Field-specific visual-evoked potentials: identifying field defects in vigabatrin-treated children

OBJECTIVE: To derive a visual-evoked potential (VEP) technique for identifying visual field defects in children with epilepsy treated with vigabatrin and unable to perform perimetry. BACKGROUND: Studies have linked vigabatrin to a specific pattern of visual field loss. Few studies have included the pediatric population because of difficulties in assessing the visual field by perimetry below a developmental age of 9 years. METHODS: A field-specific VEP was developed with a central (0 degrees to 5 degrees radius) and peripheral stimulus (30 degrees to 60 degrees radius). Stimuli consisted of black and white checks that increased in size with eccentricity. Checks reversed at different rates, allowing separate central and peripheral responses to be recorded. Five vigabatrin-treated young adults with field defects were identified using this stimulus. Electroretinograms (ERG) were recorded to examine the effects of vigabatrin on retinal function. Thirty-nine children aged 3 to 15 years were included in the study. Twelve patients were examined by both the field-specific stimulus test and perimetry. The diagnostic performance of the field-specific stimulus test was compared with that of perimetry. RESULTS: Thirty-five of 39 children complied with the field-specific stimulus, 26 of 39 complied with the ERG, and 12 of 39 complied with perimetry. Using the summed amplitude of the peripheral response from O(2) and O(1), responses below 10 microV were deemed abnormal. The field-specific stimulus identified 3 of 4 abnormal perimetry results and 7 of 8 normal perimetry results, giving a sensitivity of 75% and a specificity of 87.5%. When comparing perimetry results with the ERG parameters, only the 30-Hz flicker amplitude, with a cutoff below 70 microV, gave a useful indication of visual field loss. CONCLUSION: Field-specific VEP are well tolerated by children older than 2 years of age and are sensitive and specific in identifying vigabatrin-associated peripheral field defects.     

Visual field defects associated with vigabatrin therapy

OBJECTIVE: To estimate the prevalence of visual field defects in patients taking the anticonvulsant drug vigabatrin and to characterise the features of visual dysfunction found. METHODS: Thirty three unselected patients attending neurology and epilepsy clinics were identified as taking vigabatrin and asked to attend for neuro-ophthalmic evaluation. A control group of 16 patients with epilepsy unexposed to vigabatrin was also evaluated. Visual fields were examined by static perimetry using a Humphrey field analyser. Patients underwent detailed ophthalmic examination, various blood tests, and brain MRI where necessary. Visual evoked responses (VERs), electro-oculograms (EOGs), and electroretinograms (ERGs) were recorded. RESULTS: Of 31 assessable patients treated with vigabatrin, 16 (52%) had definitely abnormal visual fields, nine (29%) had fields that were inconclusive, four (13%) had normal fields, and two (6%) proved unable to cooperate with testing. In four patients some plausible cause was found for the field abnormality leaving 12 patients (39%) in whom a definite bilateral field defect was found, possibly caused by vigabatrin treatment. Of 16 control patients none had definitely abnormal fields, 12 (75%) had normal fields, and four (25%) had fields that were inconclusive. The field defects associated with vigabatrin treatment showed a characteristic pattern of concentric peripheral field loss with temporal and macular sparing. The VERs and ERGs were normal. The EOG Arden Index was reduced in patients taking vigabatrin, although this returned towards normal when vigabatrin was stopped, even in the presence of persistent field defects. Multifocal ERGs recorded in two patients were abnormal, showing marked reduction in amplitude of the peripheral focal ERG. CONCLUSIONS: Treatment with vigabatrin was associated with a high prevalence of peripheral visual field defects. This seemed to be the result of a toxic effect of vigabatrin on the retina and seemed to persist if the drug was withdrawn.     

