Faculty Bibliography

BACKGROUND: Inner (area adjacent to the fovea) and outer regions of the macula differ with respect to relative thicknesses of the ganglion cell layer (neurons) vs retinal nerve fiber layer (RNFL; axons). OBJECTIVE: To determine how inner vs outer macular volumes relate to peripapillary RNFL thickness and visual function in multiple sclerosis (MS) and to examine how these patterns differ among eyes with vs without a history of acute optic neuritis (ON). DESIGN: Study using cross-sectional optical coherence tomography. SETTING: Three academic tertiary care MS centers. PARTICIPANTS: Patients with MS, diagnosed by standard criteria, and disease-free control participants. MAIN OUTCOME MEASURES: Optical coherence tomography was used to measure macular volumes and RNFL thickness. Visual function was assessed using low-contrast letter acuity and high-contrast visual acuity (Early Treatment Diabetic Retinopathy Study charts). RESULTS: Among eyes of patients with MS (n = 1058 eyes of 530 patients), reduced macular volumes were associated with peripapillary RNFL thinning; 10-microm differences in RNFL thickness (9.6% of thickness in control participants without disease) corresponded to 0.20-mm(3) reductions in total macular volume (2.9% of volume in control participants without disease, P < .001). This relation was similar for eyes of MS patients with and without a history of ON. Although peripapillary RNFL thinning was more strongly associated with decrements in outer compared with inner macular volumes, correlations with inner macular volume were significant (r = 0.58, P < .001) and of slightly greater magnitude for eyes of MS patients with a history of ON vs eyes of MS patients without a history of ON (r = 0.61 vs r = 0.50). Lower (worse) visual function scores were associated with reduced total, inner, and outer macular volumes. However, accounting for peripapillary RNFL thickness, the relation between vision and inner macular volume remained significant and unchanged in magnitude, suggesting that this region contains retinal structures separate from RNFL axons that are important to vision. CONCLUSIONS: Analogous to studies of gray matter in MS, these data provide evidence that reductions of volume in the macula (approximately 34% neuronal cells by average thickness) accompany RNFL axonal loss. Peripapillary RNFL thinning and inner macular volume loss are less strongly linked in eyes of MS patients without a history of ON than in eyes of MS patients with a history of ON, suggesting alternative mechanisms for neuronal cell loss. Longitudinal studies with segmentation of retinal layers will further explore the relation and timing of ganglion cell degeneration and RNFL thinning in MS.

OBJECTIVE: To identify and describe patients with idiopathic intracranial hypertension (IIH) with concurrent functional visual loss (FVL). DESIGN: Observational, retrospective case series. PARTICIPANTS: Seventeen patients with IIH and FVL. METHODS: Clinical features were collected retrospectively. Data from 281 cases of IIH were analyzed for concurrence of FVL. MAIN OUTCOME MEASURES: Occurrence of FVL diagnosed at presentation or on subsequent follow-up. RESULTS: Seventeen patients had FVL and IIH. Of the 17 patients with FVL and IIH, 11 (65%) had FVL on presentation, with the remaining 6 patients developing FVL after initial presentation. Two patients in this cohort had documented recurrence of their IIH. There were several common patterns of FVL. All 17 patients had functional visual fields, with 82% having tubular fields and 71% exhibiting nonphysiologic constriction on perimetry testing. Seventy-six percent of patients had nerve/field mismatch showing no atrophic disc changes. Eighty-eight percent of patients had significant psychiatric, psychosocial, or other medical comorbidities. The majority of patients were managed surgically at some point in their clinical history, with 53% having nerve decompression, shunt, or both. Three patients had optic nerve sheath fenestrations after the diagnosis of FVL. CONCLUSIONS: Results suggest a high prevalence of FVL in IIH with a potential association with psychiatric illness and psychosocial stressors requiring careful consideration before surgical intervention. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

OBJECTIVE: To determine whether damage to the optic radiation (OR) in multiple sclerosis (MS) is associated with optic nerve injury and visual dysfunction. DESIGN: Case-control study. SETTING: Referral center. PARTICIPANTS: Ninety referred patients with MS and 29 healthy volunteers. MAIN OUTCOME MEASURES: Magnetic resonance imaging indices along the OR were reconstructed with diffusion tensor tractography. Retinal nerve fiber layer thickness and visual acuity at high and low contrast were measured in a subset of the MS group (n = 36). RESULTS: All tested magnetic resonance imaging indices (fractional anisotropy [FA]; mean, parallel, and perpendicular [lambda( perpendicular)] diffusivity; T2 relaxation time; and magnetization transfer ratio) were significantly abnormal in patients with MS. Mean retinal nerve fiber layer thickness was significantly correlated with FA (r = 0.55; P < .001) and lambda( perpendicular) (r = -0.37; P = .001). The retinal nerve fiber layer thickness in the nasal retinal quadrant was also specifically correlated with FA and lambda( perpendicular) in the synaptically connected contralateral OR. In individuals with less severely damaged optic nerves (mean retinal nerve fiber layer thickness >80 mum), letter acuity scores at 2.5% contrast were correlated with OR-specific FA (r = 0.55; P = .004), lambda( perpendicular) (r = -0.40; P = .04), and magnetization transfer ratio (r = 0.54; P = .01), as well as the fraction of OR volume made up of lesions (r = -0.69; P < .001). CONCLUSIONS: Fractional anisotropy and lambda( perpendicular) are potentially useful quantitative magnetic resonance imaging biomarkers of OR-specific damage in MS. Such damage is associated with retinal injury and visual disability.

