Darrel Conger

Accuracy and precision of the corneal analysis system and the topographic modeling system

Two computer-assisted topographic analysis systems were evaluated with calibrated spherical surfaces and normal human corneas. The Topographic Modeling System-1 (TMS-1) was found to be statistically more accurate in determing the power of calibrated spheres near the apex and at 1 mm from the apex than the Corneal Analysis System(CAS).The CAS, however, was statistically more accurate at 3 mm from the apex with each calibrated sphere. The small differences in accuracy between the two instruments, however, are unlikely to be of clinical significance. The topographic patterns on color-coded maps from 22 normal corneas of 11 subjects were similar with the two instruments. Simulated keratometry values with the CAS more accurately identified the keratometerdetermined major cylinder axis compared with the TMS- 1. Conversely, the TMS-1 was more accurate than the CAS at determining the level of corneal astigmatism.

Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy

Objective: The objective of this randomized, double-blind, placebo-controlled, crossover study was to examine if patients with optic neuropathy would derive a therapeutic benefit from 4-aminopyridine (4-AP) treatment. Furthermore, the study was intended to determine if patients with certain P100 latencies or retinal nerve fiber layer (RNFL) measures would be more likely to respond to therapy. Methods: Patients were enrolled in a randomized, placebo-controlled, double-blind, crossover study of 10 weeks duration. Patients underwent visual evoked potentials (VEP), optical coherence tomography (OCT), and visual acuity before starting 5 weeks of either placebo or 4-AP. After 5 weeks, they completed a second evaluation (VEP, OCT, and visual acuity) and were crossed over between treatment arms. Five weeks later, they had their final evaluation. All investigators were blinded to treatment arm until after data analysis. Results: On average, patients had faster P100s on 4-AP when compared to placebo. A subset of patients had distinct responses to 4-AP as measured by improvements in visual acuity. Finally, eyes with an RNFL measure between 60 and 80 µm had the highest response rate. Conclusions: 4-Aminopyridine is useful for improving vision in patients with demyelinating optic neuropathy. Future clinical trials may be able to enrich a patient population for potential responders using OCT and VEP measures. Selecting patients for future trials should use RNFL measures as part of inclusion/exclusion criteria. Classification of evidence: This study provides Class IV evidence supporting the use of 4-AP in certain patients with optic neuropathy to improve visual function (patients with RNFL between 60 and 80 µm).

Corneal intrastromal gatifloxacin crystal deposits after penetrating keratoplasty.

Background. An 85-year-old man developed faint crystallike white precipitates in the mid peripheral stroma of his left cornea 3 weeks after undergoing penetrating keratoplasty. The patient had been initially treated with 1% prednisolone acetate ophthalmic suspension and 0.3% gatifloxacin eyedrops to his left eye from the first day postoperatively. Three weeks later, the precipitates were more numerous, larger, and diffuse in distribution. Gatifloxacin was discontinued and substituted with a neomycin–polymixin B–dexamethasone ophthalmic ointment. Methods. A detailed history, physical examination, laboratory workup, and tandem scanning confocal microscopy were performed. Results. Tandem scanning corneal confocal microscopy confirmed the presence of crystals in the cornea. Conclusions. Gatifloxacin, a fourth-generation fluoroquinolone, can cause intrastromal macroscopic crystalline deposits through a compromised corneal epithelium, similar to what has been described for ciprofloxacin, a second-generation fluoroquinolone.

Retinal damage and vision loss in African American multiple sclerosis patients

To determine whether African American (AA) multiple sclerosis (MS) patients exhibit more retinal damage and visual impairment compared to Caucasian American (CA) MS patients.

