The cornea is an extraordinary component of vision that functions as the principal barrier to pathogens in the eye while allowing light transmission into the retina. Understanding the cellular and molecular mechanisms that maintain homeostasis in this tissue is the subject of intense scientific study given the high prevalence of corneal disease. Over the past decade, the interactions between lectins and glycans on plasma membranes have emerged as important regulatory factors in corneal biology. In particular, members of the galectin family have been shown to bind multiple β-galactoside-containing receptors to regulate immunopathological processes associated with viral and bacterial infection, transplantation, wound healing, dry eye, angiogenesis, and lymphangiogenesis. In this review, we describe the current understanding of how these surface interactions intersect with different pathways to activate unique cellular responses in cornea as well as their potential therapeutic implications.
Importance: Moderate to substantial agreement between Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field imaging and ultrawide-field (UWF) imaging has been suggested in single-center studies. Comparing images obtained by multiple centers could increase confidence that UWF images can be used reliably in place of ETDRS imaging in future clinical trials. Objective: To compare diabetic retinopathy (DR) severity from modified ETDRS 7-field imaging and UWF imaging. Design, Setting, and Participants: This preplanned, cross-sectional analysis included modified ETDRS 7-field images obtained using the Diabetic Retinopathy Clinical Research Network acquisition protocol and UWF images obtained captured with the Optos 200Tx system (Optos, PLC) from adult participants (≥18 years old) with type 1 or type 2 diabetes. Both image types were evaluated by trained graders masked to clinical data. Data collection occurred from February 2015 to December 2015, and data analysis from June 2016 to December 2017. Main Outcomes and Measures: Agreement between UWF images, UWF imagesmasked to include only the ETDRS 7-field area, and ETDRS 7-field images were calculated using κ statistics. Results: A total of 764 eyes from 385 participants were included; participants had a median (IQR) age of 62.2 (53.6-69.2) years, 194 (50.4%) were women, and 256 (66.5%) were white. Of 742 eyes with both ETDRS 7-field images and UWF masked images graded, 359 (48.4% [95% CI, 44.4%-52.4%]) eyes had exact agreement, and 653 eyes (88.0% [95% CI, 85.2%-90.3%]) agreed within 1 step (weighted κ, 0.51 [95% CI, 0.44-0.58]). After open adjudication by an independent senior grader of all images with more than a 2-step discrepancy, perfect agreement was found in 435 eyes (59.0% [95% CI, 55.1%-62.8%]) and agreement within 1 step in 714 eyes (96.9% [95% CI, 95.1%-98.0%]; κ, 0.77 [95% CI, 0.73-0.82]). Ability of the imaging modalities to detect retinopathy severity in an individual eye was considered similar in 59 eyes (50.9% [95% CI, 41.3%-60.4%]), better for ETDRS 7-field imaging in 22 eyes (19.0% [95% CI, 12.5%-27.7%]), and better for UWF-masked images in 31 eyes (26.7% [95% CI 18.8%-36.5%]). Comparing UWF masked and unmasked images, 94 of 751 eyes (12.5%) had DR graded as at least 1 step more severe on UWF unmasked images vs UWF masked images. Predominantly peripheral DR lesions were present in 308 of 751 eyes (41.0%); this suggested increased DR severity by 2 or more steps in 34 eyes (11.0%). Conclusions and Relevance: Imaging by the ETDRS 7-field and UWF imaging systems have moderate to substantial agreement when determining the severity of DR within the 7 standard fields. Disparities in an individual eye are equivalently distributed between imaging modalities and can be better or worse on 1 or the other. Longitudinal follow-up will evaluate the primary outcome of this study to determine if peripheral retinal findings are associated with future retinopathy outcomes.
