Symptom burden, management and treatment goals of people with MS spasticity: Results from SEEN-MSS, a large-scale, self-reported survey.

BACKGROUND: Spasticity occurs frequently in people with multiple sclerosis (PwMS) and may affect non-physical aspects of life. However, there is a paucity of data assessing the full impact of spasticity in PwMS. OBJECTIVE: This survey of PwMS and spasticity (PwMSS) was undertaken to understand the impact of spasticity in physical, functional, emotional, and social domains. METHODS: SEEN-MSS (Symptoms and Emotions Exploration Needed in Multiple Sclerosis Spasticity), an online survey, was developed in collaboration with three US-based MS organizations (conducted February-April 2021). RESULTS: Survey was completed by 1,177 PwMSS, 78% female, mean age 56.8yrs, 16.8yrs from MS diagnosis, 11.5yrs with spasticity. Considering day-to-day goals of treatment, respondents reported that managing symptoms(46%) was nearly as important as slowing disease progression(54%). Most reported spasticity was a constant reminder of their MS. Participants reported that spasticity limited daily activities (92%), caused pain (92%), impaired sleep (89%) and negatively impacted emotional well-being (87%). Spasticity fostered a sense of dependence (61%), isolation (40%), decline in self-confidence (75%), self-image (70%), and social connection (62%). CONCLUSIONS: Spasticity has wide-reaching negative impacts on multiple aspects of life, causing substantial burden for PwMSS. Results emphasize the need to fully understand the burden of spasticity and addressing individual needs of PwMSS.

Radiologically Isolated Syndrome: A Review for Neuroradiologists.

Radiologically isolated syndrome refers to an entity in which white matter lesions fulfilling the criteria for multiple sclerosis occur in individuals without a history of a clinical demyelinating attack or alternative etiology. Since its introduction in 2009, the diagnostic criteria of radiologically isolated syndrome and its clinical relevance have been widely debated by neurologists and radiologists. The aim of the present study was to review the following: 1) historical evolution of radiologically isolated syndrome criteria, 2) clinical and imaging findings in adults and children with radiologically isolated syndrome, 3) imaging features of patients with radiologically isolated syndrome at high risk for conversion to MS, and 4) challenges and controversies for work-up, management, and therapeutic interventions of patients with radiologically isolated syndrome.

Investigating the effects of long-term dornase alfa use on lung function using registry data.

BACKGROUND: Dornase alfa (DNase) is one of the commonest cystic fibrosis (CF) treatments and is often used for many years. However, studies have not evaluated the effectiveness of its long-term use. We aimed to use UK CF Registry data to investigate the effects of one-, two-, three-, four- and five-years of DNase use on lung function to see if the benefits of short-term treatment use are sustained long term. METHODS: We analysed data from 4,198 people in the UK CF Registry from 2007 to 2015 using g-estimation. By controlling for time-dependent confounding we estimated the effects of long-term DNase use on percent predicted FEV1 (ppFEV1) and investigated whether the effect differed by ppFEV1 at treatment initiation or by age. RESULTS: Considering the population as a whole, there was no significant effect of one-year's use of DNase; change in ppFEV1 over one year was -0.1% in the treated compared to the untreated (p = 0.51) and this did not change with long-term use. However, treatment was estimated to be more beneficial in people with lower lung function (p < 0.001); those with ppFEV1 < 70% at treatment initiation, showed an increase in lung function over one year that was sustained out to five years. The estimated effect of DNase did not depend on age (p = 0.35). CONCLUSIONS: DNase improved lung function in individuals with reduced lung function, bringing a step-change in lung function, but no change in the slope of decline. There was no evidence for a benefit in lung function in those initiating treatment with ppFEV1 > 70%.

Radiation-Induced Myelitis: Initial and Follow-Up MRI and Clinical Features in Patients at a Single Tertiary Care Institution during 20 Years.

