Vigabatrin: Lessons Learned From the United States Experience

Vigabatrin was introduced as an antiseizure medication in the United Kingdom in 1989 and was extensively used until 1997 when concerns arose regarding peripheral visual field loss. When the drug was approved in the United States in 2009, it carried a black box warning for the risk of permanent visual loss, and the pharmaceutical company was mandated to create a drug registry to assess for visual deficits. The vigabatrin drug registry has documented a relatively large percentage (37%) of preexisting, baseline visual deficits and a paucity (2%) of potential new visual findings. The vigabatrin vision study, a prospective, longitudinal, single-arm, open-label study, confirmed that adult patients with refractory complex partial seizures had a large number of visual deficits at baseline. An unexpected finding during the first year of therapy with vigabatrin was an increase in retinal thickness on optical coherence tomography. The experience from vigabatrin in the United States emphasizes the importance of baseline eye findings when considering the potential of drug toxicity involving the visual pathways.

Original Contribution Vigabatrin: Lessons Learned From the United States Experience Rod Foroozan, MD Abstract: Vigabatrin was introduced as an antiseizure medication in the United Kingdom in 1989 and was extensively used until 1997 when concerns arose regarding peripheral visual field loss. When the drug was approved in the United States in 2009, it carried a black box warning for the risk of permanent visual loss, and the pharmaceutical company was mandated to create a drug registry to assess for visual deficits. The vigabatrin drug registry has documented a relatively large percentage (37%) of preexisting, baseline visual deficits and a paucity (2%) of potential new visual findings. The vigabatrin vision study, a prospective, longitudinal, single-arm, open-label study, confirmed that adult patients with refractory complex partial seizures had a large number of visual deficits at baseline. An unexpected finding during the first year of therapy with vigabatrin was an increase in retinal thickness on optical coherence tomography. The experience from vigabatrin in the United States emphasizes the importance of baseline eye findings when considering the potential of drug toxicity involving the visual pathways. Journal of Neuro-Ophthalmology 2018;38:442-450 doi: 10.1097/WNO.0000000000000609 © 2017 by North American Neuro-Ophthalmology Society I t is often difficult to determine the validity reports of drug toxicity. In some cases, the patient received a combination of medical and surgical therapy, whereas in others, adverse effects of a medication are not the focus of the study. Many of the reports are single-case studies, whereas in others, the description of findings is incomplete or Baylor College of Medicine, Houston, Texas. Presented in part at the North American Neuro-ophthalmology Society Meeting, April 6, 2017, Washington, DC. R. Foroozan served as a speaker and consultant to Ovation and Lundbeck pharmaceuticals from 2006 through March 31, 2017. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Rod Foroozan, MD, 1977 Butler Boulevard, Houston, TX 77030; E-mail: [e-mail] 442 missing key pieces of information. In addition, the literature of drug toxicity involves numerous medical specialties, each with its own biases (1). Ideally, a causal relationship should be established with a prospective, randomized clinical trial. However, this level of evidence is frequently lacking, and the precise mechanism of toxicity often is unknown. Despite these limitations, it is essential that clinicians prescribe medications with a favorable safety profile (2,3). The focus of this report is vigabatrin and its potential for neuro-ophthalmic toxicity. HISTORICAL PERSPECTIVE OF VIGABATRIN Vigabatrin, an irreversible inhibitor of g-aminobutyric acid (GABA) transaminase, was one of the first "designer drugs" used to treat seizures (Fig. 1) (4). When first synthesized in the 1970s, it was believed that given orally, GABA levels would increase in the central nervous system. At the time, glutamate was known to be an "excitatory" and GABA an "inhibitory" neurotransmitter, and by increasing GABA levels most, if not all, seizures could be eliminated. Initially, vigabatrin seemed to be well tolerated, with sedation the primary side effect similar to other antiseizure agents. An unexpected finding in animal models, which hampered development of the drug, was the finding of intramyelinic edema (IME) (5). However, in humans no neuropathologic correlation was found (6,7), somatosensory evoked potential studies were unaffected, and, therefore, the drug was deemed to be safe (8). MRI abnormalities detected only in infants were believed to correlate with IME (9-11). These included increased T2 signals and restricted diffusion in the thalami, basal ganglia, brainstem tegmentum, and cerebellar dentate nuclei (12). These MRI findings occurred with a frequency of 20%-30% (9), and the risk increased with higher doses of vigabatrin, younger patient age, and cryptogenic etiology of infantile spasms (IS) (12). There were reports that possibly the MRI abnormalities were due to axonal Foroozan: J Neuro-Ophthalmol 2018; 38: 442-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Timeline