SEARCH

SEARCH BY CITATION

Keywords:

  • electroretinogram;
  • infantile spasms;
  • perimetry;
  • refractory epilepsy;
  • review;
  • vigabatrin;
  • visual field defect;
  • visual field testing

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Sergott RC, Westall CA. Primer on visual field testing, electroretinography, and other visual assessments for patients treated with vigabatrin. Acta Neurol Scand: 2011: 124 (Suppl. 192): 48–56. © 2011 John Wiley & Sons A/S.

Vigabatrin, an irreversible inhibitor of γ-aminobutyric acid transaminase, is an antiepileptic drug indicated in the United States as adjunctive therapy for adult patients with refractory complex partial seizures who have responded inadequately to several alternative treatments and for monotherapy treatment of infantile spasms in patients 1 month to 2 years of age. Approval of vigabatrin in the United States was contingent on the implementation of a Risk Evaluation and Mitigation Strategy (REMS) to manage the threat of a progressive, permanent bilateral concentric peripheral visual field defects (pVFDs) that may occur in patients treated with vigabatrin. The REMS is designed to promote compliance with evidence-based recommendations for baseline (within 4 weeks of the start of treatment) ophthalmologic evaluations and ongoing vision monitoring in all patients treated with vigabatrin. In view of the challenges associated with visual field testing in patients with epilepsy and in infants, clinicians must understand the qualitative (pattern of damage), quantitative (degree of damage), electrophysiologic, and adjunctive techniques recommended for monitoring vigabatrin-treated patients. The objectives of ongoing research are to characterize the onset, progression, and risk of developing vision loss during the first year of vigabatrin treatment and to evaluate the potential of noninvasive imaging as a method for monitoring retinal changes corresponding to the pVFD. This article provides an overview of visual field testing procedures and electroretinography, summarizes the clinical characteristics of vigabatrin-associated pVFDs, and provides recommendations for visual field and visual electrophysiology testing relevant to both adult and infant patients treated with vigabatrin.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Vigabatrin — an irreversible inhibitor of γ-aminobutyric acid transaminase, the enzyme responsible for the metabolism of the inhibitory neurotransmitter γ-aminobutyric acid — is indicated as an antiepileptic drug (AED) for adjunctive therapy in adult patients with refractory complex partial seizures (rCPS) who have responded inadequately to several alternative treatments and as monotherapy for patients 1 month to 2 years of age with infantile spasms (IS) (1–4). Vigabatrin has been approved for rCPS and IS outside the United States since 1989. Subsequent to the determination of vigabatrin-associated effects on peripheral vision, the European Medicines Evaluation Agency Committee for Proprietary Medicinal Products recommended that the labeling be strengthened and prescribing limited to neurologists and physicians experienced in treating patients with epilepsy. Vigabatrin was approved for use in the United States in 2009 with an accompanying special treatment initiation, management, and distribution program called Support, Help And Resources for Epilepsy (SHARE). Food and Drug Administration approval of vigabatrin was accompanied by a Risk Evaluation and Mitigation Strategy (REMS), a comprehensive program designed to mitigate the risk of vigabatrin-associated peripheral visual field defects (pVFDs). The major aspects of the REMS are (i) labeling, including a black box warning on the package insert and a patient medication guide; (ii) communication and education plan to disseminate key risk messages; and (iii) safe use programs, including restrictions on prescribing and dispensing to specialty physicians and pharmacies, benefit–risk and ophthalmologic assessments, and enrollment of each patient in a registry database. A critical component of the REMS is to promote compliance with evidence-based recommendations for baseline (within 4 weeks of the start of treatment) ophthalmologic evaluations and ongoing vision monitoring in all patients treated with vigabatrin (1, 5, 6).

Peripheral constriction of the visual fields is the predominant characteristic of vigabatrin-associated visual defects and this article will review vision testing methods, considerations, and recommendations for visual field testing of patients treated with vigabatrin, including recent findings with electroretinography and a description of a critical ongoing study to characterize the onset and progression of vigabatrin-associated pVFDs.