Myelitis is a rare complication of radiation exposure to the spinal cord and is often a diagnosis of exclusion. A retrospective review of clinical records and serial imaging was performed to identify subjects with documented myelitis and a history of prior radiation. Eleven patients fulfilled the inclusion criteria. All patients had longitudinally extensive cord involvement with homogeneous precontrast T1 hyperintense signal in the adjacent vertebrae, corresponding to the radiation field. T2 signal abnormalities involving the central two-thirds of the cord were seen in 6/11 patients (55%). The degree of cord expansion and contrast enhancement was variable but was seen in 6 (54%) and 5 (45%) patients, respectively. On follow-up, 2 patients developed cord atrophy, while complete resolution was noted in 1. Clinical improvement was noted in 5 patients, with symptom progression in 2 patients. Our results suggest that radiation myelitis is neither universally progressive nor permanent, and some radiographic and clinical improvement may occur.

Evaluation and management of longitudinally extensive transverse myelitis: a guide for radiologists.

Longitudinal extensive transverse myelitis (LETM) is defined as an intramedullary spinal cord T2 signal abnormality extending craniocaudally over at least three vertebral bodies on an MRI study. Timely and appropriate diagnosis greatly facilitates patient management. The radiologist should review the relevant clinical information and determine the patient demographics and acuity of symptoms. Herein, we review the spectrum of diseases causing LETM and propose interpretation to guide the radiologist when presented with the MRI finding of LETM.

Isotopic Incorporation and the Effects of Fasting and Dietary Lipid Content on Isotopic Discrimination in Large Carnivorous Mammals.

There has been considerable emphasis on understanding isotopic discrimination for diet estimation in omnivores. However, discrimination may differ for carnivores, particularly species that consume lipid-rich diets. Here, we examined the potential implications of several factors when using stable isotopes to estimate the diets of bears, which can consume lipid-rich diets and, alternatively, fast for weeks to months. We conducted feeding trials with captive brown bears (Ursus arctos) and polar bears (Ursus maritimus). As dietary lipid content increased to ∼90%, we observed increasing differences between blood plasma and diets that had not been lipid extracted (∆(13)Ctissue-bulk diet) and slightly decreasing differences between plasma δ(13)C and lipid-extracted diet. Plasma Δ(15)Ntissue-bulk diet increased with increasing protein content for the four polar bears in this study and data for other mammals from previous studies that were fed purely carnivorous diets. Four adult and four yearling brown bears that fasted 120 d had plasma δ(15)N values that changed by <±2‰. Fasting bears exhibited no trend in plasma δ(13)C. Isotopic incorporation in red blood cells and whole blood was ≥6 mo in subadult and adult bears, which is considerably longer than previously measured in younger and smaller black bears (Ursus americanus). Our results suggest that short-term fasting in carnivores has minimal effects on δ(13)C and δ(15)N discrimination between predators and their prey but that dietary lipid content is an important factor directly affecting δ(13)C discrimination and indirectly affecting δ(15)N discrimination via the inverse relationship with dietary protein content.

Revised Recommendations of the Consortium of MS Centers Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-Up of Multiple Sclerosis.

An international group of neurologists and radiologists developed revised guidelines for standardized brain and spinal cord MR imaging for the diagnosis and follow-up of MS. A brain MR imaging with gadolinium is recommended for the diagnosis of MS. A spinal cord MR imaging is recommended if the brain MR imaging is nondiagnostic or if the presenting symptoms are at the level of the spinal cord. A follow-up brain MR imaging with gadolinium is recommended to demonstrate dissemination in time and ongoing clinically silent disease activity while on treatment, to evaluate unexpected clinical worsening, to re-assess the original diagnosis, and as a new baseline before starting or modifying therapy. A routine brain MR imaging should be considered every 6 months to 2 years for all patients with relapsing MS. The brain MR imaging protocol includes 3D T1-weighted, 3D T2-FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences, and a DWI sequence. The progressive multifocal leukoencephalopathy surveillance protocol includes FLAIR and DWI sequences only. The spinal cord MR imaging protocol includes sagittal T1-weighted and proton attenuation, STIR or phase-sensitive inversion recovery, axial T2- or T2*-weighted imaging through suspicious lesions, and, in some cases, postcontrast gadolinium-enhanced T1-weighted imaging. The clinical question being addressed should be provided in the requisition for the MR imaging. The radiology report should be descriptive, with results referenced to previous studies. MR imaging studies should be permanently retained and available. The current revision incorporates new clinical information and imaging techniques that have become more available.