Electroretinographic and visual evoked potential abnormalities in myotonic dystrophy

Pattern visual evoked potentials (VEPs) and electroretinograms (ERGs) were recorded in 20 patients with myotonic dystrophy. Thirteen out of 20 cases presented both VEP and ERG abnormalities, 3 only ERG alterations, 2 only abnormal VEPs. A significant inverse correlation between P100 latencies and b1 wave amplitude was observed, while N1-P100 and b1 wave amplitude exhibited a parallel change. These data suggest that retinal abnormalities may have a role in inducing subclinical visual pathway alterations in myotonic dystrophy.     

Electrophysiological examinations of the visual system in multiple sclerosis

Electroretinograms (ERG) and visual evoked potentials (VEP) were recorded from 35 patients suffering from multiple sclerosis. Of these, 18 suffered from visual deficits at the time of the examinations, 8 had had transient visual symptoms in the past and 9 had no visual symptoms at any time.In contrast to previous reports on cases of multiple sclerosis, enhanced retinal responses were found. Furthermore, there was no direct correlation between the severity of the visual deficit, the duration of the visual symptoms and the abnormality reflected by the ERG and VEP. The ERG and VEP were abnormal even in the absence of visual symptoms.Among the 35 patients examined 11 exhibited in 1 or in both eyes an enhanced b-wave of the ERG and 20 others displayed at least in 1 eye subnormal retinal responses. There were only 4 patients with normal ERGs in both eyes. However, the VEPs were nearly normal only in 1 patient of the 4.No matter whether or not vision was affected at the time of the examination, the averaged visual evoked potentials of nearly all patients examined were abnormal.     

Taurine deficiency damages photoreceptors and retinal ganglion cells in vigabatrin-treated neonatal rats

The anti-epileptic drug vigabatrin induces an irreversible constriction of the visual field, but is still widely used to treat infantile spasms and some forms of epilepsy. We recently reported that vigabatrin-induced cone damage is due to a taurine deficiency. However, optic atrophy and thus retinal ganglion cell degeneration was also reported in children treated for infantile spasms. We here show in neonatal rats treated from postnatal days 4 to 29 that the vigabatrin treatment triggers not only cone photoreceptor damage, disorganisation of the photoreceptor layer and gliosis but also retinal ganglion cell loss. Furthermore, we demonstrate in these neonatal rats that taurine supplementation partially prevents these retinal lesions and in particular the retinal ganglion cell loss. These results provide the first evidence of retinal ganglion cell neuroprotection by taurine. They further confirm that taurine supplementation should be administered with the vigabatrin treatment for infantile spasms or epilepsy.     

A study of the relationship between neurological function and serum vitamin E concentrations in patients with cystic fibrosis.

A patient with cystic fibrosis and undetectable serum vitamin E concentrations is described who developed a progressive spinocerebellar syndrome and pigmentary retinopathy with abnormal somatosensory and visual evoked potentials (SSEPs and VEPs). In order to assess the relationship between neurological function and serum vitamin E concentrations in cystic fibrosis, 29 unselected patients who had no neurological symptoms were examined neurologically. Ten were randomly selected for neurophysiological assessment by recording SSEPs and VEPs. Electroretinograms (ERGs) were also performed in five cases. The findings were correlated with serum vitamin E concentrations which were unknown to the neurological investigators prior to completion of the study. Only one patient had definite reflex and sensory abnormalities, and the remaining 28 were clinically normal. The ERG was abnormal in two cases, one of whom had abnormal VEPs. SSEPs were normal in all 10 cases. Twenty six patients had serum vitamin E concentrations below the normal range. In two of the three patients who had definite neurological or electrophysiological abnormalities serum vitamin E concentrations were below the median value for the whole group.     

Visually evoked potentials and electroretinography in neurologic evaluation.

