A lack of clinically apparent vision loss among patients treated with vigabatrin with infantile spasms: The UCLA experience

Schwarz, Madeline D.; Li, Menglu; Tsao, Jackie; Zhou, Raymond; Wu, Yvonne W.; Sankar, Raman; Wu, Joyce; Hussain, Shaun A.

doi:10.1016/j.yebeh.2016.01.012

Cited by 23 publications

(29 citation statements)

References 26 publications

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“…In a pair of contemporary studies, the risk of VAVFL as determined by kinetic perimetry was <10% among children treated for <12 months, and the risk of electroretinographically defined retinotoxicity was <6% among children treated for <6 months . In our own experience, the risk of clinically apparent vision loss approaches zero with relatively short courses of therapy . Nevertheless, there are no available data confirming that the risk of relapse of infantile spasms is diminished by extended courses of vigabatrin, and there is little guidance as to what constitutes an ideal treatment duration.…”

Section: Discussionmentioning

confidence: 83%

Prevention of infantile spasms relapse: Zonisamide and topiramate provide no benefit

et al. 2016

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SUMMARYObjective: There is scant evidence to guide the management of infantile spasms after successful response to initial therapies. There is significant risk of relapse, largely because effective pharmacologic treatments cannot be continued long term because of concern for significant adverse events. Zonisamide (ZNS) and topiramate (TPM) are commonly used to prevent relapse, and the purpose of this study was to specifically evaluate the efficacy of ZNS and TPM as agents for secondary prevention of infantile spasms. Methods: Patients with video-electroencephalography (EEG) confirmed resolution of infantile spasms were retrospectively identified. Relevant clinical data were systematically collected, including lead time from onset of spasms to successful treatment response, etiology of infantile spasms, number of treatment failures prior to response, timing of relapse, and detailed exposure data for ZNS and TPM. Results: We identified 106 patients with response to hormonal therapy (n = 58), vigabatrin (n = 25), or surgery (n = 23). To prevent relapse of infantile spasms, 37 patients received ZNS, 34 received TPM, 3 received both ZNS and TPM, and 38 patients received neither ZNS nor TPM. There were 44 relapses, occurring a median of 6.9 (3.2-10.8) months after initial response. Time to relapse was not affected by treatment with ZNS or TPM. Relapse was less likely among patients who were older (hazard ratio 0.97 [per month], p = 0.036) and those who responded to surgical resection (hazard ratio = 0.28, p = 0.017). Of note, we identified a relatively refractory cohort with multiple treatment failures and long lead time to initial response. Significance: In this refractory cohort, neither ZNS nor TPM was successful in preventing relapse of infantile spasms, despite relatively high dosages. At this time, aside from surgical resection in eligible candidates, there is no known treatment that is efficacious in the prevention of relapse of infantile spasms.

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Section: Discussionmentioning

confidence: 83%

Prevention of infantile spasms relapse: Zonisamide and topiramate provide no benefit

et al. 2016

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“…It is notable that the impression that hormonal therapy exhibits superior efficacy does not necessarily generalize to children with TSC. Although a large‐scale trial of VGB versus high‐dose hormonal therapy has not been undertaken in a TSC cohort, several studies indeed suggest that response to VGB is substantially higher among patients with TSC in comparison to patients with other etiologies . Accordingly, there is broad consensus that patients with IS in the setting of TSC should receive first‐line treatment with VGB …”

Section: Vigabatrinmentioning

confidence: 99%

“…Although a large-scale trial of VGB versus highdose hormonal therapy has not been undertaken in a TSC cohort, several studies indeed suggest that response to VGB is substantially higher among patients with TSC in comparison to patients with other etiologies. 32,35,36 Accordingly, there is broad consensus that patients with IS in the setting of TSC should receive first-line treatment with VGB. 15 Despite this established efficacy, the use of VGB has been limited by reports of retinopathy manifesting with permanent bilateral concentric peripheral visual field defects in both adults 37 and children.…”

Section: Hormonal Therapymentioning

confidence: 99%

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Treatment of infantile spasms