Overview of visual field testing methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Several qualitative (pattern of damage), quantitative (degree of damage), electrophysiologic, and adjunctive techniques are available to evaluate visual function and may be employed in the assessment of vigabatrin-associated pVFDs. A summary of visual field testing options by developmental age is provided in Table 1. The descriptions that follow are not meant to provide step-by-step methodologies to the various techniques, but rather an overview of available assessments.

Table 1.   Testing options for peripheral visual field defect by developmental age and/or ability
Infants and oldera>9 years of agea
ERGConfrontation testingKinetic perimetryAutomated static perimetry
  1. aCognitive abilities should be taken into consideration.

  2. SSA, Social Security Administration; ERG, electroretinogram.

  3. Sergott RC, Wheless JW, Smith MC, et al., Neuro-opthamology, 2010;34:20–35, copyright © 2010, Informa Healthcare. Reproduced with permission of Informa Healthcare.

Only electrophysiologic testing option appropriate for infants Uses an electrode placed on the eye to monitor electrical activity in the retina in response to a flash of light Requires sedation in infants and young children, as well as qualified experience in laboratoryExaminer holds up one, two, or five fingers on one hand in each quadrant of the patient’s peripheral vision to determine roughly the border of the visual field; for children, small toys of interest are held in the peripheral field to see if any eye movement is made to the target Widely available and easily performed; however, it is not the most sensitive testExaminer moves stimulus spots projected onto a spherical dome through patient’s peripheral vision and maps visual field defects on a reference grid (e.g., Goldmann perimetry) More sensitive than confrontation testing but also requires some technical expertise to perform and is less widely available Automated kinetic perimetry test (SSA kinetic) is now widely available as menu choice on most static perimeters (Octopus and Humphrey) and is fast and easy to performUses automated visual field analyzers, such as Octopus or Humphrey visual field analyzers, to project light stimuli of short duration and map the patient’s sensitivity to spots of light presented randomly across the visual field Widely available testing option. Patient-to-patient testing variability and repeat testing variability present Testing peripheral to 30° does not provide statistical analysis Screening, suprathreshold Esterman test for disability may be an alternative

Qualitative assessments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Qualitative assessments include patient observation, medical history, and rapid visual screening techniques. These can all be conducted relatively quickly by a clinician to evaluate the symptoms of visual deficits. Caregivers and the patients themselves should be also educated about observing symptoms of impaired visual function (e.g., evidence of inability to see objects in the environment) during activities of daily living (6). Rapid ophthalmologic tests that can be conducted to evaluate visual deficits are confrontation testing and the Amsler grid technique.

Confrontation testing is a rapid screening evaluation that requires no special equipment and can indicate in many, but not all, patients whether there is constriction of the visual field. The examiner sits approximately 1 meter away from the patient; asks the patient to focus on the examiner’s nose; and presents one, two, or five fingers in each peripheral quadrant to determine the visual field border (6, 7). The Amsler grid is a rapid and relatively sensitive technique for evaluating the central 20° of the visual field. The Amsler plate is held at one-third meter from the patient’s face, and the optically corrected patient covers one eye and looks at a fixation point in the center of the grid. The patient then describes any central distortion. Amsler grid testing is often a very sensitive screening test for macular diseases (7).

Perimetry

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

The primary quantitative method for evaluating pVFDs is perimetry using either kinetic or static assessments. If a pVFD is suspected after qualitative evaluation, quantitative characterization is warranted to check for areas of decreased sensitivity in the visual field (6, 7). Overall, perimetry results are useful in quantifying the level of binocular field deficit. The resulting amount of the intact binocular field perceived in the horizontal plane can be translated into a definition of mild (120–160° in diameter), moderate (60–120°), and severe (<60°) deficits (5).