Purpose: We describe the clinical features in two pedigrees with dominantly inherited retinopathy segregating the previously reported frameshifting mutation, c.836dupG (p.Ile280Asn*78) in the terminal exon of the RGR gene, and compare their haplotypes to that of the previously reported pedigree. Methods: The probands were ascertained at West Virginia University Eye Institute (WVU) and Moorfields Eye Hospital (MEH) through next generation sequencing (NGS) and whole genome sequencing (WGS) respectively. Clinical data included visual acuity (VA), visual fields, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Haplotype analysis was performed using Sanger sequencing of the DNA from the molecularly ascertained individuals from the three pedigrees. Results: Nine heterozygous mutation carriers were identified in two families. Four carriers were asymptomatic; five carriers had variable VA reduction, visual field constriction, and experienced difficulty under dim illumination. Fundus examination of the asymptomatic carriers showed diffuse or reticular pigmentation of the retina; the symptomatic carriers had chorioretinal atrophy. FAF imaging showed widespread signal loss in advanced retinopathy, and reticular hyperautofluorescence in mild cases. OCT showed loss of outer retinal lamina in advanced disease. ERG showed moderate-to-severe rod-cone dysfunction in two symptomatic carriers; and was normal in three asymptomatic carriers. A shared haplotype flanking the mutation of up to 6.67 Mb was identified in both families. Within this region, 1.27 Mb were shared with the first family reported with this retinopathy. Conclusions: The clinical data suggest a variable and slow degeneration of the RPE. A shared chromosomal segment surrounding the RGR gene suggests a single ancestral mutational event underlying all three families.
Bonnemaijer PWM, Iglesias AI, Nadkarni GN, Sanyiwa AJ, Hassan HG, Cook C, Cook C, Simcoe M, Taylor KD, Schurmann C, Belbin GM, Kenny EE, Bottinger EP, van de Laar S, Wiliams SEI, Akafo SK, Ashaye AO, Zangwill LM, Girkin CA, Ng MCY, Rotter JI, Weinreb RN, Li Z, Allingham RR, of Consortium EAG, Nag A, Hysi PG, Meester-Smoor MA, Wiggs JL, Wiggs JL, Hauser MA, Hammond CJ, Lemij HG, Loos RJF, van Duijn CM, Thiadens AAHJ, Klaver CCW. Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations. Hum Genet 2018;137(10):847-862.Abstract
Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR 0.48; P = 3.75 × 10), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.
Buskin A, Zhu L, Chichagova V, Basu B, Mozaffari-Jovin S, Dolan D, Droop A, Collin J, Bronstein R, Mehrotra S, Farkas M, Hilgen G, White K, Pan K-T, Treumann A, Hallam D, Bialas K, Chung G, Mellough C, Ding Y, Krasnogor N, Przyborski S, Zwolinski S, Al-Aama J, Alharthi S, Xu Y, Wheway G, Szymanska K, McKibbin M, Inglehearn CF, Elliott DJ, Lindsay S, Ali RR, Steel DH, Armstrong L, Sernagor E, Urlaub H, Pierce E, Lührmann R, Grellscheid S-N, Johnson CA, Lako M. Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nat Commun 2018;9(1):4234.Abstract
Mutations in pre-mRNA processing factors (PRPFs) cause autosomal-dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause non-syndromic retinal disease. Here, we generate transcriptome profiles from RP11 (PRPF31-mutated) patient-derived retinal organoids and retinal pigment epithelium (RPE), as well as Prpf31 mouse tissues, which revealed that disrupted alternative splicing occurred for specific splicing programmes. Mis-splicing of genes encoding pre-mRNA splicing proteins was limited to patient-specific retinal cells and Prpf31 mouse retinae and RPE. Mis-splicing of genes implicated in ciliogenesis and cellular adhesion was associated with severe RPE defects that include disrupted apical - basal polarity, reduced trans-epithelial resistance and phagocytic capacity, and decreased cilia length and incidence. Disrupted cilia morphology also occurred in patient-derived photoreceptors, associated with progressive degeneration and cellular stress. In situ gene editing of a pathogenic mutation rescued protein expression and key cellular phenotypes in RPE and photoreceptors, providing proof of concept for future therapeutic strategies.
Retinopathy of prematurity (ROP) is characterized by abnormal retinal neovascularization in response to vessel loss. Platelets regulate angiogenesis and may influence ROP progression. In preterm infants, we assessed ROP and correlated with longitudinal postnatal platelet counts (n = 202). Any episode of thrombocytopenia (<100 × 109/l) at ≥30 weeks postmenstrual age (at onset of ROP) was independently associated with severe ROP, requiring treatment. Infants with severe ROP also had a lower weekly median platelet count compared with infants with less severe ROP. In a mouse oxygen-induced retinopathy model of ROP, platelet counts were lower at P17 (peak neovascularization) versus controls. Platelet transfusions at P15 and P16 suppressed neovascularization, and platelet depletion increased neovascularization. Platelet transfusion decreased retinal of vascular endothelial growth factor A (VEGFA) mRNA and protein expression; platelet depletion increased retinal VEGFA mRNA and protein expression. Resting platelets with intact granules reduced neovascularization, while thrombin-activated degranulated platelets did not. These data suggest that platelet releasate has a local antiangiogenic effect on endothelial cells to exert a downstream suppression of VEGFA in neural retina. Low platelet counts during the neovascularization phase in ROP is significantly associated with the development of severe ROP in preterm infants. In a murine model of retinopathy, platelet transfusion during the period of neovascularization suppressed retinopathy.
Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland autoimmunity spontaneously occurs only in males with testosterone playing a role in promoting lacrimal gland inflammation, while female lacrimal glands are protected by regulatory T cells (Tregs). The mechanisms of this male-specific lacrimal gland autoimmunity are not known. Here, we studied the effects of Treg depletion in hormone-manipulated NOD mice and lacrimal gland gene expression to determine early signals required for lacrimal gland inflammation. While Treg-depletion was not sufficient to drive dacryoadenitis in castrated male NOD mice, chemokines (, ) and other potentially disease-relevant genes (, ) were upregulated in male lacrimal glands. Expression of and , in particular, remained significantly upregulated in the lacrimal glands of lymphocyte-deficient NOD-severe combined immunodeficiency (SCID) mice and their expression was modulated by type I interferon signaling. Notably, -deficient NOD mice did not develop dacryoadenitis. Together these data identify disease-relevant genes upregulated in the context of male-specific dacryoadenitis and demonstrate a requisite role for type I interferon signaling in lacrimal gland autoimmunity in NOD mice.
BACKGROUND: Cerebrovascular disease (CVD) is highly comorbid with Alzheimer's disease (AD), yet its role is not entirely understood. Nailfold video capillaroscopy (NVC) is a noninvasive method of live imaging the capillaries near the fingernail's cuticle and may help to describe further vascular contributions to AD. OBJECTIVE: To examine finger nailfold capillary morphology using NVC in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition (NC). METHODS: We evaluated nailfold capillary hemorrhages, avascular zones ≥100 microns, and degree of tortuosity in 28 NC, 15 MCI, and 18 AD dementia subjects using NVC. Tortuosity was measured with a semi-quantitative rating scale. To assess the relation between nailfold capillary morphological features and diagnostic grouping, univariate and multivariable logistic regression models were fit to the data. RESULTS: 56% of subjects with AD dementia compared to 14% with NC and 13% with MCI displayed moderate to severe tortuosity. Greater severity of tortuosity was associated with 10.6-fold (95% confidence interval [CI]: 2.4, 46.2; p = 0.0018) and 7.4-fold (95% CI: 1.3, 41.3; p = 0.023) increased odds of AD dementia relative to NC and MCI, respectively, after adjusting for multiple covariates. CONCLUSION: Greater nailfold capillary tortuosity was found in participants with AD dementia compared to those with MCI or NC. These data provide preliminary evidence of a systemic microvasculopathy in AD that may be noninvasively and inexpensively evaluated through NVC.
Motion in a distorted virtual 3D space may cause visually induced motion sickness. Geometric distortions in stereoscopic 3D can result from mismatches among image capture, display, and viewing parameters. Three pairs of potential mismatches are considered, including 1) camera separation vs. eye separation, 2) camera field of view (FOV) vs. screen FOV, and 3) camera convergence distance (i.e., distance from the cameras to the point where the convergence axes intersect) vs. screen distance from the observer. The effect of the viewer's head positions (i.e., head lateral offset from the screen center) is also considered. The geometric model is expressed as a function of camera convergence distance, the ratios of the three parameter-pairs, and the offset of the head position. We analyze the impacts of these five variables separately and their interactions on geometric distortions. This model facilitates insights into the various distortions and leads to methods whereby the user can minimize geometric distortions caused by some parameter-pair mismatches through adjusting of other parameter pairs. For example, in postproduction, viewers can correct for a mismatch between camera separation and eye separation by adjusting their distance from the real screen and changing the effective camera convergence distance.
Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.
