Risk of vigabatrin‐associated brain abnormalities on MRI in the treatment of infantile spasms is dose‐dependent

Abstract

SUMMARYObjective: Although the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), namely reversible-and largely asymptomatic-signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify predictors of these phenomena. Methods: Children with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure. Results: We identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the limited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumulative) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039). Significance: We have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy. KEY WORDS: West syndrome, Epileptic spasms, Toxicity, Neuroimaging.Infantile spasms (also known as epileptic spasms in the most recently proposed International League Against Epilepsy (ILAE) classification scheme 1 ) is an often devastating form of epilepsy with onset in the first year of life; is frequently attributed to one of many structural, genetic, or metabolic disorders; and is usually accompanied by neurodevelopmental arrest or regression.2 Infantile spasms is characterized by clusters of brief seizures termed spasms and a spectrum of severe electroencephalographic abnormalities including hypsarrhythmia.3 A lack of prompt and successful treatment is associated with adverse long-term 8 Despite recognized efficacy, 9,10 the use of VGB has been limited foremost by reports of retinopathy resulting in permanent peripheral visual field defects termed VGB-associated visual field loss (VAVFL).11,12 Estimates of VAVFL risk vary substantially, though the risk appears to be lower among children, 13 and especially low among infants with treatment duration <12 months.14 Similarly, in a recent large-sca...

Treatment of infantile spasms

“…). Whereas this MRI toxicity has not been reported in older children and adults, the risk of asymptomatic MRI toxicity in infancy is approximately 20–30% . Furthermore, this risk has been linked to high dosage, younger age, “cryptogenic” etiology, and possibly concomitant hormonal therapy .…”

“…Whereas this MRI toxicity has not been reported in older children and adults, the risk of asymptomatic MRI toxicity in infancy is approximately 20–30% . Furthermore, this risk has been linked to high dosage, younger age, “cryptogenic” etiology, and possibly concomitant hormonal therapy . Although the reversibility and largely asymptomatic character of these phenomena may afford some comfort, MRI toxicity has nevertheless been observed in association with hyperkinetic movement disorders including choreoathetosis, myoclonus, and tremor, as well as life‐threatening acute encephalopathy and respiratory compromise .…”

“…These T2‐weighted MRI images were acquired in a patient with symptomatic vigabatrin‐associated toxicity (encephalopathy, respiratory compromise, and bradycardia) during vigabatrin exposure (panels A, B) and several months following vigabatrin discontinuation and symptomatic recovery (panels C, D). First published in Hussain et al …”

“…As illustrated in Figure (panels D, E), among those randomized to hormonal therapy and combination therapy, respectively, movement disorders were reported among 1% and 8% (p = 0.002), and drowsiness was reported among 2% and 24% (p < 0.001). One may speculate that the high prevalence of these particular adverse events reflects not only the effect of VGB, but an elevated risk of symptomatic MRI toxicity, which may accompany combination therapy . Although “high MRI signal in the basal ganglia” was seldom reported in either treatment group, MRI to ascertain VGB toxicity was not a dedicated study procedure, and many of the patients were treated and evaluated prior to the first published accounts of VGB‐associated MRI phenomena.…”

White matter spongiosis with vigabatrin therapy for infantile spasms

“…In addition, vigabatrin can be associated with magnetic resonance imaging (MRI) T2‐weighted hyperintensities and restricted diffusion in the basal ganglia, thalami, brainstem, and cerebellar dentate nuclei . Suggested risk factors are age, dosage, and possibly concomitant hormonal therapy …”