Hussain

2018

Epilepsia Open

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SummaryThe treatment of infantile spasms is challenging, especially in the context of the following: (1) a severe phenotype with high morbidity and mortality; (2) the urgency of diagnosis and successful early response to therapy; and (3) the paucity of effective, safe, and well‐tolerated therapies. Even after initially successful treatment, relapse risk is substantial and the most effective therapies pose considerable risk with long‐term administration. In evaluating any treatment for infantile spasms, the key short‐term outcome measure is freedom from both epileptic spasms and hypsarrhythmia. In contrast, the most important long‐term outcomes are enduring seizure‐freedom and measures of intellectual performance in later childhood and adulthood. First‐line treatment options—namely hormonal therapy and vigabatrin—display moderate to high efficacy but also exhibit substantial side‐effect burdens. Data on efficacy and safety of each class of therapy, as well as the combination of these therapies, are reviewed in detail. Specific hormonal therapies (adrenocorticotropic hormone and various corticosteroids) are contrasted. Those etiologies that prompt specific therapies are reviewed briefly, as are an array of second‐line therapies supported by less‐compelling data. The ketogenic diet is discussed in greater detail, with a focus on the limitations of numerous available studies that generally suggest that it is efficacious. Special discussion is allocated to cannabidiol—the investigational therapy that has received the most attention, and which is already in use in the form of various artisanal cannabis extracts. Finally, a treatment algorithm reflecting the concepts and controversies discussed in this review is presented.

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“…VGB is currently used as adjuvant therapy for refractory epilepsies, complex partial seizures, secondarily generalized seizures, infantile spasms, and is under active investigation in tuberous sclerosis complex . However, an extensive body of literature suggests that VGB is associated with peripheral visual field defects (pVFD), but others have suggested that VGB ocular toxicity correlates with pre‐existing anomalies, both structural and genetic . The occurrence of permanent visual field constriction in patients receiving VGB is ~6‐7%) .…”

Section: Discussionmentioning

confidence: 99%

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

Walters

Jansen

Ainslie

et al. 2019

Pharmacology Res & Perspec

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Vigabatrin (VGB; (S)‐(+)/(R)‐(‐) 4‐aminohex‐5‐enoic acid), an antiepileptic irreversibly inactivating GABA transaminase (GABA‐T), manifests use‐limiting ocular toxicity. Hypothesizing that the active S enantiomer of VGB would preferentially accumulate in eye and visual cortex (VC) as one potential mechanism for ocular toxicity, we infused racemic VGB into mice via subcutaneous minipump at 35, 70, and 140 mg/kg/d (n = 6‐8 animals/dose) for 12 days. VGB enantiomers, total GABA and β‐alanine (BALA), 4‐guanidinobutyrate (4‐GBA), and creatine were quantified by mass spectrometry in eye, brain, liver, prefrontal cortex (PFC), and VC. Plasma VGB concentrations increased linearly by dose (3 ± 0.76 (35 mg/kg/d); 15.1 ± 1.4 (70 mg/kg/d); 34.6 ± 3.2 μmol/L (140 mg/kg/d); mean ± SEM) with an S/R ratio of 0.74 ± 0.02 (n = 14). Steady state S/R ratios (35, 70 mg/kg/d doses) were highest in eye (5.5 ± 0.2; P < 0.0001), followed by VC (3.9 ± 0.4), PFC (3.6 ± 0.3), liver (2.9 ± 0.1), and brain (1.5 ± 0.1; n = 13‐14 each). Total VGB content of eye exceeded that of brain, PFC and VC at all doses. High‐dose VGB diminished endogenous metabolite production, especially in PFC and VC. GABA significantly increased in all tissues (all doses) except brain; BALA increases were confined to liver and VC; and 4‐GBA was prominently increased in brain, PFC and VC (and eye at high dose). Linear correlations between enantiomers and GABA were observed in all tissues, but only in PFC/VC for BALA, 4‐GBA, and creatine. Preferential accumulation of the VGB S isomer in eye and VC may provide new insight into VGB ocular toxicity.

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A lack of clinically apparent vision loss among patients treated with vigabatrin with infantile spasms: The UCLA experience

Cited by 23 publications

References 26 publications

Prevention of infantile spasms relapse: Zonisamide and topiramate provide no benefit

Prevention of infantile spasms relapse: Zonisamide and topiramate provide no benefit

Treatment of infantile spasms

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

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