for development of vigabatrin. degeneration rather than IME (12,13). These changes typically resolved with cessation (Fig. 2) or, in some cases, continuation of the drug and were not associated with any clinical deficits (9). Regulatory approval of vigabatrin was granted in the United Kingdom in 1989 and in the United States in 2009 for monotherapy of IS and as adjunctive therapy for refractory complex partial seizures (CPSs) (4). From 1989 to 1998, approximately 140,000 prescriptions were written in Europe (14). Effective treatment of IS early in the clinical course is critical because IS has a high mortality rate and frequently is a precursor of other forms of epilepsy (Lennox-Gastaut syndrome) and developmental delay. Treatment with vigabatrin may result in rapid cessation of seizures (often within 24 hours) and has been reported to induce complete absence of spasms by age 14 months in 76% of infants (15-17). Treatment of CPS also is essential (18). Without adequate seizure control, these patients suffer from the debilitating effects of uncontrolled epilepsy, including a 4- to Foroozan: J Neuro-Ophthalmol 2018; 38: 442-450 7-fold increase in mortality (SUDEP-the sudden, unexpected death of someone with epilepsy), an increased rate of depression, the inability to drive, and a negative impact on quality of life (19). In more than 50% of adults with refractory CPS, the addition of vigabatrin resulted in a significantly decreased frequency and severity of seizures and, in approximately 10% of patients, complete resolution of seizures (20,21). VIGABATRIN AND VISUAL FUNCTION In 1997, Eke et al (22) reported 3 patients taking vigabatrin who had constricted visual fields on testing with manual kinetic perimetry. In all 3 cases, electroretinography (ERG) testing was normal with the exception of 2 individuals with reduced oscillatory potentials. Subsequently, numerous reports appeared documenting peripheral visual field depression (pVFD) in vigabatrin-treated patients, with prevelance ranging from 10% to 90% (23-55). This broad range is likely due to a variety of factors including variability in clinical criteria (56), type of visual field testing technique (57), and dose 443 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. MRI abnormalities related to vigabatrin. A 5-month-old infant with infantile spasms related to trisomy 21 had normal axial T2 (A) and diffusion weighted imaging (DWI) (B) before treatment with vigabatrin. Four months after the onset of treatment, there was increased signal (arrows) on both T2 imaging (C) and DWI (D) in the thalamus. Vigabatrin was discontinued and MRI 3 months later showed that the abnormalities had resolved (E and F). Images courtesy of James Wheless, MD, Memphis, TN. and duration of treatment. The risk of developing pVFD best correlated with cumulative dose of vigabatrin (58), with estimate of a 4% risk with a cumulative dose of 1 kg to a 75% risk with a cumulative dose of 3-5 kg (44). Most published reports stated that pVFD was irreversible (40,59,60), although others described that it may not progress even with continued drug use. In most patients, the field deficits were asymptomatic. Although the FDA had issued an approval letter in 1997 for vigabatrin in patients with CPS, the approval was rescinded in 1998 because of the reports from Europe on pVFD. Electrophysiologic testing has shown abnormalities in patients taking vigabatrin. The most common changes included reduced b-wave amplitudes, reduced oscillatory potentials (61), and diminished 30 Hz cone flicker responses. Abnormalities also have been documented using wide-field multifocal ERG (62). While most studies related the ERG abnormalities to cumulative dose of vigabatrin, other reports found no parameter of the ERG which 444 correlated with vigabatrin usage (63). In some cases, the electrophysiologic findings resolved or improved after the drug was discontinued (64), making it difficult to distinguish between the drug effect and drug toxicity (65-67). Optical coherence tomography (OCT) of the retina, optic disc, and retinal nerve fiber layer (RNFL) (68-79) also have shown abnormalities in patients taking vigabatrin (68,76). RNFL loss most frequently was found in the superior and inferior quadrants while preserving the temporal region, consistent with sparing of central visual function (68). The mechanism by which vigabatrin is thought to cause retinal damage is believed to involve GABA. By increasing GABA levels within the retina (80), vigabatrin is believed to cause retinal atrophy through an excitotoxic mechanism (81). This is believed to be precipitated and/or enhanced by taurine deficiency in the retina. Taurine, an amino acid which plays a role in limiting damage from oxidative metabolism (82), has been noted to have an important role in Foroozan: J Neuro-Ophthalmol 2018; 38: 442-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution retinal physiology (81). Deficiency of taurine causes photoreceptor and ganglion cell degeneration in animal models (83,84). Vigabatrin competes for the taurine transport protein and has been noted to cause a reduction in serum levels of taurine. Taurine-deficient rodents may develop retinopathy after treatment with vigabatrin, and these effects are relieved with supplementation of taurine (85). This has prompted