Ocular Manifestations of Multiple Sclerosis: A Population-Based Study.

BACKGROUND: To evaluate the population-based frequency and severity of multiple sclerosis (MS)-related ocular diseases. METHODS: Retrospective, population-based study examining patients with MS between January 1, 1998 and December 31, 2011. Patients were identified using the Rochester Epidemiology Project, which is a record-linkage system of medical records for all patient-physician encounters among Olmsted County, Minnesota residents. Diagnosis of MS was confirmed based on neuroimaging, cerebrospinal fluid studies, and serum studies for each patient according to the 2017 McDonald criteria. Patient data were obtained using the medical records and followed through April 1, 2018. RESULTS: Of the 116 patients with MS, 66% were female and the median age of onset was 36 years (interquartile range 27.5-43.5 years). About half (61/116, 53%) had MS-related neuro-ophthalmic manifestations during their disease course, and about one-fourth (33/116, 28%) had visual symptoms as their presenting symptom of MS, most commonly as optic neuritis (26/116, 22%). Optic neuritis was the leading MS-related ocular condition (37%), followed by internuclear ophthalmoplegia (16%) and nystagmus (13%). Optic neuritis was mostly unilateral (40/43, 93%), with 16% (6/43) having a visual acuity of 20/200 or worse at nadir but ultimately 95% (35/37) improving to a visual acuity of 20/40 or better. CONCLUSIONS: This study provides the population-based frequency of MS-related ocular disease, which demonstrates a high frequency of ocular manifestations in MS both at disease onset and during the disease course, emphasizing the utility of neuro-ophthalmologists, or collaboration between neurologists and ophthalmologists, in the care of patients with MS.

An update on optic neuritis.

Optic neuritis (ON) is the most common cause of subacute optic neuropathy in young adults. Although most cases of optic neuritis (ON) are classified as typical, meaning idiopathic or associated with multiple sclerosis, there is a growing understanding of atypical forms of optic neuritis such as antibody mediated aquaporin-4 (AQP4)-IgG neuromyelitis optica spectrum disorder (NMOSD) and the recently described entity, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). Differentiating typical ON from atypical ON is important because they have different prognoses and treatments. Findings of atypical ON, including severe vision loss with poor recovery with steroids or steroid dependence, prominent optic disc edema, bilateral vision loss, and childhood or late adult onset, should prompt serologic testing for AQP4-IgG and MOG-IgG. Although the traditional division of typical and atypical ON can be helpful, it should be noted that there can be severe presentations of otherwise typical ON and mild presentations of atypical ON that blur these traditional lines. Rare causes of autoimmune optic neuropathies, such as glial fibrillary acidic protein (GFAP) and collapsin response-mediator protein 5 (CRMP5) autoimmunity also should be considered in patients with bilateral painless optic neuropathy associated with optic disc edema, especially if there are other accompanying suggestive neurologic symptoms/signs. Typical ON usually recovers well without treatment, though recovery may be expedited by steroids. Atypical ON is usually treated with intravenous steroids, and some forms, such as NMOSD, often require plasma exchange for acute attacks and long-term immunosuppressive therapy to prevent relapses. Since treatment is tailored to the cause of the ON, elucidating the etiology of the ON is of the utmost importance.

Left-sided valvular heart disease and retinopathy in a 38-year-old woman with attenuated mucopolysaccharidosis: a case report.

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by deficient levels and/or activity of glycosaminoglycan (GAG)-degradative enzymes. MPS are characterized by accumulation of the mucopolysaccharides heparan sulfate, dermatan sulfate, keratan sulfate, or chondroitin sulfate in tissues. We report the case of a 38-year-old woman with a history of joint restriction and retinitis pigmentosa who developed bivalvular heart failure requiring surgery. It was not until pathological examination of surgically excised valvular tissue that a diagnosis of MPS I was made. Her musculoskeletal and ophthalmologic symptoms, when placed in the context of MPS I, painted the diagnostic picture of a genetic syndrome that was overlooked until a diagnosis was made in late middle age.

