White matter spongiosis with vigabatrin therapy for infantile spasms

Abstract

The histopathology, "white matter spongiosis," defined by electron microscopy (EM) as "intramyelinic edema," has been associated with vigabatrin therapy in various animal models, but its role or significance in clinical studies is unknown. We conducted a neuropathological examination on a 27-month-old boy with bilateral polymicrogyria and epilepsy after sudden unexpected death in epilepsy (SUDEP). The patient was initiated on vigabatrin at 4 months of age, which controlled infantile spasms, and was continued as maintenance therapy. Autopsy showed a combination of developmental and acquired lesions: (1) bilateral gyral malformations of the frontal, parietal, temporal, and insular cortex; (2) agenesis of the olfactory tracts and bulbs; (3) hippocampal abnormalities: dentate gyrus bilamination and granule cell dispersion; and (4) areas of microscopic bilateral, symmetric white matter spongiosis in the brainstem central tegmental tract, amiculum and hilum of the inferior olive, medial longitudinal fasciculus, paragigantocellularis lateralis, optic nerves and chiasm, and hypothalamus. The white matter spongiosis was identical to the histopathologic lesions (which by EM exhibited intramyelinic edema) that were demonstrated in animal models on vigabatrin therapy, indicating that vigabatrin toxicity is not restricted to animal models.

Fulminant vigabatrin toxicity during combination therapy with adrenocorticotropic hormone for infantile spasms: Three cases and review of the literature

“…Findings were felt to be consistent with VGB toxicity. [14][15][16] Case 2 was a 20-month-old female with hemimegalencephaly and perisylvian polymicrogyria with a variant of unknown significance in the MTOR gene. She developed IS at 3 months but was lost to follow-up until 6 months of age.…”

“…19 In human infants receiving VGB, VABAM is associated with higher peak and average doses. 12 Pearl et al 15 recently described a case of sudden unexpected death in epilepsy in a 27-month-old with complex cerebral malformations on VGB for 13 months. On autopsy, spongiform white matter vacuolation was noted in the brainstem, including the medullary reticular formation.…”

Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues

“…The mechanism by which VGB selectively affects the visual system has not been clearly defined (Shields and Pellock 2011;Tugcu et al 2017;Peng et al 2017;Yang et al 2012), while other studies suggest that VGB does not display an increased association with visual field abnormalities (Schwarz et al 2016). More recently, VGB has been associated with white matter spongiosis and restricted globus pallidus diffusion (Pearl et al 2018;Trindade et al 2018).…”

Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use‐limiting visual field defects

“…25,33 It has been suggested that VGB-induced elevation of ocular/retinal GABA induces excitotoxicity via GABAergic receptors, [34][35][36] resulting in oxidative stress. [37][38][39][40] Other studies have suggested globus pallidi and white matter anomalies associated with chronic VGB intake, [41][42][43] and pathological roles for amino acids (ornithine, taurine) that share structural and biochemical properties of GABA have also been implicated in VGB-associated ocular toxicity. 29,44,45 Thus, there is no clear consensus as to the mechanism(s) of potential VGB ocular toxicity.…”