BACKGROUND: The initial Multiple Sclerosis Functional Composite (MSFC) proposal was a three-part composite of quantitative measures of ambulation, upper extremity function, and cognitive function expressed as a single composite Z-score. However, the clinical meaning of an MSFC Z-score change is not obvious. This study instead used MSFC component data to define a patient-specific disease progression event. OBJECTIVE: Evaluate a new method for analyzing disability progression using the MSFC. METHODS: MSFC progression was defined as worsening from baseline on scores of at least one MSFC component by 20% (MSFC Progression-20) or 15% (MSFC Progression-15), sustained for >or=3 months. Progression rates were determined using data from natalizumab clinical studies (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]). Correlations between MSFC progression and other clinical measures were determined, as was sensitivity to treatment effects. RESULTS: Substantial numbers of patients met MSFC progression criteria, with MSFC Progression-15 being more sensitive than MSFC Progression-20, at both 1 and 2 years. MSFC Progression-20 and MSFC Progression-15 were related significantly to Expanded Disability Status Scale (EDSS) score change, relapse rate, and the SF-36 Physical Component Summary (PCS) score change. MSFC Progression-20 and MSFC Progression-15 at 1 year were predictive of EDSS progression at 2 years. Both MSFC progression end points demonstrated treatment effects in AFFIRM, and results were replicated in SENTINEL. CONCLUSION: MSFC Progression-20 and MSFC Progression-15 are sensitive measures of disability progression; correlate with EDSS, relapse rates, and SF-36 PCS; and are capable of demonstrating therapeutic effects in randomized, controlled clinical studies.

OBJECTIVE: To evaluate the retinal nerve fiber layer (RNFL) thickness and macular volume in neuromyelitis optica (NMO) spectrum patients using optical coherence tomography (OCT). BACKGROUND: OCT can quantify damage to retinal ganglion cell axons and can identify abnormalities in multiple sclerosis and optic neuritis (ON) eyes. OCT may also be useful in the evaluation of patients with NMO. METHODS: OCT and visual function testing were performed in 26 NMO spectrum patients with a history of ON, 17 patients with isolated longitudinally extensive transverse myelitis (LETM) without ON, 378 patients with relapsing-remitting multiple sclerosis (RRMS), and 77 healthy controls at 2 centers. RESULTS: Substantial RNFL thinning was seen in NMO ON eyes (63.6 microm) relative to both RRMS ON eyes (88.3 microm, p < 0.0001) and control eyes (102.4 microm, p < 0.0001). A first episode of ON was estimated to cause 24 microm more loss of RNFL thickness in NMO than RRMS. Similar results were seen for macular volume. ON also was associated with more severe visual impairment in NMO spectrum patients than in RRMS patients. Eyes in the LETM group and unaffected NMO eyes were not significantly different from controls, though conclusions about these subgroups were limited by small sample sizes. CONCLUSIONS: Optical coherence tomography (OCT) shows more severe retinal damage after optic neuritis (ON) episodes in neuromyelitis optica (NMO) than in relapsing-remitting multiple sclerosis. Identification of substantial retinal nerve fiber layer loss (>15 microm) after ON in a non-multiple sclerosis patient should prompt consideration of an NMO spectrum condition. OCT may be a useful tool for the evaluation of patients with NMO.

