An investigation into the relationship between vigabatrin, movement disorders, and brain magnetic resonance imaging abnormalities in children with infantile spasms

Abstract

AIM We aimed to investigate the relationship between movement disorders, changes on brain magnetic resonance imaging (MRI), and vigabatrin therapy in children with infantile spasms. METHOD Retrospective review and brain MRI analysis of children enrolled in the InternationalCollaborative Infantile Spasms Study (ICISS) who developed a movement disorder on vigabatrin therapy. Comparisons were made with controls within ICISS who had no movement disorder. RESULTSTen of 124 infants had a movement disorder and in eight it had developed on vigabatrin therapy. Two had a movement disorder that resolved on dose-reduction of vigabatrin, one had improvement on withdrawing vigabatrin, two had resolution without any dose change, and in three it persisted despite vigabatrin withdrawal. The typical brain MRI changes associated with vigabatrin therapy were noted in two infants. Ten control infants were identified. Typical MRI changes noted with vigabatrin were noted in three controls.INTERPRETATION It is possible that in two out of eight cases, vigabatrin was associated with the development of a movement disorder. In six out of eight cases a causal relationship was less plausible. The majority of infants treated with vigabatrin did not develop a movement disorder. MRI changes associated with vigabatrin do not appear to be specifically related to the movement disorder.Infantile spasms are an age-related epileptic encephalopathy that occurs in children, usually between the ages of 3 months and 18 months. The seizures manifest typically as clusters of either flexor or extensor epileptic spasms, which are often coincident with an arrest or regression of neurodevelopment. The electroencephalograph characteristically, but not always, shows a chaotic high voltage interictal pattern known as hypsarrhythmia. Many underlying aetiologies, such as tuberous sclerosis complex, trisomy 21, neuronal migration disorders, and hypoxic-ischaemic encephalopathy, have been associated with infantile spasms but in a significant minority of cases no cause is found. There has been much debate about the most effective treatment modality for these patients but there appears to be a relatively wide consensus that the two most effective therapies are either the GABA-ergic anticonvulsant, vigabatrin, or hormonal therapies (prednisolone, adrenocorticotrophin hormone [ACTH], or synthetic ACTH). 1It has been known since the 1980s that vigabatrin usage in animals was associated with the development of intramyelinic oedema in the central nervous system, most notably in the cerebellum, reticular formation and optic tracts in rats, and columns of the fornix and the optic tracts in dogs. 2,3 Recently reports have surfaced in the literature linking vigabatrin usage in humans with characteristic magnetic resonance imaging (MRI) changes in the globus pallidus, thalamus, brain stem, and dentate nuclei of the cerebellum. 4,5 These changes appear to be dose-dependent

Recent Advances in the Pharmacotherapy of Infantile Spasms

“…Hyperintensities in basal ganglia, thalamus, brainstem and dentate nucleus have, very recently, been shown in approximately one-third of those exposed to vigabatrin [76][77][78][79]. These MRI abnormalities may occur as early as 3 months after the initiation of therapy.…”

“…They might remain unnoticed in patients with psychomotor retardation and dyskinetic movements. Infants who display new neurological abnormalities, such as dyskinetic movements, during vigabatrin therapy might have a diagnostic MRI [79].…”

Treatment of infantile spasms

“…[49][50][51][52] Furthermore, this risk has been linked to high dosage, 49,50,52 younger age, 49,51 "cryptogenic" etiology, 51 and possibly concomitant hormonal therapy. 52 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 53,54 including choreoathetosis, myoclonus, and tremor, as well as life-threatening acute encephalopathy 52,53,55 and respiratory compromise. 52 Still, the pathophysiology of these phenomena is unknown and a causal relationship between VGB and movement disorders, severe encephalopathy, and respiratory failure has not been established.…”

Treatment of Infantile Spasms: Report of the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society for Neuropediatrics

“…Magnetic resonance imaging (MRI) studies have described asymptomatic and reversible T2-weighted hyperintensities or restricted diffusion in the globi pallidi, thalami, dentate nucleus, and brainstem in approximately 22 to 45% of patients treated for IS with vigabatrin. [90][91][92][93][94] A movement disorder in children treated for IS with vigabatrin are reported in two studies, 95,96 but evidence for a causal link between vigabatrin and movement disorder or MRI abnormalities is weak.…”