In kinetic assessments (e.g., Goldmann kinetic manual perimetry), the operator uses a moving, fixed-intensity stimulus to determine the locations within the visual field where the stimulus can be detected. Points of equal sensitivity are connected to form an isopter, representing the outer limit for that stimulus intensity. Isopters from various stimuli of different intensities are combined to produce the patient’s area of central and peripheral vision (6–9).

In static visual field assessments (e.g., Humphrey visual field analyzer), stimuli of varying intensities are used to detect the minimum intensity and size that can be detected at a particular point within the visual field. The combination of threshold sensitivities defines the patient’s visual field. An automated version of the static perimetry test has come into common use in clinical practice as the results are less operator-dependent and provide more standardized testing conditions (6–9). However, in a follow-up study to the Ocular Hypertension Treatment Study, a majority of the visual field abnormalities initially identified using automated static perimetry were not verified on retest (10). More recently, this testing algorithm has been demonstrated to have significant variability and a “learning curve effect.” The results of a recent ocular hypertension trial using the new technique of Humphrey Matrix Frequency Doubling have demonstrated conclusively that patients need three to four repeat automated perimetry tests before baseline readings can be established (11).

Electrophysiologic testing: electroretinogram

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Electrophysiologic testing is a summary of aggregate responses following visual stimulation that represent the sequence of events along the visual pathway from retina to visual cortex. The results of visual electrophysiologic tests are usually displayed as graphs of voltage (in microvolts) plotted against time (in milliseconds). The graphs have characteristic waveforms. The constituent positive and negative peaks are quantified by their time to peak, relative to the onset of stimulus delivery, and their amplitude, relative to the previous peak or baseline. International professional organizations (e.g., International Society for the Electrophysiology of Vision, International Federation of Clinical Neurophysiology) have prescribed standards for evaluating the characteristic responses. The findings from electrophysiologic testing must be interpreted in conjunction with other clinical assessments of visual function (12, 13).

The electroretinogram (ERG) is a mass response evoked from the retina that is recorded by an electrode placed at the front of eye, and the stimulus parameters are recorded as flash strength in cd/s/m−2. The testing conditions and stimulus parameters can isolate five standardized rod and cone responses from the retina: (i) dark-adapted 0.01 ERG, (ii) dark-adapted 3.0 ERG, (iii) dark-adapted 3.0 oscillatory potentials, (iv) light-adapted 3.0 ERG, and (v) light-adapted 3.0 flicker ERG function (12–14). Diagnostic applications of ERG include retinal dystrophies and degeneration, disorders of dark adaptation, color vision, and visual acuity (12, 13).

The ERG response is most relevant for monitoring of vigabatrin-associated visual deficits. Given the importance of evaluating visual function in infants with IS being treated with vigabatrin, it is also important to examine the potential for using ERG testing in the pediatric population as studies have shown that there are significant developmental changes in the ERG. In infants 1–5 weeks of age, the median dark-adapted 0.01 ERG b-wave amplitude is 15% of the median for that of adults. Dark-adapted 3.0 ERG b-wave and light-adapted 3.0 responses are 32% and 46%, respectively, of the medians for those of adults (15). Dark-adapted 3.0 oscillatory potentials are of very low amplitude or are not recordable in the first 4 months of age but then develop more rapidly than other ERG parameters, reaching adult normal limits by 21 months of age. The light-adapted 3.0 ERG b-wave and the light-adapted 3.0 flicker ERG do not fall within adult levels until after 5 years of age (16). Therefore, pediatric ERG studies must be interpreted in the context of these maturational changes. Representative ERG tracings from an infant and an adult are shown in Fig. 1.

image

Figure 1.  Sample records of the International Society for Clinical Electrophysiology of Vision dark-adapted 0.01 response, dark-adapted 3.0 response, dark-adapted oscillatory potentials, light-adapted 3.0 response, and light-adapted 30-Hz flicker response for a healthy 4-month-old child (left) and a healthy 14-year-old adult (right).