Electrophysiologic testing of the visual system requires primarily the ERG and the VEP. The flash electroretinogram provides information about the outer retina only. The pattern electroretinogram is derived from both the outer retina and the innermost retinal layers including the ganglion cell layer. The VEP is based on electrical information recorded from the visual cortex in response to stimulation of the retina. Thus, the integrity of the entire visual pathway can be tested. Localizing ability of the VEP is limited. Since the visual cortex is heavily weighted by representation of the central retina, peripheral lesions, including those producing peripheral visual field abnormalities that do not impinge upon central fixation, may produce relatively little disturbance of the VEP. As with most tests, electrophysiologic studies of the visual system must be placed in context of the entire examination, including the patient's history and neurologic and especially neuro-ophthalmologic evaluation. Electrophysiologic testing has three main uses in neurology. Pattern-reversal VEPs may be useful in detecting hidden visual loss in multiple sclerosis; VEPs and ERGs can distinguish function from organic visual loss; and VEPs and ERGs can be useful in the diagnosis of visual loss in nonverbal patients, especially in children.     

Seizure outcome in infantile spasms--a retrospective study

Purpose: Prior to the United Kingdom Infantile Spasms Study (UKISS), our practice was to initiate vigabatrin for infantile spasms. However, since then we tend to use steroids as first‐line agent for infantile spasms. Herein we compare seizure‐free outcomes in children with infantile spasms on steroid therapy or vigabatrin therapy. Methods: This was a retrospective case study over 8 years of children with infantile spasms who were treated at our center. A positive response to therapy was defined as a two‐week spasm‐free interval. Key Findings: Of the 98 children presenting to us, 75 were included for this study. The ratio of cryptogenic to symptomatic spasms was 24:51. The response rate for steroid therapy was 61.1% and 42.5% for vigabatrin. Cessation of spasms was achieved faster in the group receiving steroids. Both groups had similar relapse rates. Steroids had significantly better response in the cryptogenic group, whereas in the symptomatic group both the medications were equally effective. Cryptogenic spasms have a better neurodevelopmental outcome. Early introduction of therapy for spasms did not predict a good neurodevelopmental outcome. Seventy‐eight percent of children with spasms had seizures of other types at 12 months follow‐up. Significance: At our center, steroids are now the preferred choice for initial therapy of infantile spasms. This is likely to have been a beneficial change, particularly for children with cryptogenic spasms. Spasms in 25% of the patients tend to be refractory, and the majority of patients from the cohort continue to have epilepsy with motor and cognitive disabilities.     

Pattern visual evoked potentials and flash electroretinogram in clinically definite multiple sclerosis

The authors have studied, by means of pattern visual evoked potential (VEP) and flash electroretinogram (ERG) recordings, a group of 15 patients affected by definite multiple sclerosis. All of the subjects examined presented a clinical history indicating involvement of the visual pathways; VEPs were altered in a high percentage of eyes examined (93.3%), while a lower percentage of abnormal ERGs was seen (20% of eyes examined). The only type of ERG alteration found consisted of a pathologic b wave voltage increase, observed mainly with red flash stimuli. This finding could be attributed to an involvement of centrifugal optic nerve fibers having inhibitory functions on retinal cells.     

Diagnosing children presenting with asymmetric pendular nystagmus

Horizontal asymmetric nystagmus usually occurs in one of three situations: secondary to an intracranial lesion, with monocular visual loss, or as part of the triad that constitutes the diagnosis of spasmus nutans (asymmetric nystagmus, abnormal head posture, head shake). Clinical records of 277 children, presenting with congenital nystagmus over an 8-year period were reviewed. Nystagmus was asymmetric in 24 of 277 cases. Seven of these patients were diagnosed with spasmus nutans. This is a rare condition that is only diagnosed retrospectively based on the absence of any abnormal neuroimaging or electrophysiological findings. Twelve of 24 patients had intracranial pathology and all had abnormal visual evoked potentials (VEPs). Five patients were diagnosed with congenital sensory defect nystagmus including one with albinism, three with congenital cone dysfunction, and one with cone-rod dystrophy. This paper stresses that although neuroimaging is necessary in all patients presenting with asymmetric nystagmus, such nystagmus can also occur with retinal disease or albinism and indicates the importance of non-invasive VEP/ERG testing in all forms of nystagmus.     

