lobe, or epileptic encephalopathies (EE), such as Lennox-Gastaut syndrome (LGS). For ALL survivors, the development of DRE has significant impact on morbidity, mortality, and quality of life. We describe four patients with ALL remission, who developed EEs, of which 3 had LGS. Mean age at ALL diagnosis was 1.9 years; range 1.1-2.5 years. All, but one, had normal development prior to ALL. No patient had CNS leukemic involvement. All patients received CNS prophylaxis with intrathecal methotrexate, without cranial radiotherapy. Three had symptomatic methotrexate neurotoxicity during treatment. The mean age at first seizure was 5.6 years; range 3.9-7.5 years, with a mean latency of 3.7 years from ALL diagnosis. All patients developed drug resistant EEs, moderate intellectual disability, and neuropsychiatric co-morbidities. Two patients had a minimal response to corpus callosotomy (CC), and one did not respond the ketogenic diet. Successful treatment of childhood ALL is rarely associated with the development of DRE and EEs. Young age at ALL diagnosis (<3 years) may be a predisposing factor. Palliative treatments, including ketogenic diet and CC have limited benefit in these patients. Individual genetic susceptibility to MTX toxicity is likely related to epileptogenesis, and further research is required for epilepsy biomarkers.

Keywords: Lennox–Gastaut syndrome; epileptic encephalopathy (not otherwise classified); spasms (epileptic); tonic seizure: atonic seizure.

FIGURE 1

Neuroimaging Findings (Findings depicted by arrows). (A) Case 1: Axial T2. Focal cortical tissue loss at the posteromedial left cerebral hemisphere centered on the parieto‐occipital sulcus. (B) Case 2: Coronal FLAIR. Patchy FLAIR hyperintensities in the subcortical white matter. (C) Case 3: Axial T2. ↑T2 intensities in bilateral cerebellar hemispheres. (D) Case 4: Axial FLAIR. Increased FLAIR signal of the left frontal periventricular subcortical white matter. Cases 3 and 4 had symptomatic MTX neurotoxicity and increased FLAIR signals may reflect residual MTX neurotoxicity. Increased white matter intensities in Case 2 may reflect residual asymptomatic MTX neurotoxicity.

FIGURE 2

Interictal and Ictal EEG samples (Case 4). (A) Interictal EEG during quiet sleep demonstrates generalized slow spike‐wave discharges. The background is suppressed, and no sleep architecture is present. Bipolar montage; LFF: 1 Hz; HFF: 70 Hz; Time base 30 mm/s; Sensitivity 30microV/mm. (B) Ictal EEG demonstrates an electro‐decremental response associated with a clinical tonic seizure at the time indicated by the arrow. Referential montage (A1, A2); LFF 1 Hz; HFF 70 Hz; Time base 30 mm/s; Sensitivity 30 microV/mm.