Faculty Bibliography

BACKGROUND: Disturbances in visual function are common in patients with multiple sclerosis (MS) and are often accompanied by substantial impairments in daily functioning and quality of life. Lesions associated with these impairments frequently involve the afferent visual pathway. EXPERT CLINICAL OPINION: Because these impairments are often not readily apparent on commonly used high-contrast acuity tests, low-contrast charts (e.g., low-contrast Sloan letter charts) have gained validity in the assessment of visual dysfunction in patients with MS. Decrements in low-contrast letter acuity are associated with MS and correlate with increasing disability, MRI abnormalities, and reduced retinal nerve fiber layer (RNFL) thickness as measured by optical coherence tomography (OCT). These findings suggest that low-contrast letter acuity testing is a potentially useful addition to disability scales such as the Multiple Sclerosis Functional Composite, serving as another surrogate marker for MS disability. Assessment of RNFL thickness by OCT, which is also associated with visual impairment, also may be considered for inclusion in clinical trials evaluating treatments for MS. FUTURE DIRECTIONS: The effects of disease-modifying therapies on visual dysfunction in patients with MS have been evaluated only recently. Two phase 3 studies of natalizumab showed that low-contrast letter acuity testing, included as an exploratory outcome, demonstrated treatment effects. Other ongoing studies have incorporated low-contrast acuity and OCT measures of RNFL thickness. The availability and wider use of low-contrast letter acuity tests, in combination with ocular imaging techniques, may improve assessment of treatment efficacy in patients with MS.

BACKGROUND: Patient nonattendance in neurology and other subspecialty clinics is closely linked to longer waiting times for appointments. We developed a new scheduling system for residents' clinic that reduced average waiting times from >4 months to < or =3 weeks. The purpose of this study was to compare nonattendance for clinics scheduled using the new model (termed "rapid access") vs those scheduled using the traditional system. METHODS: In the rapid access system, nonestablished (new) patients are scheduled on a first-come, first-served basis for appointments that must occur within 2 weeks of their telephone request. Nonattendance for new patient appointments (cancellations plus no-shows) was compared for patients scheduled under the traditional vs the rapid access scheduling systems. Nonattendance was compared for periods of 6, 12, and 18 months following change in scheduling system using the chi2 test and logistic regression. RESULTS: Compared to the traditional scheduling system, the rapid access system was associated with a 50% reduction in nonattendance over 18 months (64% [812/1,261 scheduled visits] vs 31% [326/1,059 scheduled visits], p < 0.0001). In logistic regression models, appointment waiting time was a major factor in the relation between rapid access scheduling and nonattendance. Demographics, diagnoses, and likelihood of scheduling follow-up visits were similar between the 2 systems. CONCLUSIONS: A new scheduling system that minimizes waiting times for new patient appointments has been effective in substantially reducing nonattendance in our neurology residents' clinic. This rapid access system should be considered for implementation and will likely enhance the outpatient educational experience for trainees in neurology.

Visual loss is a common symptom brought to the attention of the practicing neurologist. In this circumstance, the proper identification of an optic neuropathy is critical. Recognition of key clinical clues will permit the clinician to construct a likely differential diagnosis and pursue appropriate testing. This review first addresses the elements of the history and examination which are most useful in evaluating a patient with visual loss, and then briefly discusses the main entities responsible for causing unilateral and bilateral optic neuropathies.

Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia of all four limbs, dysarthria, and arreflexia. A variety of measures are currently used to quantify disease progression, including the Friedreich Ataxia Rating Scale, examiner-rated functional disability scales, self-reported activities of daily living and performance measures such as the timed 25-foot walk, 9-hole pegboard test, PATA speech test, and low-contrast letter acuity vision charts. This study examines the rate of disease progression over one and two years in a cohort of 236 Friedreich ataxia patients using these scales and performance measure composites. The Friedreich Ataxia Rating Scale and performance-measure composites captured disease progression, with a greater sensitivity to change over 2 years than over 1 year. The measures differed in their sensitivity to change and in possible bias. These results help to establish norms for progression in FRDA that can be useful in measuring the long-term success of therapeutic agents and defining sample-size calculations for double-blind clinical trials.

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: 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: 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.