Multifocal visual evoked potentials are influenced by variable contrast stimulation in MS

Objective: To test the hypothesis that patients with multiple sclerosis (MS) with intereye asymmetry on low contrast letter acuity, and thickness of the retinal nerve fiber layer (RNFL), would exhibit corresponding changes in cortical timing and amplitude responses on pattern reversal multifocal visual evoked potentials (mfVEP), contingent upon variable stimulus contrast. Methods: In a cross-sectional study, we investigated a cohort of 11 normal subjects and 40 patients with MS, 21 of whom had a history of acute optic neuritis (MS-AON) with an intereye asymmetry with respect to RNFL thickness, and on low contrast letter acuity performance. Pattern reversal mfVEP was performed at high (100%), low (33.3%), and very low (14.2%) Michelson-contrast levels. Results: Compared to baseline measures at 100% contrast, the mean amplitude of the mfVEP was reduced in MS-AON eyes, upon pattern-reversal stimulation at the 2 lower contrast levels (p < 0.0001). With respect to changes in timing responses, the intereye asymmetry was increased in the MS-AON patients upon lower contrast pattern-reversal stimulation (p < 0.0001 for 33.3% compared to 100%, and p < 0.001 for 14.2% compared to 100%). The fellow eye in 12 (57%; p < 0.001) of the patients with an abnormal eye, and a history of AON, revealed abnormal amplitude and timing responses upon low contrast stimulation (signifying unmasking of occult damage). Conclusions: Our findings support the hypothesis that mfVEP metric abnormalities are contingent upon contrast magnitude during pattern reversal stimulation. Further, this paradigm was capable of unmasking occult abnormalities in a significant number of apparently unaffected eyes.

Optic nerve head component responses of the multifocal electroretinogram in MS

Objective: To employ a novel stimulation paradigm in order to elicit multifocal electroretinography (mfERG)–induced optic nerve head component (ONHC) responses, believed to be contingent upon the transformation in electrical transmission properties of retinal ganglion cell axons from membrane to saltatory conduction mechanisms, as they traverse the lamina cribrosa and obtain oligodendrocyte myelin. We further sought to characterize abnormalities in ONHC responses in eyes from patients with multiple sclerosis (MS). Methods: In 10 normal subjects and 7 patients with MS (including eyes with and without a history of acute optic neuritis), we utilized a novel mfERG stimulation paradigm that included interleaved global flashes in order to elicit the ONHC responses from 103 retinal patches of pattern-reversal stimulation. Results: The number of abnormal or absent ONHC responses was significantly increased in MS patient eyes compared to normal subject eyes (p < 0.001, by general estimating equation modeling, and accounting for age and within-subject, intereye correlations). Conclusion: Studying the relationship between ONHC abnormalities and alterations in validated structural and functional measures of the visual system may facilitate the ability to dissect and characterize the pathobiological mechanisms that contribute to tissue damage in MS, and may have utility to detect and monitor neuroprotective or restorative effects of novel therapies.

Diffusion tensor imaging the medial longitudinal fasciculus in INO: Opportunities and challenges

The medial longitudinal fasciculus (MLF) is a white matter pathway in the brainstem that plays a key role in coordinating eye movements. Injury to the MLF leads to abnormalities in eye movements that can be measured with high precision by oculography, making it an ideal eloquent pathway to study imaging/function correlates. Tractography is an emerging method for identifying white matter pathways and offers the tantalizing promise of noninvasive, quantitative characterization of tissue integrity underlying functional deficits. However, the small caliber of the MLF and partial volume averaging with signal from nearby cerebrospinal fluid pose severe technical challenges to tractography‐based delineation of the MLF. We discuss progress toward the goal of imaging the MLF and potential benefits of achieving this goal. Initial work suggests that ultra‐high field (7 tesla) may complement tractography for characterizing the MLF.