Impact of peginterferon beta-1a and disease factors on quality of life in multiple sclerosis.

BACKGROUND: The Phase III ADVANCE study has shown clinical benefits for peginterferon beta-1a 125 µg dosed every 2 weeks versus placebo at 1 year in patients with relapsing-remitting multiple sclerosis (MS). This study assessed the impact of peginterferon beta-1a and disease factors on health-related quality of life (HRQoL) using data from ADVANCE. METHODS: HRQoL was assessed at baseline and 12, 24, and 48 weeks using the 29-item Multiple Sclerosis Impact Scale (MSIS-29) and other generic HRQoL measures. Changes in scores from baseline within each group and differences in mean change from baseline between groups were evaluated. Post-hoc mixed-effects repeated measures analyses were performed to assess the impact of confirmed disability progression and relapses, and the interactions of treatment and these MS events on HRQoL. Predictors with p≥0.1 were excluded from the final models, unless they were clinically meaningful. RESULTS: Relapses and confirmed disability progression were major drivers of HRQoL. When comparing week 48 to baseline, in placebo-treated patients (n=500), confirmed disability progression was associated with a 6.0-point worsening (p<0.0001) of MSIS-29 physical scores, relative to a 1.9-point worsening (p=0.044) with peginterferon beta-1a every 2 weeks (n=512). Such findings were observed consistently with other generic HRQoL measures. Additionally, having a recent relapse (≤29 days before the HRQoL assessment) was associated with a 10.0-point worsening (p<0.0001) of MSIS-29 psychological scores in placebo-treated patients, compared with a 3.5-point (p=0.031) worsening with peginterferon beta-1a every 2 weeks. CONCLUSION: Treatment with peginterferon beta-1a could help to improve or maintain HRQoL in addition to clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00906399.

Next-generation sequencing workflow for assembly of nonmodel mitogenomes exemplified with North Pacific albatrosses (Phoebastria spp.).

Use of complete mitochondrial genomes (mitogenomes) can greatly increase the resolution achievable in phylogeographic and historical demographic studies. Using next-generation sequencing methods, it is now feasible to efficiently sequence mitogenomes of large numbers of individuals once a reference mitogenome is available. However, assembling the initial mitogenomes of nonmodel organisms can present challenges, for example, in birds, where mtDNA is often subject to gene rearrangements and duplications. We developed a workflow based on Illumina paired-end, whole-genome shotgun sequencing, which we used to generate complete 19-kilobase mitogenomes for each of three species of North Pacific albatross, a group of birds known to carry a tandem duplication. Although this duplication had been described previously, our procedure did not depend on this prior knowledge, nor did it require a closely related reference mitogenome (e.g. a mammalian mitogenome was sufficient). We employed an iterative process including de novo assembly, reference-guided assembly and gap closing, which enabled us to detect duplications, determine gene order and identify sequence for primer positioning to resolve any mitogenome ambiguity (via minimal targeted Sanger sequencing). We present full mtDNA annotations, including 22 tRNAs, 2 rRNAs, 13 protein-coding genes, a control region and a duplicated feature for all three species. Pairwise comparisons supported previous hypotheses regarding the phylogenetic relationships within this group and occurrence of a shared tandem duplication. The resulting mitogenome sequences will enable rapid, high-throughput NGS mitogenome sequencing of North Pacific albatrosses via direct reference-guided assembly. Moreover, our approach to assembling mitogenomes should be applicable to any taxon.

Diffusion tensor imaging of the optic nerve in multiple sclerosis: association with retinal damage and visual disability.

