To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two "hierarchical" levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed; Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and examples to illustrate its application in clinical practice are provided.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2009.02397.x

Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.

*Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China; yInstitute for Children and Adolescents with Epilepsy-IDEE, University Hospital of Lyon (HCL) and Inserm U821, Lyon, France; zDepartment of Biology, Northern Illinois University, DeKalb, Illinois, U.S.A.; xEpilepsy Unit, Western Infirmary, Glasgow, United Kingdom;{GH Sergievsky Center, Columbia University, New York, New York, U.S.A.; #Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, U.S.A.; **The Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience and Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, U.S.A.; yyClinical Trial Center, Institute of Neurology IRCCS C. Mondino Foundation, and Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; zzDepartment of Clinical Neurosciences, University of Calgary, and Hotchkiss Brain Institute, Calgary, Alberta, Canada; and xxNYU Comprehensive Epilepsy Center, New York, New York, U.S.A.

Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies

In clinical practice, there has been a need to grade the magnitude or the severity of the functions and qualities that are assessed in the examination. It is popular to use a four-step grading scale to categorize the severity of clinical findings. The authors discuss clinical grading scales and their influence on the clinician's ability to detect change. These principles have been applied to grades or measures derived from either objective measuring instruments, subjective tests, or techniques in which the clinician makes subjective judgments. A hypothetical data set was used to show the problems associated with using grading scales that are too coarse. The authors presented a mathematic model that helps to estimate the benefits of using use of a finer scale. Data were presented from two separate studies, one on visual acuity measurement and the other on grading nuclear opacity, to show the advantages of using finer scales to enhance the sensitivity of clinical measurement. High levels of concordance between independent observations indicated that the grading scale was too coarse and that these scales needlessly reduced the clinician's ability to detect change in the parameter being assessed. For moderate sensitivity, the size of the scale increments should not exceed one standard deviation of the discrepancy so that the concordance of paired comparisons would not exceed 37%. For fine clinical sensitivity, the size of the scale increments should not exceed one third of the standard deviation of the discrepancy, in which case the concordance of paired comparisons would not exceed 13%. The theory and evidence presented here could prompt re-evaluations of common methods of clinical grading.

Clinical grading and the effects of scaling.

Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII).

PURPOSE. To investigate the relationship between ganglion cell losses and visual field defects caused by glaucoma. METHODS. Behavioral perimetry and histology data were obtained from 10 rhesus monkeys with unilateral experimental glaucoma that was induced by argon laser treatments to their trabecular meshwork. After significant visual field defects had developed, the retinas were collected for histologic analysis. The ganglion cells were counted by light microscopy in cresyl violet-stained retina sections, and the percentage of ganglion cell loss (treated to control eye counts) was compared with the depth of visual field defect (treated to control eye thresholds) at corresponding retinal and perimetry test locations. Sensitivity losses as a function of ganglion cell losses were analyzed for Goldmann III, white and Goldmann V, and short- and long-wavelength perimetry test stimuli. RESULTS. The relationship between the proportional losses of ganglion cells and visual sensitivity, measured with either white or colored stimuli, was nonlinear. With white stimuli, the visual sensitivity losses were relatively constant (approximately 6 dB) for ganglion cell losses of less than 30% to 50%, and then with greater amounts of cell loss the visual defects were more systematically related to ganglion cell loss (approximately 0.42 dB/percent cell loss). The forms of the neural-sensitivity relationships for visual defects measured with short- or long-wavelength perimetry stimuli were similar when the visual thresholds were normalized to compensate for differences in expected normal thresholds for white and colored perimetry stimuli. CONCLUSIONS. Current perimetry regimens with either white or monochromatic stimuli do not provide a useful estimate of ganglion cell loss until a substantial proportion have died. The variance in ganglion cell loss is large for mild defects that would be diagnostic of early glaucoma and for visual field locations near the fovea where sensitivity losses occur relatively late in the disease process. The neural-sensitivity relationships were essentially identical for both white and monochromatic test stimuli, and it therefore seems unlikely that the higher sensitivity for detecting glaucoma with monochromatic stimuli is based on the size-dependent susceptibility of ganglion cells to injury from glaucoma.

Ganglion cell losses underlying visual field defects from experimental glaucoma

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 16patients 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 12patients (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.

https://jnnp.bmj.com/content/jnnp/67/6/716.full.pdf

Visual field defects associated with vigabatrin therapy

Purpose. To determine using a routine clinical program the time course of the fatigue effect in both eyes at a given examination, the influence of rest periods during the examination, and the differences in the fatigue effect between persons with ocular hypertension and age-matched normal subjects. Methods. Perimetry was undertaken for both eyes of 20 normal persons and 20 persons with ocular hypertension using Program G1X (Interzeag AG, Schlieren, Switzerland) of the Octopus 1-2-3 perimeter. Global mean defect and loss variance were calculated for each of the eight individual stages and global SF was calculated for stages 5 to 8. The superoinferior and nasotemporal hemifield indices and those for within and beyond 17° eccentricity were calculated separately to investigate the locus of the fatigue effect. Results. Group mean mean defect and loss variance deteriorated over stages (P < 0.001) and between eyes for both groups (P < 0.001; P < 0.004). The deterioration in the mean defect was more marked peripherally (P < 0.001) and inferiorly with age and group (P < 0.001) whereas the localized loss was more pronounced peripherally {P < 0.001), superiorly (P < 0.010) and nasally (P < 0.001). A 1-minute break during the examination of a given eye and a 3-minute break between eyes was insufficient to overcome the fatigue effect. The performance of the two groups was almost indistinguishable. Conclusions. The deterioration in the visual field indices mean defect and loss variance challenges the currently accepted ideal length of a perimetric examination with the conventional algorithms. Confidence limits for the definition of abnormality with these algorithms should reflect the presence of the fatigue effect and be different for the second eye. Invest Ophthalmol Vis Sci. 1994;35:268-280

Fatigue effects during a single session of automated static threshold perimetry.