Retinal architecture and mfERG: Optic nerve head component response characteristics in MS

Objective: To describe a novel neurophysiologic signature of the retinal ganglion cell and to elucidate its relationship to abnormalities in validated structural and functional measures of the visual system. Methods: We used multifocal electroretinogram–generated optic nerve head component (ONHC) responses from normal subjects (n = 18), patients with multiple sclerosis (MS) (n = 18), and those with glaucoma (n = 3). We then characterized the relationship between ONHC response abnormalities and performance on low-contrast visual acuity, multifocal visual-evoked potential–induced cortical responses, and average and quadrant retinal nerve fiber layer (RNFL) thicknesses, as measured by spectral-domain optical coherence tomography. Results: Compared with the eyes of normal subjects, the eyes of patients with MS exhibited an increased number of abnormal or absent ONHC responses (p < 0.0001). For every 7-letter reduction in low-contrast letter acuity, there were corresponding 4.6 abnormal ONHC responses at 2.5% contrast (p < 0.0001) and 6.6 abnormalities at the 1.25% contrast level (p < 0.0001). Regarding average RNFL thickness, for each 10-μm thickness reduction, we correspondingly observed 6.8 abnormal ONHC responses (p = 0.0002). The most robust association was between RNFL thinning in the temporal quadrant and ONHC response abnormalities (p < 0.0001). Conclusion: Further characterization of ONHC abnormalities (those that are reversible and irreversible) may contribute to the development of novel neurotherapeutic strategies aimed at achieving neuroprotective, and perhaps even neurorestorative, effects in disorders that target the CNS in general, and MS in particular.

Retinal Architecture and Melanopsin-Mediated Pupillary Response Characteristics: A Putative Pathophysiologic Signature for the Retino-Hypothalamic Tract in Multiple Sclerosis.

Importance A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflex may represent a surrogate biomarker for the integrity of the retinohypothalamic tract, with potential utility for investigating alterations in homeostatic mechanisms associated with brain disorders and implications for identifying new treatments. Objective To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response. Design, Setting, and Participants The case-control study was an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center for MS from September 6, 2012, to February 2015. Twenty-four patients with MS (48 eyes) and 15 individuals serving as controls (30 eyes) participated. The melanopsin-mediated, sustained pupillary constriction phase response following cessation of a blue light stimulus was compared with the photoreceptor-mediated pupillary constriction phase response following cessation of a red light stimulus. Optical coherence tomography was used to characterize the association between pupillary response characteristics and alterations in retinal architecture, specifically, the thickness of the retinal ganglion cell layer and inner plexiform layer (GCL + IPL). Main Outcomes and Measures Association of pupillary response characteristics with alterations in retinal architecture. Results Of 24 patients with MS included in the analysis, 17 were women (71%); mean (SD) age was 47 (11) years. Compared with eyes from individuals with MS who had normal optical coherence tomography–derived measures of retinal GCL + IPL thickness, eyes of patients who had GCL + IPL thickness reductions to less than the first percentile exhibited a correspondingly significant attenuation of the melanopsin-mediated sustained pupillary response (mean [SD] pupillary diameter ratios at a point in time, 0.18 [0.1] vs 0.33 [0.09]; P < .001, generalized estimating equation models accounting for age and within-patient intereye correlations). Conclusions and Relevance In this case-control study, attenuation of the melanopsin-mediated sustained pupillary constriction response was significantly associated with thinning of the GCL + IPL sector of the retina in the eyes of patients with MS, particularly those with a history of acute optic neuritis. Melanopsin-containing ganglion cells in the retina represent, at least in part, the composition of the retinohypothalamic tract. As such, our findings may signify the ability to elucidate a putative surrogate neurophysiologic signature that correlates with a constellation of homeostatic mechanisms in both health and illness.

Optical coherence tomography features in brothers with aspartylglucosaminuria

Aspartylglucosaminuria is a lysosomal storage disorder enriched in Finland. We report on a pair of non‐Finnish siblings with aspartylglucosaminuria with autofluorescent inclusion bodies on optical coherence tomography, a finding not previously reported in this disorder. We performed a record review, neurological and neuropsychological evaluation, brain MRI, and optical coherence tomography for each patient. They are compound heterozygous for a 34‐kb deletion and a c.365C>A novel variant of the AGA gene. Autofluorescent inclusion bodies were found on optical coherence tomography in the older, more severely affected brother. We hypothesize the finding represents a noninvasive biomarker of disease severity for aspartylglucosaminuria.