Download figure to PowerPoint

Imaging: optical coherence tomography

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Optical coherence tomography (OCT) is a procedure for noninvasive imaging of cross-sectional images of ocular tissue. Three-dimensional tomographic images are created by reflected light waves from the retina and optic nerve. OCT can produce a retinal thickness map, and sedation is generally not required for patients who can sit still during the very short testing time (generally 1–2 min per eye when the test is performed by an experienced operator) (6). While OCT for infants requires sedation or general anesthesia, OCT is quite feasible for very cooperative children (i.e., those ≥ 3 years of age). Thus, future work may be able to support the usefulness of this technique in diagnosis of visual function abnormalities in impaired patients and children. Spectral domain OCT (SD–OCT) provides greater anatomical detail of retinal nerve fiber layer (RNFL) thickness compared with time domain OCT (TD–OCT) (17, 18) (Fig. 2) and may prove useful in the identification of retinal damage corresponding to pVFDs.

image

Figure 2.  (A) Greater detail of retinal nerve fiber layer (RNFL) thickness observed with SD–OCT vs TD–OCT. (B) Anatomical detail of RNFL thickness observed with SD–OCT. RPE, retinal pigment epithelium. Reprinted courtesy of Heidelberg Engineering, Inc.

Download figure to PowerPoint

Vigabatrin-associated pVFDs

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Vigabatrin-associated vision loss is characterized by progressive and permanent bilateral, concentric peripheral constriction of the visual field. Evidence for vigabatrin-associated deficits in visual acuity and color vision is limited. The underlying cause of the peripheral deficit is believed to be damage to the RNFL (1, 5, 6, 9) from the outside in. Representative reports supporting this pattern have been provided by Frisén and Malmgren (19) and Buncic et al. (20). Frisén and Malmgren (19) conducted a retrospective analysis of ocular photographs, results of kinetic vision testing, and treatment history of 25 vigabatrin-treated patients. Their findings suggested that the primary damage to the RNFL was in the nasal aspect serving the temporal visual field. Buncic et al. (20) evaluated 138 children using clinical and ERG evaluations to correlate those findings with recognizable optic and retinal atrophy. Three children treated with vigabatrin had a form of peripheral retinal atrophy with nasal optic disc atrophy, and the ERG results supported the presence of decreased retinal function. Because many of the studies to date have suffered from methodologic errors in visual testing and have involved primarily cross-sectional data, a Phase IV study gathering prospective, reading-center, controlled data is now in progress to characterize the onset, progression, and risk of developing vision loss during the first year of vigabatrin treatment (18).

Potential risk factors for vigabatrin-associated pVFDs are described by Plant and Sergott (21) in a separate article in this supplement. In general, the risk of vision loss increases with increasing dosage and cumulative exposure, but no minimum toxic dosage has been established. In one study of 155 presurgical patients (99 had been treated with vigabatrin), the prevalence of pVFDs increased significantly with total vigabatrin dosage from 4% in patients exposed to ≤1 kg to 75% in patients who had received 3–5 kg. In addition, pVFDs were both more common in patients treated for longer periods with vigabatrin and irreversible (22). Rarebit (microdot) perimetry was used to examine 12 patients treated with vigabatrin, and the results showed that the visual deficits were proportional to cumulative dosage (23).

Previous or concomitant use of other AEDs may also be associated with greater risk of developing a pVFD. In a retrospective study of 160 patients, AED dosages, duration of treatment, and ERG results were evaluated in relation to findings of retinal toxicity. Of 18 patients with retinal damage, only four received vigabatrin as monotherapy, suggesting that there may be a greater risk of retinal damage in patients treated with vigabatrin in combination with other AEDs instead of when used as monotherapy (24).