Summary: Purpose: Vigabatrin (VGB) therapy is associated with a loss of peripheral vision. The characteristics and prevalence of VGB-attributed visual field loss (V-AVFL) and associated risk factors were evaluated in patients with epilepsy.



Methods: The material comprised the visual fields and case notes of 88 patients with suspected V-AVFL (25 spontaneous reports and 63 cases from an open-label extension trial) and of 42 patients receiving alternative antiepileptic drugs (AEDs) from a cross-sectional study.



Results: Forty-two reliable cases of visual field loss could not be assigned to an alternative known cause and were therefore attributed to VGB (13 spontaneous reports and 29 from the open-label study). All cases except one were asymptomatic. Seven cases of field loss were present in the reference cohort of 42 patients; all cases could be attributed to a known aetiology. Thirty-six of the 42 confirmed cases of V-AVFL exhibited a bilateral defect that was most profound nasally, and three, a concentric constriction. The prevalence of V-AVFL was 29% (95% confidence interval, 21–39%). Male gender was associated with a 2.1-fold increased relative risk of V-AVFL (95% confidence interval, 1.20–4.6%). Age, body weight, duration of epilepsy, and daily dose of VGB, and concomitant AEDs did not predict the occurrence of V-AVFL.



Conclusions: The unique visual field defect attributed to VGB is profound in terms of the frequency of occurrence and the location and severity of loss. The asymptomatic nature of the field loss indicates that V-AVFL can be elicited only by visual field examination.

Characteristics of a unique visual field defect attributed to vigabatrin.

Purpose: 
Vigabatrin is an efficacious antiepileptic drug licensed as add-on therapy in refractory epilepsy and used in infantile spasms. Eight years after licensing, there emerged a strong and possibly causative association with bilateral visual field loss. We report a systematic review ascertaining the magnitude of risk of vigabatrin associated visual field loss (VAVFL) and any clinical predictors of risk.
 
Methods:
 
Electronic searches, including MEDLINE (1966-2009), EMBASE (1974-2009), and CINAHL (1982-2009), were conducted. Reports, published in full, of observational studies investigating the prevalence of visual field loss in patients with partial epilepsy treated with vigabatrin were included. Outcomes were the proportion with visual field loss, and the relative risk of VAVFL compared to similar nonexposed patients with epilepsy.
 
Key Findings:
 
Thirty-two studies were identified, which included 1,678 patients exposed to vigabatrin and 406 controls. Of the 1,678 exposed patients, 738 (44%) had visual field loss compared to just 30 (7%) among the 406 controls. The random-effects estimate for the proportion of adults with visual field loss was 52% [95% confidence interval (CI) 46-59]. The estimate for children was lower at 34% (95% CI 25-42). The relative risk for field loss in vigabatrin-exposed patients was 4.0 (95% CI 2.9-5.5). Larger mean cumulative dose of vigabatrin and increasing age were associated with a higher proportion of patients with visual field loss.
 
Significance:
 
Vigabatrin should be reserved for patients with epilepsy for whom there is no other alternative or for patients who have determined the benefit of ongoing treatment to outweigh the risk of VAVFL.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2010.02772.x

Prevalence of visual field loss following exposure to vigabatrin therapy: A systematic review

Case notes of 1113 consecutive new patients referred to a consultant ophthalmologist at a district general hospital were reviewed to determine the source and efficacy of referrals and the current screening practices of general practitioners and ophthalmic opticians. General practitioners initiated referral in 546 cases (49%) and ophthalmic opticians referral in 439 (39%). Visual loss or visual disturbance was the most important single reason for referral (345 cases; 31%), followed by suspected glaucoma (145 cases; 13%), abnormalities of binocular vision (140; 12.5%), disorders of eyelids or ocular adnexa (127; 11%), and red eye (86; 8%). General practitioners referred many more patients with disorders of the eyelids and adnexa and ophthalmic opticians many more patients with suspected glaucoma. Ophthalmic opticians were far more likely than general practitioners to refer patients with suspected glaucoma correctly. A total of 180 patients (16%) were referred from ocular screening, in 149 cases by ophthalmic opticians and in 10 by general practitioners. Seventy patients had glaucoma or incomplete features of glaucoma, all of them referred by ophthalmic opticians. Of eight diabetic patients referred by ophthalmic opticians, three had asymptomatic disease and in two diabetes was diagnosed as a result of ocular screening. No patient was referred for asymptomatic diabetic retinopathy from screening by general practitioners. Ophthalmic opticians were more likely than general practitioners to diagnose retinopathy requiring photocoagulation. Use of a community based service to screen for glaucoma could save unnecessary consultant outpatient appointments. A similar service could facilitate detection of diabetic retinopathy at a stage when treatment is most effective.

https://www.bmj.com/content/bmj/297/6657/1162.full.pdf

Referral patterns to an ophthalmic outpatient clinic by general practitioners and ophthalmic opticians and the role of these professionals in screening for ocular disease.

John M. Wild

Papers

Visual field defects associated with vigabatrin therapy

Fatigue effects during a single session of automated static threshold perimetry.

Characteristics of a unique visual field defect attributed to vigabatrin.

Prevalence of visual field loss following exposure to vigabatrin therapy: A systematic review

Referral patterns to an ophthalmic outpatient clinic by general practitioners and ophthalmic opticians and the role of these professionals in screening for ocular disease.