• A 38-year-old woman with heart failure had heart valve surgery. Examining her cardiac valve tissue under the microscope suggested a metabolic disorder called mucopolysaccharidosis type I (MPS I). • MPS I is due to defective breakdown of sugar molecules (called glycosaminoglycans or GAGs for short) in the body which then can accumulate, causing dysfunction. • Our patient had short stature, a curved spine, stiff joints, and a degenerative eye disease called retinitis pigmentosa, all of which were due to her undiagnosed MPS I. • Most patients with MPS I are discovered on newborn screening when they are babies, or at very young ages due to severe symptoms related to the disease. • Our patient had a form of MPS I that was less severe, and the first symptom she received medical care for was her eye symptoms. • A diagnosis of MPS I made in middle adulthood is unusual for MPS I, and so is an important learning case for providers as there were clues hidden in her medical history that suggested a genetic or inherited syndrome. • Our genetics specialists were able to make a definitive diagnosis of MPS I and begin treatment with enzyme replacement therapy, as well as provide information for the patient about her risk of passing this disease on to children.

PROGRESSION OF PARTIAL POSTERIOR VITREOUS DETACHMENT OVER TIME.

PURPOSE: We investigated interindividual differences in the rate of change of posterior vitreous detachment (PVD) stage and vitreomacular adhesion area (VMAA). Crosssectional studies demonstrated increasing PVD stage and decreasing VMAA with age, but population-level means may mask interindividual variation in the rate of change. METHODS: We retrospectively evaluated PVD stage and VMAA in asymptomatic eyes of subjects who underwent repeated optical coherence tomography screening for high-risk medication use or isolated retinal disease in the fellow eye. A Turnbull estimator modeled changes in the PVD stage, and linear mixed models evaluated VMAA change. RESULTS: We evaluated 101 eyes of 101 subjects. Seventy-six eyes remained in the same stage. Twenty-three eyes progressed to a higher stage. Modeling of longitudinal data predicts that at age 30, time to convert to Stage 4 is 26 years; at age 40, it is 16 years; at age 50, it is 9 years; and at age 60, it is 8 years. In 37 eyes with Stage 1 partial PVD, VMAA decreased at a similar rate. The average population level decline in VMAA was 0.13 mm2/year. CONCLUSION: Individuals vary in age at which they progress to complete PVD. In early partial PVD, VMAA decreases at a similar rate across individuals.

Training in Neurology: How Lessons Learned on Teaching, Well-being and Telemedicine During the COVID-19 Pandemic Can Shape the Future of Neurology Education.

The COVID-19 pandemic has a disruptive impact on neurology education, necessitating creative adjustments in the delivery of education, clinical training and wellbeing. In this piece, a group of educators reflects on challenges and lessons learnt on teaching, wellbeing and telemedicine, and how these can shape the future of neurology education. Developing standardized, rigorous evaluation of teaching methods and telemedicine, reinforcing wellbeing resources and promoting international educational collaborations can improve neurology training during and after the pandemic.

Assessing the Influence of OCT-A Device and Scan Size on Retinal Vascular Metrics.

Purpose: The purpose of this study was to investigate the effect of device and scan size on quantitative optical coherence tomography angiography (OCT-A) metrics. Methods: The 3 × 3 mm scans from Optovue AngioVue and Zeiss AngioPlex systems were included for 18 eyes of 18 subjects without ocular pathology. The foveal avascular zone (FAZ) was segmented manually by two observers, from which estimates of FAZ area (using both the nominal image scale and the axial length corrected image scale) and acircularity were derived. Three scan sizes (3 mm, 6 mm HD, and 8 mm) from the AngioVue system were included for 15 eyes of 15 subjects without ocular pathology. For each subject, larger image sizes were resized to the same resolution as 3 × 3 mm scans, aligned, then cropped to a common area. FAZ area, FAZ acircularity, average and total parafoveal intercapillary area, vessel density, and vessel end points were computed. Results: Between the devices used here, there were no significant differences in FAZ acircularity (P = 0.88) or FAZ area using scaled (P = 0.11) or unscaled images (P = 0.069). Although there was no significant difference in FAZ area across scan sizes (P = 0.30), vessel morphometry metrics were all significantly influenced by scan size. Conclusions: The scan devices and sizes used here do not affect FAZ area measures derived from manual segmentations. In contrast, vessel morphometry metrics are affected by scan size. As individual differences in axial length induce differences in absolute scan size, extreme care should be taken when interpreting metrics of vessel morphometry, both between and within OCT-A devices. Translational Relevance: A better characterization of the confounds surrounding OCT-A retinal vasculature metrics can lead to improved application of these metrics as biomarkers for retinal and systemic diseases.