Registry initiated to characterize vision loss associated with vigabatrin therapy

The vigabatrin patient registry was implemented in August 2009 in conjunction with Food and Drug Administration approval of vigabatrin. All US vigabatrin-treated patients must enroll in the registry. Data on prescriber specialty/location, patient demographics, and clinical characteristics are collected. Benefit-risk assessments are required early in the course of therapy. Vision assessments are required at baseline (≤ 4 weeks after therapy initiation), every 3 months during therapy, and 3 to 6 months after discontinuation. As of February 1, 2011, 2473 patients (1500 with infantile spasms, 846 with refractory complex partial seizures, 120 with other diagnoses) had enrolled; 30.4% were previously exposed to vigabatrin. Kaplan-Meier analysis of time in registry indicated that 83 and 97% of all enrolled patients with refractory complex partial seizures and infantile spasms remained beyond 3 and 1 month, respectively. The ongoing registry will provide visual status and other information on vigabatrin-treated patients for both the infantile spasm and refractory complex partial seizure indications.     

Visual fields at school-age in children treated with vigabatrin in infancy

Purpose:   The use of vigabatrin (VGB) as an antiepileptic drug (AED) has been limited by evidence showing that it causes vigabatrin-attributed visual field loss (VAVFL) in at least 20–40% of patients exposed at school age or later. VGB is an effective drug for infantile spasms, but there are no reports on later visual field testing after such treatment. Our aim was to investigate the risk of VAVFL in school-age children who had received VGB in infancy.
Methods:   Visual fields of 16 children treated with VGB for infantile spasms were examined by Goldmann kinetic perimetry at age 6–12 years. Normal fields were defined as the temporal meridian extending to more than 70°, and mild VAVFL between 50 and 70°. Abnormal findings were always confirmed by repeating the test. Exposure data were collected from hospital charts.
Results:   Vigabatrin was started at a mean age of 7.6 (range, 3.2–20.3) months. The mean duration of therapy was 21.0 (9.3–29.8) months and cumulative dose 655 g (209–1,109 g). Eight children were never treated with other AEDs, five received only adrenocorticotropic hormone (ACTH) in addition to VGB, and three children had been treated with other AEDs. Fifteen children had normal visual fields. Mild VAVFL was observed in one child (6%) who had been treated with VGB for 19 months and who received a cumulative dose of 572 g.
Conclusions:   The risk of VAVFL may be lower in children who are treated with VGB in infancy compared to patients who receive VGB at a later age.     

Clinical imitators of infantile spasms.

We report 53 infants who by clinical history were thought to have infantile spasms but who video-electroencephalograms showed were having other episodes that closely mimicked infantile spasms. Nine patients had other types of seizures. Forty-five patients had episodic symptoms that were not seizures: 11 patients had spasticity, four had gastroesophageal reflux, and the other patients had nonepileptic myoclonus, including 19 patients with benign neonatal sleep myoclonus. Three patients had more than one type of symptom. Infantile spasms imitators occurred in neurologically normal or abnormal infants, in patients with normal or abnormal interictal electroencephalograms, and in patients who also had previous or current infantile spasms. Differentiation of these episodes from infantile spasms prevented the initiation or continuation of anticonvulsant treatment appropriate for infantile spasms but inappropriate for these other behaviors.     