ERG studies of pediatric patients treated with vigabatrin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Westall et al. have conducted longitudinal studies to assess retinal toxicity in children before, during, and after vigabatrin treatment (25–27). Their results are consistent with previous findings that the ERG parameter most vulnerable to change is the 30-Hz flicker response (28–31). Fig. 3 shows the cone response and 30-Hz flicker response recorded at several time points during vigabatrin treatment. A total of 228 children were tested consecutively on at least three occasions. The ERG defect, defined as reduction in ERG on two consecutive occasions, can occur as early as 3 months after drug initiation. This is the first of the two abnormal flicker responses required to meet the definition of ERG defect. Contrast sensitivity and visual acuity, as measured by visual evoked potentials, are altered in vigabatrin-treated patients with IS, but evidence suggests that the deficits are a function of IS and not treatment with vigabatrin (32, 33).

image

Figure 3.  Sample electroretinogram (ERG) traces (left) and percentage deviation from age-matched control (right) (13). Left: Cone-isolated responses (top) and the 30-Hz flicker (bottom) are shown with months on vigabatrin (y-axis). A reduction in amplitude is seen with time on vigabatrin, which persists when vigabatrin is discontinued (OFF). The lowermost waveform is the ERG recorded from a 30-month-old control (with normal vision). Time is shown in milliseconds. Positive electrical signals are in the upward direction. Vertical arrows and numbers represent microvolts. Right: Data expressed as difference from age-matched control. At 5 months on vigabatrin, the ERG amplitudes are greater than control data. The amplitudes decrease, reaching a plateau after about 16 months on vigabatrin.

Download figure to PowerPoint

Study of retinal structure and function in adult patients with rCPS treated with vigabatrin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

A prospective, open-label, Phase IV study (ClinicalTrials.gov identifier: NCT01278173) is underway to evaluate changes in visual fields by means of automated static perimetry and changes in retinal structure by means of SD–OCT in patients with rCPS without previous vigabatrin exposure (18). The study is expected to validate SD–OCT as a potentially more robust method for monitoring retinal changes — and providing earlier detection of vision loss — in vigabatrin-treated patients. The study will enroll approximately 80 patients aged ≥18 years at approximately 25 centers in the United States with access to Humphrey static perimetry and SD–OCT. To be eligible to participate in the study, patients must have had rCPS for ≥1 year and no other seizure type within the past year, be currently receiving ≥1 AED, have experienced non-response to ≥3 treatment trials including ≥3 AEDs of differing pharmacology administered as monotherapy or polytherapy, and report an average of ≥2 seizures per month (averaged over the past 3 months). Vision assessments will occur at baseline (before first vigabatrin dose), within 14 days of the first vigabatrin dose (two assessments), every 3 months throughout vigabatrin therapy, and 3 months after discontinuing vigabatrin. Vision assessments will include the 30-2 Swedish Interactive Threshold Algorithm standard, horizontal meridian full-field automated static perimetry (Humphrey Visual Field Analyzer), and SD–OCT. Potentially clinically significant thresholds for vigabatrin-associated vision changes are operationally defined as the percentages of patients with ≥1 of the following changes in ≥1 eyes: (i) changes in binocular visual field along the horizontal meridian of the reference value for patients with ≥20° of constriction, (ii) changes in mean deviation >3.0 dB as measured by the 30-2 Swedish Interactive Threshold Algorithm standard, (iii) decreases in retinal nerve fiber layer thickness >20%, or (iv) decreases in macular thickness >20%. The means of SD–OCT and static perimetry assessments at Visits 1, 2, and 3 will establish the reference value for these readings.

Key primary endpoints will include the change from reference value in field width as measured by static perimetry and the changes from reference value in RNFL thickness and macular thickness as measured by SD–OCT. Quantitative changes in visual fields, RNFL thickness, and macular thickness will be summarized as a function of time, total daily exposure, and cumulative exposure to vigabatrin. Exploratory endpoints of the study will include changes in central acuity and color vision, as well as vision-related quality of life. The goals of the study are to further characterize the onset, progression, and risk of developing vigabatrin-associated vision loss during the first year of use and to validate SD–OCT as a method for monitoring retinal changes corresponding to the visual deficits. Although the study is open-label, this design feature will allow for the evaluation of visual function and retinal changes on an ongoing basis.