Standard 6-mm Compared with Widefield 16.5-mm OCT for Staging of Posterior Vitreous Detachment.

PURPOSE: To assess whether 6-mm OCT scans, which image the macula, can distinguish complete from partial posterior vitreous detachment (PVD) in comparison with 16.5-mm OCT scans, which image the macula, optic nerve, and mid periphery. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: We compared 6-mm and 16.5-mm scans in 157 eyes of 157 retina clinic patients (mean age, 50 years; range, 10-64 years) with diabetic retinopathy (36%), no retinal disease (19%), and various retinal conditions (45%). We also analyzed 16.5-mm scans in 35 healthy eyes (asymptomatic fellow eyes of patients with unilateral retinal conditions; mean age, 46 years; range, 9-63 years). METHODS: Each participant underwent Heidelberg Spectralis imaging with the standard lens (6-mm scan) and/or the 55° lens (16.5-mm scan). On 6-mm scans, we classified eyes as stage 3 partial PVD when the posterior vitreous cortex was visualized without visible attachment. On 16.5-mm scans, we classified eyes as stage 3 when the vitreous was attached at the optic nerve and separated from the macula. On both scan types, we classified eyes as stage 4 when neither the premacular bursa nor the posterior vitreous cortex were visualized. We assessed the accuracy of this system for detecting complete PVD on 6-mm scans by calculating test characteristics using 16.5-mm scans as a reference standard. MAIN OUTCOME MEASURE: Posterior vitreous detachment stage (0-4). RESULTS: Posterior vitreous detachment stage was identical in 6-mm and 16.5-mm scans in 88% of eyes. Compared with 16.5-mm scans, 6-mm scans detected complete PVD (vs. earlier stages 0-3) with 91% sensitivity and 99% specificity. Seven eyes were classified as no PVD on 6-mm scans and were classified as partial PVD on 16.5-mm scans because vitreoretinal separation was localized to the mid periphery. All 16.5-mm scans showed some degree of PVD, including scans from 9 participants between 9 and 20 years of age. CONCLUSIONS: Six-millimeter scans distinguished complete from partial PVD with good sensitivity and specificity but missed the earliest stages of PVD, which occur in the mid periphery. Posterior vitreous detachment may begin as early as the second decade of life.

Active Learning in Psychiatry Education: Current Practices and Future Perspectives.

Over the past few decades, medical education has seen increased interest in the use of active learning formats to engage learners and promote knowledge application over knowledge acquisition. The field of psychiatry, in particular, has pioneered a host of novel active learning paradigms. These have contributed to our understanding of the role of andragogy along the continuum of medical education, from undergraduate to continuing medical education. In an effort to frame the successes and failures of various attempts at integrating active learning into healthcare curricula, a group of educators from the A. B. Baker Section on Neurological Education from the American Academy of Neurology reviewed the state of the field in its partner field of medical neuroscience. Herein we provide a narrative review of the literature, outlining the basis for implementing active learning, the novel formats that have been used, and the lessons learned from qualitative and quantitative analysis of the research that has been done to date. While preparation time seems to present the greatest obstacle to acceptance from learners and educators, there is generally positive reception to the new educational formats. Additionally, most assessments of trainee performance have suggested non-inferiority (if not superiority). However, occasional mixed findings point to a need for better assessments of the type of learning that these new formats engender: knowledge application rather than acquisition. Moreover, this field is relatively nascent and, in order to ascertain how best to integrate active learning into psychiatry education, a framework for quantitative outcome assessments is needed going forward.

Strategic Considerations for Applying the Flipped Classroom to Neurology Education.

Nowadays, the "flipped classroom" approach is taking the center stage within medical education. However, very few reports on the implementation of the flipped classroom in neurology have been published to date, and this educational model still represents a challenge for students and educators alike. In this article, neurology educators from the American Academy of Neurology's A. B. Baker Section on Neurological Education analyze reports of flipped classroom in other medical/surgical subspecialties, review the current implementation in neurology, and discuss future strategies to flip the neurology curriculum through contextualization of the benefits and the consequences. ANN NEUROL 2020;87:4-9.

