Faculty Bibliography

Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

Whether clinical cancer research currently focuses on gaps in the evidentiary basis for clinical guidelines and/or on cancers that impose greater societal burden is unclear. This study assessed the relationship between cancer research efforts in terms of planned randomized controlled trial (RCT) enrollment, objective measures of evidence quality, and a cancer's burden on society. The authors calculated the planned RCT enrollment listed on ClinicalTrials.gov for the 17 most prevalent solid cancers. Using cancer type as the unit of analysis, linear regression was used to examine the association between planned enrollment in RCTs and 1) evidence quality, as measured by the absolute number and percent of highest quality category (category 1 [C1]) recommendations in the NCCN Clinical Practice Guidelines in Oncology for each cancer, and 2) measures of burden on society, including prevalence, incidence, person-years of life lost (PYLL), and disability-adjusted life years (DALY). Non-normal distributions were log transformed when appropriate. Overall, 15% of the NCCN recommendations were based on the highest quality evidence. Results produced 1260 RCTs. Planned RCT enrollment ranged from 2270 (testis) to 492,876 (breast) and was correlated neither with absolute number nor percent of C1 recommendations for that cancer. Planned RCT enrollment was positively correlated with a cancer's prevalence (P=.01), incidence (P<.01), PYLL (P<.01), and DALY (P<0.01). In multivariate analysis, prevalence (P<.01) and PYLL (P<.01) had the strongest association with planned RCT enrollment. Findings showed, therefore, that planned cancer RCT enrollment is associated with higher societal disease burden, not the quality of a cancer's clinical guidelines.

OBJECTIVE: Quality of life (QOL) is a multidimensional construct that includes physical, psychological, and relationship well-being. METHODS: We conducted a systematic review and meta-analysis of randomized controlled studies published between 1980 and 2012 of interventions conducted with both cancer patients and their partners that were aimed at improving QOL. Using bibliographic software and manual review, two independent raters reviewed 752 articles with a systematic process for reconciling disagreement, yielding 23 articles for systematic review and 20 for meta-analysis. RESULTS: Most studies were conducted in breast and prostate cancer populations. Study participants (N = 2645) were primarily middle aged (mean = 55 years old) and white (84%). For patients, the weighted average effect size (g) across studies was 0.25 (95% CI = 0.12-0.32) for psychological outcomes (17 studies), 0.31 (95% CI = 0.11-0.50) for physical outcomes (12 studies), and 0.28 (95% CI = 0.14-0.43) for relationship outcomes (10 studies). For partners, the weighted average effect size was 0.21 (95% CI = 0.08-0.34) for psychological outcomes (12 studies) and 0.24 (95% CI = 0.6-0.43) for relationship outcomes (7 studies). CONCLUSION: Therefore, couple-based interventions had small but beneficial effects in terms of improving multiple aspects of QOL for both patients and their partners. Questions remain regarding when such interventions should be delivered and for how long. Identifying theoretically based mediators and key features that distinguish couple-based from patient-only interventions may help strengthen their effects on patient and partner QOL

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.

PURPOSE: To estimate the proportion of patients presenting with isolated third, fourth, or sixth cranial nerve palsy of presumed microvascular origin versus other causes. DESIGN: Prospective, multicenter, observational case series. PARTICIPANTS: A total of 109 patients aged 50 years or older with acute isolated ocular motor nerve palsy. TESTING: Magnetic resonance imaging (MRI) of the brain. MAIN OUTCOME MEASURES: Causes of acute isolated ocular motor nerve palsy (presumed microvascular or other) as determined with early MRI and clinical assessment. RESULTS: Among 109 patients enrolled in the study, 22 had cranial nerve III palsy, 25 had cranial nerve IV palsy, and 62 had cranial nerve VI palsy. A cause other than presumed microvascular ischemia was identified in 18 patients (16.5%; 95% confidence interval, 10.7-24.6). The presence of 1 or more vasculopathic risk factors (diabetes, hypertension, hypercholesterolemia, coronary artery disease, myocardial infarction, stroke, and smoking) was significantly associated with a presumed microvascular cause (P = 0.003, Fisher exact test). Vasculopathic risk factors were also present in 61% of patients (11/18) with other causes. In the group of patients who had vasculopathic risk factors only, with no other significant medical condition, 10% of patients (8/80) were found to have other causes, including midbrain infarction, neoplasms, inflammation, pituitary apoplexy, and giant cell arteritis (GCA). By excluding patients with third cranial nerve palsies and those with GCA, the incidence of other causes for isolated fourth and sixth cranial nerve palsies was 4.7% (3/64). CONCLUSIONS: In our series of patients with acute isolated ocular motor nerve palsies, a substantial proportion of patients had other causes, including neoplasm, GCA, and brain stem infarction. Brain MRI and laboratory workup have a role in the initial evaluation of older patients with isolated acute ocular motor nerve palsies regardless of whether vascular risk factors are present. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