some epileptologists to prescribe supplementation with taurine in patients treated with vigabatrin; however, there is little evidence to support a definite benefit, and taurine plasma levels are not clinically affected in patients taking vigabatrin (86). Since the early reports of vigabatrin-induced pVFD, nearly every antiseizure agent has been implicated in some type of toxicity affecting the visual system (87-90). Of particular concern was any drug that could alter GABA metabolism (43,87,91-93). This included widely used drugs such as gabapentin, which also was reported to have caused bilaterally constricted visual fields (94). This was described in a 52-year-old woman who had been taking gabapentin for 9 months. This publication only showed the grayscale plots of the visual fields without any other data including reliability indicies. The pVPD resolved with cessation of the medication. A subsequent letter pointed out that the visual field changes were likely due to an artifact of testing (95). At one point, visual field defects were reported in 24% of patients with epilepsy taking antiseizure drugs other than vigabatrin (96). However, it became clear that much of these data were based on visual field studies that were subject to artifacts of testing. Over time concern of other antiseizure medications, with the exception of vigabatrin causing abnormal visual fields gradually resolved. A major concern that permeates the literature dealing with the effect of antiseizure medications on visual function is the role played by epilepsy. For example, ongoing seizures cause cerebral damage, which leads to reduced brain parenchyma, both directly and through trans-synaptic degeneration (97). This leads to a neurodegenerative process including intellectual disability. These factors alone may play a significant role in the reliability of perimetric results. An additional factor is the challenges encountered with vision testing in children (24). THE FDA AND VIGABATRIN In its final data analysis, the FDA determined that vigabatrin caused permanent, bilateral concentric visual field constriction in 30% (it was not clear precisely how this figure was determined) or more of patients, ranging from mild to severe. Although there was very limited information that visual deficits develop rapidly after initiation of therapy, in 2009, the approval of vigabatrin in the United States was contingent on including a black box warning of permanent visual loss (see Supplemental Digital Content, Figure E1, Foroozan: J Neuro-Ophthalmol 2018; 38: 442-450 http://links.lww.com/WNO/A287), which could be noted "at any time after starting treatment (98)." The FDA approval of vigabatrin was accompanied by a Risk Evaluation and Mitigation Strategy, a comprehensive program designed to reduce the risk of vigabatrin-induced vision loss, while providing risk-benefit analyses for appropriate patient populations (99). This led to the creation of a vigabatrin drug registry with mandatory participation by prescribers and patients. Oversight was provided by a group of external experts and staff from Lundbeck Inc (99). Enrollment of 9,423 patients in the vigabatrin drug registry occurred from 2009 to 2016 (14,100,101). All prescribers were required to have a signed ophthalmologic assessment form (OAF) which recorded ophthalmologic assessments or the reason why a patient was exempted from testing (e.g., general neurologic condition, comorbidities preventing vision evaluation, or "other" reasons). The OAFs, while reviewed by the pharmaceutical company, did not undergo independent ophthalmologic review. Nearly, 30% of patients enrolled in the vigabatrin drug registry were exempt from ophthalmologic testing. Ophthalmologic testing results were sent to the drug registry on 1,509 patients. Of these, 565 (37%) had existing clinically significant pathology affecting the visual system that was not related to vigabatrin (Table 1). These data were reviewed by 2 independent neuroophthalmologists who identified 30 patients (2.0%) with a potential vigabatrin-associated effect on vision. The deficits remained "potential" in most cases. For example, visual acuity changes of 3 lines or more occurred in a subgroup of patients and in nearly every case the acuity reverted to baseline or better with subsequent eye examinations despite the continuation of vigabatrin, suggesting that the drug was not likely the cause of the difference in acuity measurements. The most likely explanation in these patients is the inherent difficulty and variability in performing psychophysical testing in patients with epilepsy (35,102). Another finding, particularly in infants, was a decrease in the amplitude of the ERG. The clinical impact of ERG changes seemed to be limited, as a change in visual behavior was not detected in any of these patients. However, in some patients with a decrement in the amplitude of the ERG, vigabatrin was discontinued, and the amplitude nearly uniformly improved. Yet, several patients had an ERG before the institution of vigabatrin, which showed decreased amplitude. Initially, this was interpreted as consistent with drug toxicity, until the examiner was informed that the patient had yet to start the medication. Investigators from Children's Hospital, Boston, MA, have one of the largest experiences with ERG in vigabatrin-treated patients (63). They reported 114 pediatric patients, and none of the ERG parameters changed significantly with increasing duration of vigabatrin use. Four of 27 patients tested longitudinally showed systematic 445 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Most common underlying conditions causing visual impairment in the vigabatrin drug registry listed in estimated order of frequency Site of Visual Impairment Infantile Spasms Refractory Complex Partial Seizures Cerebral visual Cortical visual impairment including from periventricular loss leukomalacia; cortical dysplasia; homonymous visual field loss related to stroke, head trauma, and neurosurgery (including temporal lobectomy) Optic Optic atrophy, including related to head trauma, neuropathy papilledema, and compressive causes; optic disc hypoplasia and coloboma; optic neuropathy related to a genetic condition Retinopathy Retinal hamartomas related to tuberous sclerosis; coloboma most commonly related to Aicardi syndrome; retinal degeneration related to a genetic condition Other ocular Including cataract and retinopathy of prematurity causes Efferent Nystagmus and strabismic amblyopia worsening of log ó (derived from the b-wave stimulus- response function) with duration of vigabatrin use. In a subset of patients who underwent perimetry, there was no significant association of any ERG parameter with visual field defects. The authors were not able to determine whether the ERG abnormalities were solely from the effects of vigabatrin. Furthermore, a subsequent study at the same institution reported that in pigmented and albino rats, vigabatrin enhanced dark-adapted ERG responses but retinal neuronal dysplasia was observed (103). Characterization of the visual field defects in the vigabatrin registry was limited because of the small number of patients who could perform perimetry reliably. The total number of automated and kinetic visual fields performed was approximately 500. Of these, at least in one-third reliability was poor with diffuse field constriction recorded. The difficulty with perimetric results in the registry was highlighted by an adverse event reported in 2011. A 50year-old woman with tuberous sclerosis had normal perimetry at baseline and returned 4 months later for repeat examination. She was taking a higher dose (5 g/d) of vigabatrin than typically recommended (3 g/d). She had no new visual symptoms; however, after repeat perimetry was performed, vigabatrin was discontinued because of concern for pVFD. There were more than 50% false-negative errors in each eye and the perimetrist noted that the patient had fallen asleep during the test. Despite the difficulty in testing these patients and OAFs which noted that patients had discontinued therapy because of a "visual field defect" (not substantiated by independent review), there was no evidence in the registry that any patient had developed symptomatic visual dysfunction related to vigabatrin. 446 Homonymous visual field loss related to stroke, head trauma, and neurosurgery (including temporal lobectomy) Optic atrophy, including related to head trauma, papilledema, and compressive causes Retinal hamartomas related to tuberous sclerosis Including cataract and diabetic retinopathy Nystagmus and strabismic amblyopia PHASE IV VIGABATRIN VISION STUDY In part related to the challenges in gathering accurate data for the vigabatrin registry, the pharmaceutical company Lundbeck Inc (Deerfield, IL) initiated the vigabatrin vision study 13098A (NCT01278173) (104). This was a prospective, longitudinal, single-arm, open-label study of patients aged 18 years and older. This was the largest prospective study that evaluated vision changes in adult patients with refractory CPS defined as $2 seizures per month over the previous 3 months who had failed $3 antiseizure medications and were currently receiving $1 such drug. Vigabatrin was added to their treatment regimen, and ophthalmology assessment was performed within 1 month and at 3, 6, 9, and 12 months. Assessment included Humphrey automated perimetry (30-2 Swedish Interactive Threshold Algorithm [SITA: Standard or FAST programs]), horizontal meridian test (middle peripheral fields-an exploratory test), tangent corner test (far peripheral fields-an exploratory test), spectral domain optical coherence tomography (SD OCT) of the RNFL, and visual acuity by Early Treatment Diabetic Retinopathy Study (ETDRS) measures. The study group was biased to epileptics with better cognition because all the vision tests, including perimetry, had to be completed successfully for the patient to be enrolled. The visual fields and OCTs were assessed independently at different reading centers. Primary endpoints included perimetry: mean change from reference value in mean deviation (in decibels) and SD OCT: mean change from reference value in average RNFL thickness (in micrometers). Exploratory endpoints included change in visual acuity from baseline and percentage of patients meeting any of the following criteria for potentially Foroozan: J Neuro-Ophthalmol 2018; 38: 442-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution clinically significant vision change in at least 1 eye at 2 or more consecutive visits: Perimetry 1. Change in mean deviation .3.0 dB as measured by automated static perimetry central 30° fields. 