BACKGROUND AND PURPOSE: There is a well-known relationship between MS and damage to the optic nerve, but advanced, quantitative MR imaging methods have not been applied to large cohorts. Our objective was to determine whether a short imaging protocol (< 10 minutes), implemented with standard hardware, could detect abnormal water diffusion in the optic nerves of patients with MS. MATERIALS AND METHODS: We examined water diffusion in human optic nerves via DTI in the largest MS cohort reported to date (104 individuals, including 38 optic nerves previously affected by optic neuritis). We also assessed whether such abnormalities are associated with loss of visual acuity (both high and low contrast) and damage to the retinal nerve fiber layer (assessed via optical coherence tomography). RESULTS: The most abnormal diffusion was found in the optic nerves of patients with SPMS, especially in optic nerves previously affected by optic neuritis (19% drop in FA). DTI abnormalities correlated with both retinal nerve fiber layer thinning (correlation coefficient, 0.41) and loss of visual acuity, particularly at high contrast and in nerves previously affected by optic neuritis (correlation coefficient, 0.54). However, diffusion abnormalities were overall less pronounced than retinal nerve fiber layer thinning. CONCLUSIONS: DTI is sensitive to optic nerve damage in patients with MS, but a short imaging sequence added to standard clinical protocols may not be the most reliable indicator of optic nerve damage.

Fulminant encephalopathy with basal ganglia hyperintensities in HIV-infected drug users.

OBJECTIVE: To define a clinical syndrome associated with active drug abuse in HIV-infected individuals. METHODS: We performed a retrospective review to identify individuals treated at the Johns Hopkins Hospital from 1993 to 2008 who were HIV-infected and were actively abusing drugs and had bilateral basal ganglia lesions on MRI. They were identified using a key word search in the radiology database, autopsy database, and the Moore HIV clinic database. Clinical, laboratory, and radiographic findings were correlated to define the syndrome. RESULTS: Ten individuals were identified who presented with a change in mental status or seizures, used cocaine or cocaine with heroin, had uncontrolled HIV infection (>190,000 copies/mL of plasma), elevated CSF protein (63-313 mg/dL), and diffuse hyperintense bilateral basal ganglia lesions on imaging. The majority of patients (8/10) had renal failure and despite supportive therapy most (7/9) ultimately died (median survival 21 days). Postmortem examination in one individual showed the presence of overwhelming microglial activation in the basal ganglia. The 2 surviving individuals were started on combined antiretroviral therapy (CART) during hospitalization. CONCLUSION: We describe a unique clinical syndrome of a fulminant encephalopathy associated with primarily basal ganglia involvement in HIV-infected drug abusers. This syndrome is a rare but serious condition that is associated with a high mortality rate. Early CART institution may be useful and neuroprotective in this disorder, although this requires further investigation.

Dispersal provided resilience to range collapse in a marine mammal: insights from the past to inform conservation biology.

Population loss is often a harbinger of species extinction, but few opportunities exist to follow a species' demography and genetics through both time and space while this occurs. Previous research has shown that the northern fur seal (Callorhinus ursinus) was extirpated from most of its range over the past 200-800 years and that some of the extirpated populations had unique life history strategies. In this study, widespread availability of subfossils in the eastern Pacific allowed us to examine temporal changes in spatial genetic structure during massive population range contraction and partial recovery. We sequenced the mitochondrial control region from 40 ancient and 365 modern samples and analyzed them through extensive simulations within a serial Approximate Bayesian Computation framework. These analyses suggest that the species maintained a high abundance, probably in subarctic refugia, that dispersal rates are likely 85% per generation into new breeding colonies, and that population structure was not higher in the past. Despite substantial loss of breeding range, this species' high dispersal rates and refugia appear to have prevented a loss of genetic diversity. High dispersal rates also suggest that previous evidence for divergent life history strategies in ancient populations likely resulted from behavioral plasticity. Our results support the proposal that panmictic, or nearly panmictic, species with large ranges will be more resilient to future disturbance and environmental change. When appropriately verified, evidence of low population structure can be powerful information for conservation decision-making.

Vitamin D status and effect of low-dose cholecalciferol and high-dose ergocalciferol supplementation in multiple sclerosis.