Visual field constriction in 91 Finnish children treated with vigabatrin

Summary: Purpose: To study the prevalence and features of visual field constrictions (VFCs) associated with vigabatrin (VGB) in children. Methods: A systematic collection of all children with any history of VGB treatment in fifteen Finnish neuropediatric units was performed, and children were included after being able to cooperate reliably in repeated visual field tests by Goldmann kinetic perimetry. This inclusion criterion yielded 91 children (45 boys; 46 girls) between ages 5.6 and 17.9 years. Visual field extent <70 degrees in the temporal meridian was considered abnormal VFC. Results: There was a notable variation in visual field extents between successive test sessions and between different individuals. VFCs <70 degrees were found in repeated test sessions in 17 (18.7%) of 91 children. There was no difference in the ages at the study, the ages at the beginning of treatment, the total duration of the treatment, general cognitive performance, or neuroradiologic findings between the patients with normal visual fields and those with VFC, but the patients with VFC had received a higher total dose of VGB. In linear regression analysis, there were statistically significant inverse correlations between the temporal extent of the visual fields and the total dose and the duration of VGB treatment. The shortest duration of VGB treatment associated with VFC was 15 months, and the lowest total dose 914 g. Conclusions. Because of a wide variation in normal visual‐field test results in children, the prevalence figures of VFCs are highly dependent on the definition of normality. Although our results confirm the previous findings that VFC may occur in children treated with VGB, our study points out the need to reevaluate critically any suspected VFC to avoid misdiagnosis. Nevertheless, our study suggests that the prevalence of VFC may be lower in children than in adults, and that the cumulative dose of VGB or length of VGB therapy may add to the personal predisposition for developing VFC.     

Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review

The purpose of this report is to review the efficacy and safety of vigabatrin in the treatment of infantile spasms in infants suffering from tuberous sclerosis complex. We reviewed all studies published in the English-language literature investigating the use of vigabatrin in the treatment of infantile spasms. Ten studies gave results for the efficacy of vigabatrin in infantile spasms for infants both with and without underlying diagnoses of tuberous sclerosis. Of the 313 patients without tuberous sclerosis complex, 170 (54%) had complete cessation of their infantile spasms; of the 77 patients with tuberous sclerosis complex, 73 (95%) had complete cessation of their seizures. We conclude that vigabatrin should be considered as first-line monotherapy for the treatment of infantile spasms in infants with either a confirmed diagnosis of tuberous sclerosis or those at high risk, ie, those with a first-degree relative with tuberous sclerosis complex. Paradoxically, in those without tuberous sclerosis complex, vigabatrin might be less efficacious than suggested by studies including patients with tuberous sclerosis complex.     

Registry initiated to characterize vision loss associated with vigabatrin therapy

The vigabatrin patient registry was implemented in August 2009 in conjunction with Food and Drug Administration approval of vigabatrin. All US vigabatrin-treated patients must enroll in the registry. Data on prescriber specialty/location, patient demographics, and clinical characteristics are collected. Benefit–risk assessments are required early in the course of therapy. Vision assessments are required at baseline (≤ 4 weeks after therapy initiation), every 3 months during therapy, and 3 to 6 months after discontinuation. As of February 1, 2011, 2473 patients (1500 with infantile spasms, 846 with refractory complex partial seizures, 120 with other diagnoses) had enrolled; 30.4% were previously exposed to vigabatrin. Kaplan–Meier analysis of time in registry indicated that 83 and 97% of all enrolled patients with refractory complex partial seizures and infantile spasms remained beyond 3 and 1 month, respectively. The ongoing registry will provide visual status and other information on vigabatrin-treated patients for both the infantile spasm and refractory complex partial seizure indications.     

Place of VEP's and ERG in neonatal encephalopathies and impaired visual maturation in the infant and young child

Visual evoked potentials (VEPs) induced by brief flashes and electroretinograms (ERGs) were recorded in 15 infants (9 prematures and 6 babies with perinatal cerebral injuries) suffering from important disturbances in their visual behavior (abnormal fixation, cortical blindness). The parallel evolution of the visual symptoms and the electrophysiological signs were studied and a good correlation was observed between these clinical and electrical signs. The authors insist on the clinical and prognostic value of the VEP in this category of infants.     