Accuracy of Spectral-Domain OCT of the Macula for Detection of Complete Posterior Vitreous Detachment.

PURPOSE: To assess the accuracy of macular spectral-domain OCT in detecting complete posterior vitreous detachment (PVD). DESIGN: Evaluation of diagnostic test or technology using a retrospective comparative study. PARTICIPANTS: One hundred seventy-five eyes in 175 patients (111 women and 64 men; mean age, 65 years) with preoperative OCT within 90 days of vitrectomy. METHODS: Posterior vitreous detachment status on preoperative macular OCT was compared with PVD determination during vitrectomy. Attached vitreous was identified on OCT by visualizing the posterior vitreous cortex or premacular bursa. Complete PVD was identified by the absence of these findings and considered a positive outcome for the purpose of analysis. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value, and negative predictive value of macular OCT for detection of complete PVD compared with findings at surgery. RESULTS: Of the 38 eyes graded as showing complete PVD on OCT, 20 eyes were found to have pre-existing PVD at the time of surgery (true-positive results), and 18 eyes were found to have attached vitreous at the time of surgery (false-positive results). Of the 137 eyes graded as showing attached vitreous on OCT, 129 eyes had attached vitreous at the time of surgery (true-negative results), and 8 eyes had pre-existing PVD at the time of surgery (false-negative results). The sensitivity of OCT for detecting complete PVD was 71% and the specificity was 88%. In the study population, the positive predictive value of an OCT scan showing complete PVD was 53%, whereas the negative predictive value of an OCT scan showing attached vitreous was 94%. CONCLUSIONS: If the premacular bursa or posterior vitreous cortex are visualized on macular OCT, an accurate determination of attached vitreous can be made. The diagnosis of complete PVD by macular OCT is less accurate and requires ultrasound.

Education Research: Flipped classroom in neurology: Principles, practices, and perspectives.

How to most effectively deliver a large amount of information in an engaging environment that encourages critical thinking is a question that has long plagued educators. With ever-increasing demands on both resident and faculty time, from shrinking duty hours to increased patient complexity, combined with the exponential growth of medical knowledge and unequal access to the spectrum of neurologic subspecialties around the country, this question has become especially pertinent to neurology residency training. A team of educators from the American Academy of Neurology's A.B. Baker Section on Neurological Education sought to review the current evidence regarding the implementation of the flipped classroom format. This educational model has only recently been applied to health care education along the training continuum, and a small collection of articles has, so far, used disparate methods of curricular implementation and assessment. While the feedback from learners is generally positive, a number of obstacles to implementation exist, most notably learner time commitments. These are presented with discussion of potential solutions along with suggestions for future studies.

Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants.

The South Asian population, numbered at 1.8 billion, is estimated to comprise around 20% of the global population and 1% of the American population, and has one of the highest rates of cardiovascular disease. While South Asians show increased classical risk factors for developing heart failure, the role of population-specific genetic risk factors has not yet been examined for this group. Hypertrophic cardiomyopathy (HCM) is one of the major cardiac genetic disorders among South Asians, leading to contractile dysfunction, heart failure, and sudden cardiac death. This disease displays autosomal dominant inheritance, and it is associated with a large number of variants in both sarcomeric and non-sarcomeric proteins. The South Asians, a population with large ethnic diversity, potentially carries region-specific polymorphisms. There is high variability in disease penetrance and phenotypic expression of variants associated with HCM. Thus, extensive studies are required to decipher pathogenicity and the physiological mechanisms of these variants, as well as the contribution of modifier genes and environmental factors to disease phenotypes. Conducting genotype-phenotype correlation studies will lead to improved understanding of HCM and, consequently, improved treatment options for this high-risk population. The objective of this review is to report the history of cardiovascular disease and HCM in South Asians, present previously published pathogenic variants, and introduce current efforts to study HCM using induced pluripotent stem cell-derived cardiomyocytes, next-generation sequencing, and gene editing technologies. The authors ultimately hope that this review will stimulate further research, drive novel discoveries, and contribute to the development of personalized medicine with the aim of expanding therapeutic strategies for HCM.