Recommendations for visual field testing for patients treated with vigabatrin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Many patients with epilepsy or IS have behavioral and cognitive limitations to visual field testing. In addition to close patient observation and monitoring of activities of daily living, recommendations for age-specific visual field testing (Table 1) require that the neurologist work closely with an ophthalmologist to conduct the visual screening procedures. Based on the report of an expert panel, neurologists should utilize the qualitative techniques of clinical observation and family reports at all ages as well as age-adapted confrontation testing (5, 6). Ophthalmologists and/or neuro-ophthalmologists should repeat the qualitative evaluations and conduct an age-appropriate complete ophthalmologic evaluation for patients of all ages. For patients with an approximate developmental age of 9 years or greater, perimetry testing should be used if possible. For infants, children, and those not able to perform perimetry, ERG and/or OCT (age ≥ 6 years) can be considered. Sedation may be needed for ERG procedures in young children, and there is no significant difference in timing and amplitude of ERGs compared with ERGs recorded without sedation (5, 6, 9, 13). A summary of testing reliability in relation to pVFD severity is provided in Table 2.

Table 2.   Summary of testing reliability for vigabatrin-associated pVFDs
pVFD severityConfrontationKinetic perimetryAutomated kinetic perimetryStatic PerimetryERGOCT
  1. pVFD, peripheral visual field defects; OCT, Optical coherence tomography; ERG, electroretinogram.

  2. −, not reliable; ±, may or may not be reliable; ✓, reliable test.

Mild (120–160°)±±±±±
Moderate (60–120°)
Severe (<60°)

The symptoms of vigabatrin-associated vision loss are generally not self-recognized by the patient before the deficits are severe, so early and routine visual testing is required. Many patients may also develop strategies in their daily lives to compensate for the visual loss. The recommended screening algorithms for patients with rCPS and IS are provided in Fig. 4. Patients should be tested at baseline (within 4 weeks of starting treatment), every 3 months during therapy, and at 3–6 months following discontinuation of vigabatrin. Evidence of a visual abnormality should be further evaluated and a decision made as to the overall risk/benefit on continuing treatment (34). For patients in the United States, a record of the periodic vision monitoring must be documented through the SHARE program (1).

image

Figure 4.  Screening algorithm for vision testing in vigabatrin-treated patients with complex partial seizures (A) and infantile spasms (B). VGB, vigabatrin. Sergott RC, Wheless JW, Smith MC, et al., Neuro-opthamology, 2010;34:20-35, copyright © 2010, Informa Healthcare. Reproduced with permission of Informa Healthcare.