Understanding and interpreting vision safety issues with vigabatrin therapy

Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid (GABA) transaminase. It is effective as adjunctive therapy for adult patients with refractory complex partial seizures (rCPS) who have inadequately responded to several alternative treatments and as monotherapy for children aged 1 month to 2 years with infantile spasms. The well-documented safety profile of vigabatrin includes risk of retinopathy characterized by irreversible, bilateral, concentric peripheral visual field constriction. Thus, monitoring of visual function to understand the occurrence and manage the potential consequences of peripheral visual field defects (pVFDs) is now required for all patients who receive vigabatrin. However, screening for pVFDs for patients with epilepsy was conducted only after the association between vigabatrin and pVFDs was established. We examined the potential association between pVFDs and epilepsy in vigabatrin-na?ve patients and attempted to identify confounding factors (e.g., concomitant medications, method of vision assessment) to more accurately delineate the prevalence of pVFDs directly associated with vigabatrin. Results of a prospective cohort study as well as several case series and case reports suggest that bilateral visual field constriction is not restricted to patients exposed to vigabatrin but has also been detected, although much less frequently, in vigabatrin-na?ve patients with epilepsy, including those who received treatment with other GABAergic antiepileptic therapy. We also reviewed published data suggesting an association between vigabatrin-associated retinal toxicity and taurine deficiency, as well as the potential role of taurine in the prevention of this retinopathy.     

Separating the retinal electrophysiologic effects of vigabatrin: treatment versus field loss

OBJECTIVE: To separate the retinal electrophysiologic markers associated with vigabatrin-attributed visual field loss (VGB-VFL) from those associated with current vigabatrin therapy. METHODS: A nonrandomly selected cohort of 8 previous and 18 current vigabatrin users and a reference cohort of 8 never vigabatrin-treated patients with epilepsy receiving other antiepilepsy drugs (AED) underwent electro-oculography (EOG), electroretinography (ERG), and automated static threshold perimetry. A cohort of 22 normal subjects underwent ERG. The validity of the retinal electrophysiologic variables to detect the presence and severity of VGB-VFL was assessed using receiver operator characteristic curves. RESULTS: Of 26 patients exposed to vigabatrin, 18 exhibited VGB-VFL. No patients receiving alternative AED showed this type of visual field abnormality. The presence and severity of VGB-VFL was significantly associated with the latency (implicit time) and amplitude of the ERG cone function. The amplitude of the cone flicker response was the strongest predictor of VGB-VFL and revealed a sensitivity of 100% at a specificity of 75%. The EOG, the photopic and scotopic ERG, and the latency of the ERG second oscillatory potential (OP2) were not significantly related to the presence of VGB-VFL. Vigabatrin therapy was significantly associated with the photopic amplitude, the scotopic a-wave latency, and the latency of OP2. CONCLUSION: In patients who cannot perform reliable perimetry, the cone-specific ERG flicker amplitude provides the best screening method for detecting VGB-VFL.     

Combined treatment with vigabatrin and topiramate in West syndrome

The clinical and electroencephalographic (EEG) response to combined therapy with vigabatrin and topiramate was evaluated in five patients ages 7 to 15 months affected by West syndrome in an open-label trial. Four patients had cryptogenic and one patient had symptomatic (tuberous sclerosis) West syndrome. In cryptogenic patients who failed to respond to pyridoxine, vigabatrin was titrated to 80 to 100 mg/kg. Because control of infantile spasms or an EEG improvement was not obtained with vigabatrin treatment, topiramate was added (3-3.8 mg/kg/day). In all patients, the combined therapy with topiramate and vigabatrin achieved a rapid and complete normalization of infantile spasms, and in three patients with cryptogenic West syndrome, the EEG also became normal. In only one patient, transient anorexia was observed. This drug combination led to rapid neurodevelopmental normalization in cryptogenic patients. The results are promising and justify more trials in larger numbers of children with West syndrome.