BACKGROUND: Measurement of retinal nerve fiber layer (RNFL) thickness in multiple sclerosis (MS) is gaining increasing attention. OBJECTIVES: To explore the relationship between RNFL thickness as measured by optical coherence tomography (OCT) and scanning laser polarimetry with variable corneal compensation (GDx), and conventional and non-conventional optic nerve and brain MRI measures. METHODS: Twelve relapsing-remitting (RR) MS patients (12 affected and 12 unaffected eyes) and 4 age- and sex-matched normal controls (NC) (8 unaffected eyes) were enrolled. Four MS patients had a history of bilateral optic neuritis (ON), four had a history of unilateral ON, and 4 had no history of ON. Optic nerve MRI measurements included the length of T2 lesions, measurement of optic nerve atrophy, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) measures. Optic nerve atrophy was measured by a novel method with high reproducibility. Brain MRI measurements included T1 and T2 lesion volumes (LVs) and their relative MTRs, and tissue class specific atrophy, MTR and DTI measures. Measures of RNFL were evaluated with OCT and GDx. We also evaluated both high and low contrast letter acuities (LCLA) in order to determine the relationship between vision, MRI metrics, and retinal structural architecture. RESULTS: LCLA, RNFL-OCT and optic nerve radius measures showed more robust differences between NC and MS patients, and between MS patients with affected and unaffected eyes. T2-LV and T1-LV, as well as gray matter atrophy, DTI and MTR measures were related to LCLA and RNFL thickness. Unique additive variance regression models showed that both brain and optic nerve MRI measures independently accounted for about 50% of the variance in LCLA and RNFL thickness. In reverse models, about 20% of the additional independent variance was explained by optic nerve or brain MRI metrics. CONCLUSIONS: Measurement of RNFL thickness and radius of the optic nerve should be preferred to the other optic nerve MRI measures in clinical studies. Whole brain lesion and GM measures are predictive of impaired visual function with corresponding structural concomitants.

OBJECTIVE: To examine the relation between low contrast letter acuity, a new visual function test for multiple sclerosis (MS) trials, and vision targeted health related quality of life (HRQOL). METHODS: Patients in this cross sectional study were part of an ongoing investigation of visual function in MS. Patients were tested binocularly using low contrast letter acuity and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) charts. The 25 Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), 10 Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, Impact of Visual Impairment Scale and Short Form 36 Health Survey (SF-36) were administered. RESULTS: Among 167 patients, mean age was 48 (10) years, with median Expanded Disability Status Scale (EDSS) 2.0 (range 1.0-7.5), and median binocular Snellen acuity equivalent (ETDRS charts) 20/16 (range 20/12.5 to 20/100). Reductions in vision specific HRQOL were associated with lower (worse) scores for low contrast letter acuity and VA (p<0.001, linear regression, accounting for age). Two line differences in visual function were associated, on average, with >4 point (6.7-10.9 point) worsening in the NEI-VFQ-25 composite score, reductions that are considered clinically meaningful. Scores for the 10 Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25 also correlated well with visual function. Associations between reduced low contrast acuity and worse vision targeted HRQOL remained significant in models accounting for high contrast VA, EDSS and history of acute optic neuritis. CONCLUSIONS: Low contrast letter acuity scores correlate well with HRQOL in MS. Two line differences in scores for low contrast acuity and VA reflect clinically meaningful differences in vision targeted HRQOL. Low contrast acuity testing provides information on patient reported aspects of vision, supporting use of these measures in MS clinical trials.

BACKGROUND: There is considerable interest in tissue-protective treatments for multiple sclerosis (MS). METHODS AND OBJECTIVES: We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods. RESULTS: Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3-6 months after starting treatment) to the final visit 1 year later. Study designs aimed at reducing residual deficits following acute exacerbations are less straightforward, depending greatly on the anticipated rapidity of treatment effect onset. CONCLUSIONS: The next step would be to perform one or more studies of potential tissue-protective agents with these designs in mind, creating the longitudinal data necessary to refine endpoint selection, eligibility criteria, and sample size estimates for future trials.

BACKGROUND: Optic neuritis is often the initial presentation of multiple sclerosis (MS). As established by the Optic Neuritis Treatment Trial, an abnormal baseline brain MRI is a strong predictor of MS after isolated optic neuritis in adults. However, the rate of conversion to MS after optic neuritis in children based upon brain MRI findings is unknown. METHODS: We reviewed the medical records of children (<18 years) presenting with optic neuritis between 1993 and 2004 at the Children's Hospital of Philadelphia. Children with a history of demyelinating disease or prior optic neuritis were excluded. Symptoms, ophthalmologic findings, MRI findings, and clinical outcomes were recorded. RESULTS: We identified 29 consecutive children with idiopathic optic neuritis. Eleven patients (38%) had white matter T2/FLAIR lesions in the brain (not including the optic nerves). Eighteen patients were followed for more than 24 months, and 3 of the 18 (17%) developed MS. All 3 patients had an abnormal brain MRI scan at their initial presentation of optic neuritis. None of the patients with a normal brain MRI scan at presentation developed MS over an average follow-up of 88.5 months. Patients with one or more white matter lesions on MRI were more likely to develop MS (3/7 vs 0/11, p = 0.04, Fisher exact test). CONCLUSIONS: Children with brain MRI abnormalities at the time of the diagnosis of optic neuritis have an increased risk of multiple sclerosis. Larger collaborative studies are needed to further define the prognosis for childhood optic neuritis.