Download figure to PowerPoint

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References

Vigabatrin has been shown to be effective as adjunctive therapy for adult patients with rCPS who have responded inadequately to several alternative treatments and as monotherapy for pediatric patients aged 1 month to 2 years with IS, and compliance with the REMS and regular, age-appropriate vision testing is critical to minimizing the incidence and severity of the bilateral, concentric constriction of the visual field associated with the use of vigabatrin. Visual function should be evaluated early during the course of vigabatrin therapy and continually monitored throughout therapy and after discontinuation from the drug using the methodologies recommended by the expert panel (5, 6). Despite challenges associated with vision testing in children, a regular schedule of vision monitoring for infants and children should be followed, using a combination of observational, qualitative, quantitative, anatomic, and electrophysiologic techniques, of which the 30-Hz flicker response in the ERG is the most relevant for these patients. Neurologists and ophthalmologists must be aware of the advantages and limitations of the various age-specific vision testing methodologies. The risk of vigabatrin-associated vision loss should be managed by ongoing risk–benefit assessments through appropriate monitoring of vision and discontinuation of vigabatrin therapy for patients who experience inadequate clinical response (34). Although vigabatrin-associated pVFDs are reasonably well-characterized, a Phase IV study is currently ongoing (18) to characterize the onset, progression, and risk of developing vision loss during the first year of vigabatrin treatment and to evaluate the potential of SD–OCT as a method for monitoring retinal changes corresponding to the pVFD.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Overview of visual field testing methods
  5. Qualitative assessments
  6. Perimetry
  7. Electrophysiologic testing: electroretinogram
  8. Imaging: optical coherence tomography
  9. Vigabatrin-associated pVFDs
  10. ERG studies of pediatric patients treated with vigabatrin
  11. Study of retinal structure and function in adult patients with rCPS treated with vigabatrin
  12. Recommendations for visual field testing for patients treated with vigabatrin
  13. Conclusions
  14. Conflicts of interest
  15. Acknowledgments
  16. References
  • 1
    SABRIL® [prescribing information]. Deerfield, IL: Lundbeck Inc., 2010.
  • 2
    Ben-Menachem E, Sander JW. Vigabatrin therapy for refractory complex partial seizures: review of major European trials. Acta Neurol Scand 2011;124(Suppl. 192):1628.
  • 3
    Carmant L. Vigabatrin therapy for infantile spasms: review of major trials in Europe, Canada, and the United States; and recommendations for dosing. Acta Neurol Scand 2011;124(Suppl. 192):3647.
  • 4
    Faught RE. Vigabatrin therapy for refractory complex partial seizures: review of major US trials. Acta Neurol Scand 2011;124(Suppl. 192):2935.
  • 5
    Sergott RC. Recommendations for visual evaluations of patients treated with vigabatrin. Curr Opin Ophthalmol 2010;21:4426.
  • 6
    Sergott RC, Wheless JW, Smith MC et al. Evidence-based review of recommendations for visual function testing in patients treated with vigabatrin. Neuro-opthalmology 2010;34:2035.
  • 7
    American Academy of Ophthalmology. The patient with decreased vision: evaluation. In: American Academy of Ophthalmology, ed. Neuro-ophthalmology, section 5, basic and clinical science course. San Francisco: American Academy of Ophthalmology, 2009;91110.
  • 8
    Cohen S, Kawasaki A. Introduction to formal visual field testing: Goldmann and Humphrey perimetry. J Ophthalmic Nurs Technol 1999;18:711.
  • 9
    Kälviäinen R, Nousiainen I. Visual field defects with vigabatrin: epidemiology and therapeutic implications. CNS Drugs 2001;15:21730.
  • 10
    Keltner JL, Johnson CA, Quigg JM et al. Confirmation of visual field abnormalities in the Ocular Hypertension Treatment Study. Arch Ophthalmol 2000;118:118794.
  • 11
    Centofanti M, Fogagnola P, Oddone F. Learning effect of Humphrey matrix frequency doubling technology perimetry in patients with ocular hypertension. J Glaucoma 2008;17:43641.