BACKGROUND: Vitamin D is important for bone health and immune regulation, and has been shown to be low in multiple sclerosis (MS). We sought to determine the effect of over the counter low dose cholecalciferol (LDC) and high dose ergocalciferol (HDE) on the vitamin D levels in MS patients. METHODS: We retrospectively evaluated serum 25-hydroxy-vitamin D [25(OH)D] levels of 199 patients (CIS, n = 32; RRMS, n = 115; PPMS, n = 10; SPMS, n = 16; Transverse Myelitis (TM), n = 9; other neurological diseases, n = 16) attending our clinic between 2004 and 2008. We examined the change in 25(OH)D levels in 40 MS patients who took either LDC (< or =800 IU/day) or HDE (50,000 IU/day for 7-10 days, followed by 50,000 IU weekly or biweekly). RESULTS: The average 25(OH)D level was 71 +/- 39 nmol/L (Mean +/- SD), and 167(84%) patients had insufficient levels (< or =100 nmol/L) of 25(OH)D. The patients supplemented with LDC did not have a significant increase in their 25(OH)D levels. However, 25(OH)D levels increased by 42 nmol/L (P = 0.01) in the patients originally taking LDC and then prescribed HDE. Optimal levels (> or =100 nmol/L) were only achieved in less than 40% of patients. CONCLUSIONS: We conclude that large numbers of patients with MS and TM in our cohort are deficient in vitamin D. HDE significantly elevated 25(OH)D levels in MS patients and was more effective at increasing 25(OH)D levels than LDC. Prospective studies are required to determine appropriate dosing regimen to achieve optimal levels in the majority of MS patients and to ascertain the safety, immunological response, and ultimately the clinical efficacy of vitamin D replacement therapy.

Cushing's syndrome in a clinic population with diabetes.

BACKGROUND: A recent report has suggested that occult Cushing's syndrome (CS) may be present in a significant number of patients with type 2 diabetes mellitus. The aim of this study was to determine whether any patients in our clinic population with diabetes had this condition. METHODS: One hundred and seventy-one consecutive overweight attendees at the diabetic clinic were enrolled in a study to assess the presence of occult CS. The initial screen was with the 1 mg overnight dexamethasone suppression test and follow-up testing, where indicated was with a 24 h collection for urine-free cortisol. RESULTS: Thirty-one of 171 patients had a positive result from the overnight dexamethasone suppression test. Follow-up testing with 24 h urine-free cortisol reduced the number of patients with positive results to 3. Two of these were shown to have alcoholic pseudo-CS. The third patient has had several high urine-free cortisol results, in the presence of normal scans of pituitary and adrenals. He has no stigmata of CS and is being observed. CONCLUSION: Based on the results of our study, there would appear to be little value in screening type 2 diabetics for CS, in the absence of clinical suspicion.

Pleistocene to recent dietary shifts in California condors.

We used carbon and nitrogen isotopes to investigate changes in the diet of California condors from the Pleistocene to the recent. During the Pleistocene, condors from California fed on both terrestrial megafauna and marine mammals. Early accounts reported condors feeding on the carcasses of marine mammals, but by the late 1700s, condor diets had shifted predominantly to terrestrial animals, following the commercial harvesting of marine mammals and the development of cattle ranching on land. At present, dairy calves provided by humans significantly augment condor diet, constituting an artificial support of the current population. Reestablishing a marine mammal component in the condor diet may be an effective strategy for fostering viable condor populations independent of direct human subsidies.

Word shape's in poor shape for the race to the lexicon.

Current models of fluent reading often assume that fast and automatic word recognition involves the use of a supraletter feature corresponding to the envelope or shape of the word when it is printed in lowercase. The advantages of mixed case over pure case and of pure lowercase over pure uppercase have often been taken as evidence favoring the word-shape hypothesis. Alternative explanations for these phenomena are offered. Experiment 1 shows that previous demonstrations of word-shape effects during proofreading are better described as individual letter effects. Experiments 2-4 explore the possibility that word shape facilitates lexical access through uncertainty reduction. In all three experiments performance on words with rare shapes is compared to those with common shapes. There were no effects of shape frequency in either tachistoscopic recognition or lexical-decision tasks. This was true regardless of the degree to which the visual shape cue was supplemented by the nonvisual factors of familiarity and expectancy. Possible reasons why fluent readers ignore word shape are discussed within the framework of a model that assumes that automatic word recognition is mediated by the activation of abstract letter identities.