BACKGROUND: Alemtuzumab is a monoclonal antibody directed against CD52 that depletes T and B lymphocytes. OBJECTIVE: To evaluate the treatment effect of alemtuzumab on low-contrast vision in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: This was a pre-defined exploratory analysis within a randomized, rater-blinded trial (CAMMS223) that was run at 49 academic medical centers in the US and in Europe. Patients with untreated, early, RRMS (McDonald, n = 334) were randomized 1:1:1 to subcutaneous interferon beta-1a (IFNB-1a), or alemtuzumab 12 mg or 24 mg. Visual contrast sensitivity was measured for each eye at baseline and quarterly, with Pelli-Robson charts. RESULTS: The eyes of patients in the pooled alemtuzumab group (versus IFNB-1a) had a greater than 2-fold higher rate of both 3-month and 6-month sustained visual improvement, of at least 0.3 log units (2 triplets, 6 letters) (At 3 months the hazard ratio (HR) = 2.26; CI = 1.19 to 4.31; P = 0.013; and at 6 months the HR = 2.44; CI =1.16 to 5.15; P = 0.019), and they had a lower risk of 3- and 6-month sustained worsening of at least 0.15 log units (1 triplet, 3 letters) (At 3 months the HR = 0.58; CI = 0.38 to 0.89; P = 0.012; and at 6 months HR = 0.55; CI=0.35 to 0.87; P = 0.010). Over the 36-month study period, the eyes of patients in the pooled alemtuzumab group improved in mean contrast sensitivity to a greater extent than those in the IFNB-1a group (0.080 log units versus 0.038 log units; P = 0.0102). CONCLUSIONS: Alemtuzumab was associated with a greater chance of improved contrast sensitivity in patients with RRMS and may delay the worsening of visual function. Contrast sensitivity testing was sensitive to treatment effects, even within an active comparator study design. These results support the validity of low-contrast vision testing as a clinical outcome in MS trials.

Purpose of Review: This review covers causes of visual impairment in multiple sclerosis (MS), differential diagnosis, and treatment. Emerging technologies are sometimes used in assessing the visual system and may require a neurologist's familiarity. The most common causes are emphasized and discussed in detail, including illustrative cases.Recent Findings: The use of optical coherence tomography as both a clinical and research tool has advanced our understanding of how the afferent visual system is affected by MS.Summary: Optic neuritis remains one of the most common initial manifestations of MS, although a number of other causes of visual impairment are possible even in the patient with known MS. Some causes of visual impairment are consequences or complications of MS treatment and are particularly important to recognize. Low-contrast letter acuity and optical coherence tomography are techniques or tests emerging from the research arena that may inform care of the patient with MS and are important for the neurologist to be aware of.

To use optical coherence tomography (OCT) and contrast letter acuity to characterize vision loss in Friedreich ataxia (FRDA). High- and low-contrast letter acuity and neurological measures were assessed in 507 patients with FRDA. In addition, OCT was performed on 63 FRDA patients to evaluate retinal nerve fiber layer (RNFL) and macular thickness. Both OCT and acuity measures were analyzed in relation to genetic severity, neurologic function, and other disease features. High- and low-contrast letter acuity was significantly predicted by age and GAA repeat length, and highly correlated with neurological outcomes. When tested by OCT, 52.7 % of eyes (n = 110) had RNFL thickness values below the fifth percentile for age-matched controls. RNFL thickness was significantly lowest for those with worse scores on the Friedreich ataxia rating scale (FARS), worse performance measure composite Z 2 scores, and lower scores for high- and low-contrast acuity. In linear regression analysis, GAA repeat length and age independently predicted RNFL thickness. In a subcohort of participants, 21 % of eyes from adult subjects (n = 29 eyes) had macular thickness values below the first percentile for age-matched controls, suggesting that macular abnormalities can also be present in FRDA. Low-contrast acuity and RNFL thickness capture visual and neurologic function in FRDA, and reflect genetic severity and disease progression independently. This suggests that such measures are useful markers of neurologic progression in FRDA.

OBJECTIVE: To assess eyes with neuromyelitis optica (NMO) for morphologic retinal abnormalities utilizing high-definition optical coherence tomography (OCT) imaging. METHODS: In this cross-sectional study, 39 patients with NMO spectrum disorders and 39 age- and sex-matched healthy controls underwent spectral-domain OCT and visual function testing. RESULTS: Microcystic macular edema (MME) of the inner nuclear layer (INL) was identified in 10 of 39 patients (26%) and was exclusively found in eyes with a history of optic neuritis (ON). MME eyes had lower high- and low-contrast letter-acuity scores (100%: p = 0.002; 2.5%: p = 0.002; 1.25%: p = 0.004), lower peripapillary retinal nerve fiber layer (RNFL) thickness (p = 0.04), lower macular RNFL thickness (p = 0.004), lower ganglion cell layer + inner plexiform layer (GCIP) thickness (p = 0.007), higher INL thickness (p < 0.001), and a greater number of ON episodes (p = 0.008) relative to non-MME eyes with a history of ON. After adjusting for history of multiple ON episodes, these findings remained significant for macular-RNFL thickness (p = 0.03), INL thickness (p < 0.001), and 100% and 2.5% contrast letter-acuity scores (p = 0.008 and p = 0.03, respectively). NMO spectrum eyes without ON history had lower macular RNFL thickness (p = 0.003), GCIP thickness (p = 0.002), outer nuclear layer thickness (p = 0.02), and low-contrast letter-acuity scores (2.5%: p = 0.03; 1.25%: p = 0.002) compared to healthy controls. CONCLUSIONS: We have identified a pattern of retinal morphologic abnormalities in NMO that is associated with severe retinal axonal and neuronal loss and corresponding visual disability. MME may contribute to poor visual outcomes following NMO-associated ON or alternatively represent a marker of ON severity. Additionally, our results support that subclinical involvement of the anterior visual pathway may occur in NMO spectrum disorders.