Faculty Bibliography

PURPOSE: The goal of this study is to (1) provide clinically useful, previously unpublished comparative analyses of seizure-freedom rates for newer antiepileptic drugs (AEDs), and (2) recommend a standard for data presentation and analysis. METHODS: Data were reviewed from placebo-controlled adjunctive trials in refractory patients of gabapentin (GPN), lamotrigine (LTG), topiramate (TOP), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), zonisamide (ZNS), and pregabalin (PGB). Seizure-freedom analyses in these publications, if included at all, consistently included both patients who completed the trial, and those who dropped out prior to completion (last observation carried forward, LOCF). This has the potential to increase reported seizure-free outcomes. Pharmaceutical companies were contacted for the provision of unpublished seizure-free data in the patients who completed the entire study. RESULTS: In most cases, LOCF analysis produced a higher rate of seizure freedom compared to complete analysis. A total of 0%-1.1% of the LOCF population was seizure-free in the GPN trials (complete data not available). For the remaining AEDs, seizure-freedom results in the LOCF versus complete populations were: 0.7% versus 0.8% (LTG trial); 12% versus 2.6% (OXC trial); 3.6%-6.4% versus 3.9%-7.1% (LEV trial); 3.7%-7.9% versus 1.3%-1.4% (PGB trial); and 6.0% versus 3.0% (ZNS trial, minus titration period). CONCLUSIONS: By employing LOCF, a clinically unrealistic picture of seizure-free rates may be reported. Access to complete data is informative, as it includes only those patients who were able to tolerate the drug at doses that produced seizure freedom. Ideally, data from both ITT and complete analyses should be made available

OBJECTIVE: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS). METHODS: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%). RESULTS: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups. CONCLUSIONS: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

PURPOSE: Obesity and weight gain are known risk factors for idiopathic intracranial hypertension (IIH; or pseudotumor cerebri). The authors examined profiles of body mass index (BMI) and patterns of weight gain associated with IIH. They also examined vision-specific health-related quality of life (HRQOL) in newly diagnosed IIH patients and explored the relative contribution of obesity and weight gain to overall HRQOL in this disorder. DESIGN: Matched case-control study. METHODS: Female patients with newly diagnosed IIH (n = 34) and other neuro-ophthalmologic disorders (n = 41) were enrolled in a case-control study to assess patterns of self-reported weight gain. The HRQOL was examined using the 25-Item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and the SF-36 Health Survey (Physical Components Summary and Mental Components Summary [MCS]). RESULTS: Higher BMIs were associated with greater risk of IIH (P = .003, logistic regression analysis adjusting for case-control matching), as were higher percentages of weight gain during the year before symptom onset (P = .004). Moderate weight gain (5% to 15%) was associated with a greater risk of IIH among both obese and nonobese patients. Obesity and weight gain influenced the relation between HRQOL and IIH only for subscale scores reflecting mental health (SF-36 MCS). The NEI-VFQ-25 and SF-36 subscale scores were lower in IIH compared with other neuro-ophthalmologic disorders and published norms. CONCLUSIONS: Higher levels of weight gain and BMI are associated with greater risk of IIH. Even nonobese patients (BMI <30) are at greater risk for IIH in the setting of moderate weight gain. Vision-specific and overall HRQOL are affected to a greater extent in IIH than in other neuro-ophthalmologic disorders.

Multiple sclerosis is a common demyelinating disorder of the central nervous system, and neuro-ophthalmologic manifestations occur in the majority of patients. This article provides a review of the pathogenesis, epidemiology, and classification of multiple sclerosis. Neuro-ophthalmologic abnormalities associated with multiple sclerosis, including acute demyelinating optic neuritis and internuclear ophthalmoplegia, are described in detail. Current and emerging technologies designed to assess visual function in multiple sclerosis are discussed. A summary presents the appropriate evaluation and management of patients with optic neuritis and other first demyelinating events (also referred to as clinically isolated syndromes).

Psychogenic nonepileptic seizures (PNES) remain a poorly understood phenomenon for both patients and their physicians. Recent work has begun to focus on the possible psychological underpinnings of this diagnosis, but few studies have focused on specific emotional pathologies. This study sought to investigate the impact of a specific emotional measure: self-reported fear sensitivity. Three patient groups (patients with PNES, patients with epilepsy, and healthy volunteers) were administered the Modified Fear Survey Schedule, along with other neuropsychological batteries. As expected, the PNES and epilepsy cohorts demonstrated elevated levels of depression, anxiety, and comorbid psychiatric conditions. The PNES group independently exhibited a statistically significant higher level of fear sensitivity compared with both patients with epilepsy and healthy volunteers. This fear-specific trait was independent of other comorbid psychological factors or psychiatric conditions. These results suggest that patients with PNES exhibit disproportionately elevated fear sensitivity on self-report measures when compared with patients with epilepsy. This finding may reflect an elevated internal 'setpoint' for appraising the intensity of emotional settings