Importance: Ranibizumab is a viable treatment option for eyes with proliferative diabetic retinopathy (PDR) through 2 years. However, longer-term results are needed. Objective: To evaluate efficacy and safety of 0.5-mg intravitreous ranibizumab vs panretinal photocoagulation (PRP) over 5 years for PDR. Design, Setting, and Participants: Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial evaluated 394 study eyes with PDR enrolled February through December 2012. Analysis began in January 2018. Interventions: Eyes were randomly assigned to receive intravitreous ranibizumab (n = 191) or PRP (n = 203). Frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group. Main Outcomes and Measures: Mean change in visual acuity (intention-to-treat analysis) was the main outcome. Secondary outcomes included peripheral visual field loss, development of vision-impairing diabetic macular edema, and ocular and systemic safety. Results: The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in visual acuity letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95% CI, -2.3 to 3.5; P = .68); the mean visual acuity was 20/25 (approximate Snellen equivalent) in both groups at 5 years. The mean (SD) change in cumulative visual field total point score was -330 (645) vs -527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively (adjusted difference, 208 dB; 95% CI, 9-408). Vision-impairing diabetic macular edema developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively (cumulative probabilities: 22% vs 38%; hazard ratio, 0.4; 95% CI, 0.3-0.7). No statistically significant differences between groups in major systemic adverse event rates were identified. Conclusions and Relevance: Although loss to follow-up was relatively high, visual acuity in most study eyes that completed follow-up was very good at 5 years and was similar in both groups. Severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing diabetic macular edema and less visual field loss. Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for patients with PDR. These findings support either anti-vascular endothelial growth factor therapy or PRP as viable treatments for patients with PDR. Trial Registration: ClinicalTrials.gov Identifier: NCT01489189.
OBJECTIVE: Evaluations of vision prostheses and sensory substitution devices have frequently relied on repeated training and then testing with the same small set of items. These multiple forced-choice tasks produced above chance performance in blind users, but it is unclear if the observed performance represents restoration of vision that transfers to novel, untrained items. APPROACH: Here, we tested the generalizability of the forced-choice paradigm on discrimination of low-resolution word images. Extensive visual training was conducted with the same 10 words used in previous BrainPort tongue stimulation studies. The performance on these 10 words and an additional 50 words was measured before and after the training sessions. MAIN RESULTS: The results revealed minimal performance improvement with the untrained words, demonstrating instead pattern discrimination limited mostly to the trained words. SIGNIFICANCE: These findings highlight the need to reconsider current evaluation practices, in particular, the use of forced-choice paradigms with a few highly trained items. While appropriate for measuring the performance thresholds in acuity or contrast sensitivity of a functioning visual system, performance on such tasks cannot be taken to indicate restored spatial pattern vision.
The majority of visual recognition studies have focused on the neural responses to repeated presentations of static stimuli with abrupt and well-defined onset and offset times. In contrast, natural vision involves unique renderings of visual inputs that are continuously changing without explicitly defined temporal transitions. Here we considered commercial movies as a coarse proxy to natural vision. We recorded intracranial field potential signals from 1,284 electrodes implanted in 15 patients with epilepsy while the subjects passively viewed commercial movies. We could rapidly detect large changes in the visual inputs within approximately 100 ms of their occurrence, using exclusively field potential signals from ventral visual cortical areas including the inferior temporal gyrus and inferior occipital gyrus. Furthermore, we could decode the content of those visual changes even in a single movie presentation, generalizing across the wide range of transformations present in a movie. These results present a methodological framework for studying cognition during dynamic and natural vision.
OBJECTIVE: We evaluated the relation of prediagnostic sex hormone levels in postmenopausal women with primary open-angle glaucoma (POAG) and intraocular pressure (IOP). METHODS: Among postmenopausal participants of the Nurses' Health Study, POAG cases (n = 189; diagnosed 1990-2008) and controls (n = 189) were matched on age, fasting status, and postmenopausal hormone use at blood draw (1989-1990). Plasma concentrations of estrone sulfate, estradiol, testosterone, sex hormone binding globulin, and dehydroepiandrosterone sulfate were assessed. The primary outcome was POAG; in secondary analyses, among cases only, we evaluated maximum untreated IOP at diagnosis. Multivariable-adjusted logistic/multiple linear regression models were used to evaluate tertiles (Ts) of biomarker levels and the two outcomes, adjusting for various potential confounders. RESULTS: We observed no significant associations of estrone, estradiol, sex hormone binding globulin, or dehydroepiandrosterone sulfate with POAG risk or with maximum IOP at glaucoma diagnosis among cases. Suggestive significant associations were observed with highest testosterone and POAG risk (T3 vs T1 multivariable-adjusted odds ratio 1.84; 95% confidence interval 1.02, 3.33; P trend 0.10). Similarly, for maximum IOP at diagnosis among cases only (mean 8 years after blood draw), higher testosterone was significantly associated with higher IOP (multivariable-adjusted difference in IOP T3 vs T1 2.17 mm Hg; 95% confidence interval 0.34, 3.99; P trend 0.02). CONCLUSIONS: Overall, plasma sex hormone levels in postmenopausal women were not associated with POAG risk; however, a trend of higher testosterone levels being associated with higher POAG risk and higher IOP at diagnosis was observed and needs confirmation.
