Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study

Riikonen, Raili; Rener-Primec, Zvonka; Carmant, Lionel; Дорофеева, М. Ю.; Hollódy, Katalin; Szabó, I.; Krajnc, B; Wohlrab, Gabriele; Sorri, Iiris

doi:10.1111/dmcn.12573

Cited by 82 publications

(65 citation statements)

References 31 publications

(86 reference statements)

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“…Although IS is self-limiting, its dramatic presentation and association with significant developmental delays have led to considerable interest in expanding the currently limited repertoire of therapeutic approaches. Typical anti-seizure drugs are ineffective, but adrenocorticotropic hormone and vigabatrin are known to alleviate symptoms in select patients, leading to the speculation that that neurosteroid imbalances and GABAergic derangements may play a role in the pathophysiology of IS [83, 84]. To facilitate this analysis, a rat model of IS was developed using betamethasone and NMDA to prime and trigger the IS-like state, along with scoring criteria to assess seizure severity [85].…”

Section: Infantile Spasmsmentioning

confidence: 99%

Clinical Potential of Neurosteroids for CNS Disorders

Reddy

Estes

2016

Trends in Pharmacological Sciences

145

164

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Summary Neurosteroids are key endogenous molecules in the brain that affect many neural functions. Here, we describe recent advances in NIH-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neurosteroids can maximally enhance synaptic phasic and extrasynaptic tonic inhibition. The resulting chloride current conductance generates a form of shunting inhibition that controls network excitability, seizures, and behavior. Such mechanisms of neurosteroids are providing innovative therapies for epilepsy, status epilepticus, brain injury, Fragile X syndrome, and chemical neurotoxicity. The neurosteroid field has entered a new era, as many compounds have reached advanced clinical trials. Synthetic analogs have several advantages over natural neurosteroids for clinical use because of their superior bioavailability and safety trends.

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Section: Infantile Spasmsmentioning

confidence: 99%

Clinical Potential of Neurosteroids for CNS Disorders

Reddy

Estes

2016

Trends in Pharmacological Sciences

145

164

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“…The risk for infants has been considered to be low [69,70]. A larger recent multicentre study on visual field defects in schoolage children treated with vigabatrin during infancy for infantile spasms [71] shows that vigabatrin causes visual field defects in children at rates comparable to adults.…”

Section: Side Effects Of Corticosteroids and Vigabatrinmentioning

confidence: 99%

“…A pharmacogenetic exploration of vigabatrin-induced visual field constriction has also been undertaken, although no clear association has been identified [75]. However, genetic differences could explain why some children do not show any defects, even after long use of vigabatrin therapy [71].…”

Section: Side Effects Of Corticosteroids and Vigabatrinmentioning

confidence: 99%

Recent Advances in the Pharmacotherapy of Infantile Spasms

Riikonen

2014

CNS Drugs

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Adrenocorticotrophic hormone (ACTH), oral corticosteroids and vigabatrin are now first-line treatments for infantile spasms in the US and Europe. There is now increased knowledge regarding the role of ACTH, corticosteroids and vigabatrin (e.g. efficacy, doses, side effects, treatment in specific aetiological subtypes of infantile spasms), and other antiepileptic drugs (i.e. topiramate, valproate, zonisamide, sulthiame, levetiracetam, lamotrigine, pyridoxine, ganaxolone), as well as adjunctive flunarizine and novel drugs not yet in clinical use for infantile spasms (i.e. pulse rapamycin and melanocortin receptor agonists). The existence of a latent period, weeks to months following a precipitating brain insult, raises the possibility of preventive interventions. Recent experimental data emerging from animal models of infantile spasms have provided optimism that new and innovative treatments can be developed, and knowledge that drug treatment can affect long-term cognitive outcome is increasing. The aim of this article is to review recent developments in the pharmacotherapy of infantile spasms and to highlight the practical implications of the latest research.

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“…In a study of school age children who had received VGB as infants, Riikonen et al 29 detected peripheral visual field deficits (pVFDs) in one third, and the rate of pVFDs increased from 9% to 63% as VGB treatment duration increased. 29 To track the retinal toxicity associated with VGB, pediatric neurologists currently rely on serial funduscopic examinations (which are insensitive) and occasionally ERGs, as well as ocular coherence tomography (investigational).…”

Section: Discussionmentioning

confidence: 99%

mTOR Inhibition Mitigates Molecular and Biochemical Alterations of Vigabatrin-Induced Visual Field Toxicity in Mice

Vogel

Ainslie

Schmidt

et al. 2017

Pediatric Neurology

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BACKGROUND Gamma-vinyl–γ-aminobutyric acid (GABA) (vigabatrin) is an antiepileptic drug and irreversible GABA transaminase inhibitor associated with visual field impairment, which limits its clinical utility. We sought to relate altered visual evoked potentials associated with vigabatrin intake to transcriptional changes in the mechanistic target of rapamycin (mTOR) pathway and GABA receptors to expose further mechanisms of vigabatrin-induced visual field loss. METHODS Vigabatrin was administered to mice via an osmotic pump for two weeks to increase GABA levels. Visual evoked potentials were examined, eye samples were collected, and gene expression was measured by quantitative reverse transcription-polymerase chain reaction. Similarly, human retinal pigment epithelial cells (ARPE19) were exposed to vigabatrin and treated with mTOR inhibitors for mTOR pathway analysis and to assess alterations in organelle accumulation by microscopy. RESULTS Dysregulated expression of transcripts in the mTOR pathway, GABAA/B receptors, metabotropic glutamate (Glu) receptors 1/6, and GABA/glutamate transporters in the eye were found in association with visual evoked potential changes during vigabatrin administration. Rrag genes were upregulated in both mouse eye and ARPE19 cells. Immunoblot of whole eye revealed greater than three fold upregulation of a 200 kDa band when immunoblotted for ras-related guanosine triphosphate binding D. Microscopy of ARPE19 cells revealed selective reversal of vigabatrin-induced organelle accumulation by autophagy-inducing drugs, notably Torin 2. Changes in the mTOR pathway gene expression, including Rrag genes, were corrected by Torin 2 in ARPE19 cells. CONCLUSIONS Our studies, indicating GABA-associated augmentation of RRAG and mTOR signaling, support further preclinical evaluation of mTOR inhibitors as a therapeutic strategy to potentially mitigate vigabatrin-induced ocular toxicity.

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Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study

Cited by 82 publications

References 31 publications

Clinical Potential of Neurosteroids for CNS Disorders

Clinical Potential of Neurosteroids for CNS Disorders

Recent Advances in the Pharmacotherapy of Infantile Spasms

mTOR Inhibition Mitigates Molecular and Biochemical Alterations of Vigabatrin-Induced Visual Field Toxicity in Mice

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