  • 12
    American Academy of Ophthalmology. Retinal physiology and psychophysics. In: American Academy of Ophthalmology, ed. Retina and vitreous, section 12, basic and clinical science course. San Francisco: American Academy of Ophthalmology, 2010;3353.
  • 13
    Westall C, Kriss A, Thompson D. Pediatric visual electrophysiology. In: Wright K, ed. Pediatric ophthalmology and strabismus, 3rd edn. Oxford University Press, 2012; in press.
  • 14
    Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M. ISCEV Standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol 2009;118:6977.
  • 15
    Fulton AB, Hansen RM, Westall CA. Development of ERG responses: the ISCEV rod, maximal and cone responses in normal subjects. Doc Ophthalmol 2003;107:23541.
  • 16
    Westall CA, Panton CM, Levin AV. Time courses for maturation of electroretinogram responses from infancy to adulthood. Doc Ophthalmol 1999;96:35579.
  • 17
    American Academy of Ophthalmology. Diagnostic approach to retinal disease. In: American academy of ophthalmology, ed. Retina and vitreous, section 12, basic and clinical science course. San Francisco: American Academy of Ophthalmology, 2010;1931.
  • 18
    Sergott RC, Faught E, Torri S, Wesche D. Retinal structure and function in adult patients with refractory complex partial seizures treated with SABRIL® (vigabatrin): an open-label, Phase IV study. Poster 1.294. Presented at the 64th annual meeting of the American Epilepsy Society; December 3–7, 2010; San Antonio, TX.
  • 19
    Frisén L, Malmgren K. Characterization of vigabatrin-associated optic atrophy. Acta Ophthalmol Scand 2003;81:46673.
  • 20
    Buncic JR, Westall CA, Panton CM, Munn JR, MacKeen LD, Logan WJ. Characteristic retinal atrophy with secondary “inverse” optic atrophy identifies vigabatrin toxicity in children. Ophthalmology 2004;111:193542.
  • 21
    Plant GT, Sergott RC. Understanding and interpreting vision safety issues with vigabatrin 2011;124(Suppl. 192):5771.
  • 22
    Malmgren K, Ben-Menachem E, Frisén L. Vigabatrin visual toxicity: evolution and dose dependence. Epilepsia 2001;42:60915.
  • 23
    Frisén L. Vigabatrin-associated loss of vision: rarebit perimetry illuminates the dose-damage relationship. Acta Ophthalmol Scand 2004;82:548.
  • 24
    McCoy B, Wright T, Weiss S, Go C, Westall CA. Electroretinogram changes in a pediatric population with epilepsy: is vigabatrin acting alone? J Child Neurol 2011;26:72933.
  • 25
    Morong S, Westall CA, Nobile R et al. Longitudinal changes in photopic OPs occurring with vigabatrin treatment. Doc Ophthalmol 2003;107:28997.
  • 26
    Westall CA, Logan WJ, Smith K, Buncic JR, Panton CM, Abdolell M. The Hospital for Sick Children, Toronto, Longitudinal ERG study of children on vigabatrin. Doc Ophthalmol 2002;104:13349.
  • 27
    Westall CA, Nobile R, Morong S, Buncic JR, Logan WJ, Panton CM. Changes in the electroretinogram resulting from discontinuation of vigabatrin in children. Doc Ophthalmol 2003;107:299309.
  • 28
    Harding GF, Robertson K, Spencer EL, Holliday I. Vigabatrin: its effect on the electrophysiology of vision. Doc Ophthalmol 2002;104:21329.
  • 29
    Harding GF, Wild JM, Robertson KA et al. Electro-oculography, electroretinography, visual evoked potentials, and multifocal electroretinography in patients with vigabatrin-attributed visual field constriction. Epilepsia 2000;41:142031.
  • 30
    Harding GF, Wild JM, Robertson KA, Rietbrock S, Martinez C. Separating the retinal electrophysiologic effects of vigabatrin: treatment versus field loss. Neurology 2000;55:34752.
  • 31
    Spencer EL, Harding GF. Examining visual field defects in the paediatric population exposed to vigabatrin. Doc Ophthalmol 2003;107:2817.
  • 32
    Hammoudi DS, Lee SSF, Madison A et al. Reduced visual function associated with infantile spasms in children on vigabatrin therapy. Invest Ophthalmol Vis Sci 2005;46:51420.
  • 33
    Mirabella G, Morong S, Buncic JR et al. Contrast sensitivity is reduced in children with infantile spasms. Invest Ophthalomol Vis Sci 2007;48:36105.
  • 34
    Pellock JM. Balancing the clinical benefit of vigabatrin with its associated risk of vision loss. Acta Neurol Scand 2011;124(Suppl. 192):8391.