PURPOSE: To investigate systemic and ocular determinants of peripapillary retinal nerve fiber layer thickness (pRNFLT) in the European population. DESIGN: Cross-sectional meta-analysis. PARTICIPANTS: A total of 16 084 European adults from 8 cohort studies (mean age range, 56.9±12.3-82.1±4.2 years) of the European Eye Epidemiology (E3) consortium. METHODS: We examined associations with pRNFLT measured by spectral-domain OCT in each study using multivariable linear regression and pooled results using random effects meta-analysis. MAIN OUTCOME MEASURES: Determinants of pRNFLT. RESULTS: Mean pRNFLT ranged from 86.8±21.4 μm in the Rotterdam Study I to 104.7±12.5 μm in the Rotterdam Study III. We found the following factors to be associated with reduced pRNFLT: Older age (β = -0.38 μm/year; 95% confidence interval [CI], -0.57 to -0.18), higher intraocular pressure (IOP) (β = -0.36 μm/mmHg; 95% CI, -0.56 to -0.15), visual impairment (β = -5.50 μm; 95% CI, -9.37 to -1.64), and history of systemic hypertension (β = -0.54 μm; 95% CI, -1.01 to -0.07) and stroke (β = -1.94 μm; 95% CI, -3.17 to -0.72). A suggestive, albeit nonsignificant, association was observed for dementia (β = -3.11 μm; 95% CI, -6.22 to 0.01). Higher pRNFLT was associated with more hyperopic spherical equivalent (β = 1.39 μm/diopter; 95% CI, 1.19-1.59) and smoking (β = 1.53 μm; 95% CI, 1.00-2.06 for current smokers compared with never-smokers). CONCLUSIONS: In addition to previously described determinants such as age and refraction, we found that systemic vascular and neurovascular diseases were associated with reduced pRNFLT. These may be of clinical relevance, especially in glaucoma monitoring of patients with newly occurring vascular comorbidities.
Nanji KC, Fain B, Morley MG, Bayes J. In Response. Anesth Analg 2018;127(4):e67-e68.
Nanji KC, Fain B, Morley MG, Bayes J. In Response. Anesth Analg 2018;127(4):e69-e70.
Aversion to light is common among migraineurs undergoing acute attacks. Using psychophysical assessments in patients with episodic migraine, we reported that white, blue, amber, and red lights exacerbate migraine headache in a significantly larger percentage of patients and to a greater extent compared with green light. This study aimed at determining whether these findings are phase-dependent-namely, manifested exclusively during migraine (ictally) but not in its absence (interictally), or condition-dependent-ie, expressed uniquely in migraineurs but not in healthy controls. To determine whether the color preference of migraine-type photophobia is phase- or condition-dependent, we compared the effects of each color of light in each intensity between migraineurs during and in-between attacks and healthy controls. During the ictal and interictal phases, the proportion of migraineurs reporting changes in headache severity when exposed to the different colors of light increased in accordance with elevated light intensities. During the ictal phase, white, blue, amber, and red lights exacerbated headaches in ∼80% of the patients; however, during the interictal phase, light initiated headache in only 16% to 19%. Notably, green light exacerbated headaches in 40% and triggered headaches in 3% of the patients studied during the ictal and interictal phases, respectively. With one exception (highest red light intensity), no control subject reported headache in response to the light stimuli. These findings suggest that color preference is unique to migraineurs-as it was not found in control subjects-and that it is independent of whether or not the patients are in their ictal or interictal phase.