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

Abstract

Adrenocorticotropic hormone (ACTH), prednisone, and vigabatrin (VGB) are first-line treatments for infantile spasms (IS). 1 The antiseizure properties of VGB, an irreversible inhibitor of γ-aminobutyric acid (GABA) transaminase, are thought to emerge from increased levels of GABA. VGB can produce significant adverse effects, including irreversible visual field defects, movement disorders, and vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM). 2,3 VABAM, characterized by diffusion restriction in the globus pallidus, corpus callosum, thalamus, cerebellar dentate nuclei, midbrain, and brainstem, is reported to occur in 22%-32% of IS patients receiving VGB. 4-6 It is dose-dependent, 3 with peak discovery 3-12 months following initiation of VGB. 4,5 It is partially or completely reversed on cessation or dose reduction of VGB. 4-6 Most VABAM are asymptomatic 5 ; however, several case reports describe associated movement disorders (including choreoathetosis, myoclonus, titubation, abnormal eye movements, dystonia, opisthotonos, and tremor), dysautonomia (including bradycardia and respiratory arrest), and acute encephalopathy, together termed symptomatic VABAM. 7-12 In 2017, the International Collaborative Infantile Spasms Study (ICISS), a multicenter, randomized prospective clinical trial, demonstrated increased efficacy of combined hormonal therapy with VGB over hormonal therapy alone for IS. 13 Here, we describe three IS patients who developed symptomatic VABAM when treated contemporaneously with VGB and ACTH, characterized by encephalopathy, dyskinesias, and dysautonomia. A literature review suggests the combination of VGB with hormonal therapy (VGB-HT) is associated with fulminant symptomatic VABAM.

Risk of vigabatrin‐associated brain abnormalities on MRI: A retrospective and controlled study

“…17 Pearl et al 18 reported a case of sudden epileptic death in a child with a 13-month history of VGB exposure, and the autopsy report indicated that spongy white matter was vacuolated, including medullary reticulum. In the study of Bhalla et al, 8 a child with epilepsy taking VGB developed fulminant VGB toxicity, and autopsy results suggested spongiform vacuolar edema throughout the white matter tract and typical VABAM area, which was associated with fatal encephalopathy. The vacuolar edema in the above study cases and animal models may explain the abnormally high signal on DWI in the VABAM group.…”

“…Recent studies have shown that VGB exposure may cause vigabatrin‐associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), that is, the reversible high T2‐weighted imaging (T2WI) signal and diffusion restriction of the thalamus, basal ganglia, brainstem, and cerebellar dentate nucleus. This phenomenon has not been reported in older children and adults, but the incidence of VABAM in infants could be as high as 21%–32% 8–11 . Although many studies have shown that this abnormality is usually reversible and is not accompanied by clinical symptoms, there are still some cases with movement disorders, encephalopathy, dysautonomia, or even death after the occurrence of VABAM 8 …”

“…This phenomenon has not been reported in older children and adults, but the incidence of VABAM in infants could be as high as 21%-32%. [8][9][10][11] Although many studies have shown that this abnormality is usually reversible and is not accompanied by clinical symptoms, there are still some cases with movement disorders, encephalopathy, dysautonomia, or even death after the occurrence of VABAM. 8 Previous literature has shown that VABAM is most likely to occur between 3 and 12 months after VGB exposure.…”

“…[8][9][10][11] Although many studies have shown that this abnormality is usually reversible and is not accompanied by clinical symptoms, there are still some cases with movement disorders, encephalopathy, dysautonomia, or even death after the occurrence of VABAM. 8 Previous literature has shown that VABAM is most likely to occur between 3 and 12 months after VGB exposure. The younger the age of first VGB exposure is, the higher the risk.…”

Treatment of Infantile Spasm Syndrome: Update from the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society of Neuropediatrics

“…The presurgical assessment should be performed at an epilepsy center with pediatric expertise. If drug resistance is proven, the timing for the operation should be chosen as early as possible (►Table 14).…”