2. Change in binocular visual field along the horizontal meridian (middle of the peripheral fields) based on the central readers' interpretation of the test results. 3. $20° constriction of the mean linear measurement of the tangent corner test. Spectral Domain Optical Coherence Tomography 1. Decrease in average RNFL thickness (in micrometers) .20%. 2. Decrease of any of the measured sectors of the macula (in micrometers) 20%. 3. Decrease in total macular volume (in cubic millimeters) .10%. Ninety-one patients were screened, and 26 (29%) patients failed. The most common reason for screening failure was inability to complete vision testing, most commonly perimetry. Sixty-five patients were enrolled, and 38 patients completed the study. Approximately twothirds had some type of vision abnormality detected at baseline. Twenty-one (32%) and 10 (15%) patients had an abnormally thin RNFL or abnormal (,20/30) visual acuity, respectively, at the baseline visit. Thirteen patients (20%) had abnormal central 30° visual field measurements. The change from reference values in central 30° visual field measurements (mean deviation, in decibels) was not statistically significant at any visit within 1 year of vigabatrin treatment. An unexpected finding was that compared with the baseline values, the average RNFL thickness increased significantly, which regression analysis confirmed to progress with duration of vigabatrin exposure. No patient had a confirmed three-line or more decrease in visual acuity at 2 or more consecutive visits. Five patients with valid baseline values met the predefined criteria for potentially clinically significant perimetry changes at $2 consecutive visits in at least 1 eye. Unfortunately, these were not confirmed beyond the study period with subsequent testing. No patient developed visual symptoms attributed to vigabatrin during the study. There were no relevant changes from baseline in the National Eye Institute Visual Function Questionnare-39 general health or vision-targeted overall composite scores, including in the 5 patients who met the predefined criteria for potentially clinically significant visual field changes. Although most patients in the trial had RNFL thickening after treatment with vigabatrin, 20 had RNFL Foroozan: J Neuro-Ophthalmol 2018; 38: 442-450 thickening .20% in at least 1 quadrant. The cause of the retinal thickening remained unclear, but it might have been because of intra-axonal and intracellular edema. Given that most evidence suggests that clinically apparent toxicity to the visual system from vigabatrin occurs only after months to years of therapy, the study results are limited by the short duration (1 year) of follow-up. THE FUTURE OF VIGABATRIN There remain a number of unanswered questions, including the original questions posed by the FDA as to the frequency and severity of visual deficits caused by vigabatrin. Perhaps if microperimetry and electrophysiologic testing had been performed for the entire visual field, it might have been easier to distinguish drug effects from drug toxicity. My assessment is that the importance of knowing the true frequency of toxicity has been outweighed by the clinical benefit derived by treating poorly controlled seizures in the absence of a clinically important impact on visual function. This was underscored by Schwarz et al (105) who evaluated 143 patients with IS treated with vigabatrin and failed to detect any clinically apparent visual loss. It seems that in some ways, the pendulum has swung back to a more favorable benefit-risk assessment of vigabatrin in the treatment of IS and refractory CPS (106). The precise duration of treatment which can result in visual toxicity remains unclear; however, the experience thus far in the United States has provided no evidence that toxicity occurs "at any time after treatment," a statement that some practitioners and patients have taken to imply they can (and will) lose vision after a single dose of the medication. Although a few previous reports have suggested that visual deficits may occur rapidly (107), an estimate based on the experience in the United States is that it takes months to years for toxicity to surface in a clinically meaningful manner. CONCLUSION The experience with vigabatrin in the United States has shown a relative paucity of new visual deficits compared with what was anticipated when the drug received approval by the FDA in 2009. In October of 2013, the FDA granted a label change that lowered the age (from 17 years to 10 years) at which vigabatrin could be prescribed. Neither the drug registry nor the phase IV vision study has revealed patients with symptomatic visual loss attributed to vigabatrin. As of June 2016, the language in the package insert regarding eye examinations to monitor for drug toxicity was changed from "required" (98) to "recommended" (see Supplemental Digital Content, Figure E2, http://links.lww. com/WNO/A288) (108). In addition, the black box warning from June 2016 omitted the "30 percent or more" found in previous prescribing information. 447 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Most importantly, the clinical experience with vigabatrin emphasizes the difficulties inherent in assessing drug toxicity using retrospective and cross-sectional studies without baseline eye examinations. 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