PURPOSE: To determine whether a 10-Item Neuro-Ophthalmic Supplement increases the capacity of the 25-Item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) to capture self-reported visual dysfunction in patients with neuro-ophthalmologic disorders. DESIGN: A cross-sectional survey to examine the characteristics of a 10-Item Neuro-Ophthalmic Supplement to the 25-Item NEI-VFQ-25 in a cohort of patients with neuro-ophthalmologic disorders. METHODS: The 10-Item Neuro-Ophthalmic Supplement was designed previously by our research group by survey and focus-group methods. In the present study, the NEI-VFQ-25 and 10-Item Supplement were administered concurrently to patients and disease-free control subjects. High-contrast visual acuities with patient usual distance correction were measured with the use of Early Treatment Diabetic Retinopathy Study (ETDRS) charts. RESULTS: Diagnoses for patients (n = 215) included optic neuritis, multiple sclerosis, idiopathic intracranial hypertension, ischemic optic neuropathy, stroke, ocular myasthenia gravis, ocular motor palsies, and thyroid eye disease. Scores for the 10-Item Supplement had a significant capacity to distinguish patients vs disease-free control subjects that was independent of the NEI-VFQ-25 composite score (odds ratio in favor of patient vs control status for 10-point worsening in Supplement scores: 2.7 [95% confidence interval [CI], 1.6, 4.6]; P < .001, logistic regression models that account for NEI-VFQ-25 composite score, age, and gender). Patients with visual dysfunction (binocular Snellen equivalents worse than 20/20) had significantly lower mean scores (9-21 points lower); these differences remained significant after accounting for age and gender (P >or= .001, linear regression). Supplement items and composite scores demonstrated appropriate degrees of internal consistency reliability. CONCLUSION: The 10-Item Neuro-Ophthalmic Supplement demonstrates a capacity to capture self-reported visual dysfunction beyond that of the NEI-VFQ-25 alone, which supports validity for this new scale. The use of the 10-Item Supplement in clinical trials and epidemiologic studies will examine its capacity to demonstrate treatment effects in longitudinal cohorts.

We identified characteristics associated with future publication record and academic rank in a cohort of neurology residents from a single institution. Seventy-six percent of women and 94% of men currently hold academic positions (p = 0.10). Early publications may lay the foundation for future academic investigation as publishing before (p = 0.01) and during (p < 0.001) residency was associated with higher post-residency publication rates. Publication differences between women and men (1.5 vs 2.4 publications/year; p = 0.03) warrant further investigation.

We do not have currently satisfactory clinical and anatomical correlates to gauge disability in multiple sclerosis. Structural biomarkers (such as MRI) are hindered because they cannot precisely segregate demyelination from axonal elements of tissue injury within the CNS. Axonal degeneration in multiple sclerosis is related to irreversible disability, which suggests that the confirmation of neuroprotective strategies needs highly quantifiable measures of axon loss that can be correlated with reliable measures of physiological function. The coupling of quantifiable measures of visual function with ocular imaging techniques, such as optical coherence tomography, enables us to begin to understand how structural changes in the visual system influence function in patients with multiple sclerosis. In this review, we consider the usefulness of optical imaging of the retina as a biomarker for neurodegeneration in multiple-sclerosis.

PURPOSE: To describe the clinical presentation, orbital echography (OE) findings, and neuroimaging results of patients with chronic unexplained ocular misalignment, which includes patients with clinically occult thyroid eye disease (TED) that is identifiable through a characteristic OE appearance. DESIGN: Retrospective observational case series. METHODS: Seventy-eight patients with chronic ocular misalignment suspected of TED because of a history of systemic thyroid disease, proptosis, dysmotility, positive forced ductions, or eyelid retraction or lag were categorized as TED positive, negative, and indeterminate with the use of standardized OE. Demographic, clinical, OE, computed tomography, and magnetic resonance imaging information was collected. Analyses determined the prevalence of TED and differences between TED positive, negative, and indeterminate groups. RESULTS: Fifty-five percent of the findings were suspicious for and most consistent with TED (TED positive); 26% of the findings were TED negative, and 19% of the findings were TED indeterminate. Of 30 patients with newly diagnosed TED by OE, 70% had no lid retraction, and 20% had no other findings of TED. The inferior rectus followed by the superior rectus/levator complex, medial rectus, and lateral rectus muscles were the most frequently involved muscles. Neuroimaging that was performed in only 26 of 78 patients (33%) did not appear to yield additional diagnostic information. CONCLUSION: TED is a potential cause of chronic unexplained ocular misalignment in a substantial proportion of patients. These patients frequently present in an occult fashion without other clinical findings that are typical of TED. In these patients, a diagnosis of TED by OE can reduce further costly evaluation. OE appears to have significant clinical usefulness in the diagnosis of TED in patients with unexplained ocular misalignment.

OBJECTIVE: To examine the potential validity of performance measures and examination-based scales in Friedreich ataxia (FA) by examining their correlation with disease characteristics. METHODS: The authors assessed the properties of a candidate clinical outcome measure, the Friedreich Ataxia Rating Scale (FARS), and simple performance measures (9-hole peg test, the timed 25-foot walk, PATA test, and low-contrast letter acuity) in 155 patients with FA from six institutions, and correlated the scores with disease duration, functional disability, activity of daily living scores, age, and shorter GAA repeat length to assess whether these measures capture the severity of neurologic dysfunction in FA. RESULTS: Scores for the FARS and performance measures correlated significantly with functional disability, activities of daily living scores, and disease duration, showing that these measures meet essential criteria for construct validity for measuring the progressive nature of FA. In addition, the FARS and transformed performance measures scores were predicted by age and shorter GAA repeat length in linear regression models accounting for sex and testing site. Correlations between performance measures were moderate in magnitude, suggesting that each test captures separate yet related dimensions of neurologic function in FA and that a composite measure might better predict disease status. Composite measures created using cohort means and standard deviations predicted disease status better than or equal to single performance measures or examination-based measures. CONCLUSIONS: The Friedreich Ataxia Rating Scale, performance measures, and performance measure composites provide valid assessments of disease progression in Friedreich ataxia.