Autoimmune neuromuscular disorders.

Autoimmune neuromuscular disorders affecting peripheral nerves, neuromuscular junction or muscle have a wide clinical spectrum with diverse pathogenetic mechanisms. Peripheral nervous system may be targeted in the context of complex immune reactions involving different cytokines, antigen-presenting cells, B cells and different types of T cells. Various immunomodulating and cytotoxic treatments block proliferation or activation of immune cells by different mechanisms attempting to control the response of the immune system and limit target organ injury. Most treatment protocols for autoimmune neuromuscular disorders are based on the use of corticosteroids, intravenous immunoglobulins and plasmapheresis, with cytotoxic agents mostly used as steroid-sparing medications. More recently, development of specific monoclonal antibodies targeting individual cell types allowed a different approach targeting specific immune pathways, but these new treatments are also associated with various adverse effects and their long-term efficacy is still unknown.

Quantitative structure-activity relationship (QSAR) modeling of human blood: air partitioning with proper statistical methods and validation.

Blood: air partition coefficient (BApc) is important in assessing toxicokinetics of chemicals. Since very few experimental data are available, quantitative structure-activity relationship (QSAR) models based on calculated molecular descriptors can be useful in estimating BApc. Since all descriptors used in the analysis are computed strictly from structure, they can be applied to any chemical, real or hypothetical. In this article, we report models for BApc estimation using four methods, including stepwise ordinary least-squares regression, which is commonly used in QSAR studies but often results in an inflated 'naïve' q2, over-representing the predictive ability of the model. The models developed using proper statistical techniques had q2 values of 0.825 and 0.841, and may be used to reliably predict BApc values for new compounds that are structurally similar to those upon which the models are based. The models developed using improper techniques had associated q2 values, as computed using naïve methods, of 0.920 and 0.934, severely overstating their actual quality.

Treatment of anti-Ma2/Ta paraneoplastic syndrome.

The paraneoplastic syndrome caused by Ma2/Ta antibodies alone (not in conjunction with Ma1 or Ma3 antibodies) varies in presentation from classic limbic encephalitis. The Ma2 syndrome may present with symptoms referable to the brainstem, diencephalon, and limbic system. These clinical symptoms are accompanied by MRI changes and abnormal electroencephalographic findings. It is important to recognize when the encephalitic syndrome is secondary to Ma2 paraneoplastic antibodies, as the patients improve or stabilize most often when the underlying carcinoma is treated. Treatment of the paraneoplastic syndrome begins with recognition of the symptoms, such as memory impairment, seizures, sleep disturbances, bradykinesia or hypokinesia, and eye movement abnormalities. If a primary tumor is discovered during the workup, it should be removed and treated with the most up-to-date oncologic treatment available. In addition to oncologic treatment, the syndrome may be treated with an immunosuppressant regimen to optimize the neurologic outcome. Leaving the patient untreated will result in decline and eventual death from the cancer itself or from complications of the paraneoplastic syndrome.

Combining chemodescriptors and biodescriptors in quantitative structure-activity relationship modeling.

In view of the wide distribution of halocarbons in our world, their toxicity is a public health concern. Previous work has shown that various measures of toxicity can be predicted with standard molecular descriptors. In our work, biodescriptors of the effect of halocarbons on the liver were obtained by exposing hepatocytes to 14 halocarbons and a control and by producing two-dimensional electrophoresis gels to assess the expressed proteome. The resulting spot abundances provide additional biological information that might be used in toxicity prediction. QSAR models were fitted via ridge regression to predict eight dependent toxicity measures: d37, arr, EC50MTT, EC50LDH, EC20SH, LECLP, LECROS, and LECCAT. Three predictor sets were used for each-the chemodescriptors alone, the biodescriptors alone, and the combined set of both chemo- and biodescriptors. The results differed somewhat from one dependent to another, but overall it was shown that better results could be obtained by using both chemo- and biodescriptors in the model than by using either chemo- or biodescriptors alone. The library of compounds used was small and quite homogeneous, so our immediate conclusions are correspondingly limited in scope, but we believe the underlying methodologies have broad applicability at the interface of chemical and biological descriptors.