Body composition in amyotrophic lateral sclerosis subjects and its effect on disease progression and survival.

BACKGROUND: Motor neuron degeneration and malnutrition alter body composition in amyotrophic lateral sclerosis (ALS). Resulting losses of weight, fat mass (FM), and fat-free mass (FFM) shorten survival. Nutritional management relies on body weight or BMI; neither reliably indicates malnutrition nor differentiates body compartments. OBJECTIVES: We aimed to 1) develop an equation to compute FM and FFM using clinical data, validated against DXA; and 2) examine the effect of computed FM and FFM on disease course and survival. METHODS: We studied 364 ALS patients from 3 cohorts. In Cohort #1 we used logistic regression on clinical and demographic data to create an equation (test cohort). In Cohort #2 we validated FM and FFM computed using this equation against DXA (validation cohort). In Cohort #3, we examined the effect of computed body composition on disease course and survival. RESULTS: In Cohort #1 (n = 29) the model incorporated sex, age, BMI, and bulbar-onset to create an equation to estimate body fat: % body fat = 1.73 - [19.80*gender (1 if male or 0 if female)] + [0.25*weight (kg)] + [0.95*BMI (kg/m2)] - (5.20*1 if bulbar-onset or *0 if limb-onset). In Cohort #2 (n = 104), body composition using this equation, compared to other published equations, showed the least variance from DXA values. In Cohort #3 (n = 314), loss of body composition over 6 mo was greater in males. Adjusted survival was predicted by low baseline FM (HR: 1.39; 95% CI: 1.07, 1.80), and loss of FM (HR: 1.87; 95% CI: 1.30, 2.69) and FFM (HR: 1.73; 95% CI: 1.20, 2.49) over 6 mo. CONCLUSIONS: Our equation broadens the traditional nutritional evaluation in clinics and reliably estimates body composition. Measuring body composition could target FM as a focus for nutritional management to ensure adequate energy intake and complement measures, such as the ALS functional rating scale-revised score and forced vital capacity, currently used.

Thymectomy may not be associated with clinical improvement in MuSK myasthenia gravis.

INTRODUCTION: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG. METHODS: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG. RESULTS: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19). DISCUSSION: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019.

Hydration measured by doubly labeled water in ALS and its effects on survival.

We present a study of hydration in ALS patients and its effects on survival. This was a multicenter study over 48 weeks in 80 ALS patients who underwent 250 individual measurements using doubly labeled water (DLW). Total body water (TBW) and water turnover (a surrogate for water intake) were 3.4% and 8.6% lower, respectively, in patients compared to age- and gender-matched healthy controls, and both significantly decreased over study duration. In 20% of patients, water turnover measured over 10 d was 2 standard deviations below the mean value in healthy controls. In a separate clinic cohort of 208 patients, water intake estimated from a de novo equation created from common clinical endpoints was a prognostic indicator of survival. Regardless of nutritional state assessed by BMI, survival was two-fold longer in the group above the median for estimated water intake, suggesting that hydration may be a more important predictor of survival than malnutrition. Risk factors for poor hydration were identified. Water intake equations recommended by US Centers for Medicare and Medicaid Services in healthy elderly were inaccurate for use in ALS patients. We developed equations to estimate TBW and water intake in ALS patients for use in clinics to accurately estimate hydration and improve clinical care.

Rituximab treatment of myasthenia gravis: A systematic review.

Rituximab is a chimeric mouse/human anti-CD20 monoclonal immunoglobulin. We reviewed the efficacy and safety of rituximab in 169 myasthenia gravis (MG) patients from case reports and series. Antibodies to the acetylcholine receptor (AChR) were present in 59% and muscle-specific tyrosine kinase (MuSK) in 34%. Modified Myasthenia Gravis Foundation of America postintervention scale of minimal manifestations (MM) or better occurred in 44%, and combined pharmacologic and chronic stable remission in 27% overall; MM or better was achieved in 72% of MuSK MG and 30% of AChR MG (P < 0.001). Posttreatment relapses decreased more in MuSK MG (P = 0.05). Response predictors were MuSK MG, less severe disease, and younger age at treatment. Among a responder subset, 26% of AChR and 82% of MuSK MG patients showed decreased posttreatment antibody titers. Rituximab was generally well tolerated. Detectable serum rituximab and depleted CD20+ B-cells were observed up to 20 and 16 weeks, respectively, after 4 weekly infusions. Muscle Nerve 56: 185-196, 2017.

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study.

OBJECTIVE: To characterize patients misdiagnosed with multiple sclerosis (MS). METHODS: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. RESULTS: Of 110 misdiagnosed patients, 51 (46%) were classified as "definite" and 59 (54%) "probable" misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. CONCLUSIONS: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

"Central vessel sign" on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine.

OBJECTIVE: The diagnosis of multiple sclerosis (MS) presently relies on radiographic assessments of imperfect specificity. Recent data using T2* methodology for the detection of the "central vessel sign" (CVS) in MS lesions suggests this novel MRI technique may distinguish MS from other disorders. Our aim was to determine if evaluation for CVS on 3T FLAIR* MRI differentiates MS from migraine. METHODS: Patients with MS or migraine and a prior brain MRI demonstrating at least two hyperintense lesions ≥3 mm were recruited. Exclusion criteria included any additional comorbidity known to cause brain MRI abnormalities. 3T MRI was performed in each participant with administration of gadopentetate dimeglumine, and FLAIR* images were generated in postprocessing. The total number of discrete ovoid lesions ≥3 mm were counted on FLAIR, per participant, and subsequently evaluated for presence of CVS on FLAIR*. An exploratory method evaluating for CVS in a maximum of 12 lesions per subject was also completed. RESULTS: Ten participants with MS and 10 with migraine completed the study. The median percentage (quartiles) of lesions in MS participants with CVS was 84 (79, 94) compared to 22 (15, 54) in migraine (P = 0.008). In a subanalysis by brain region, in the subcortical and deep white matter, the median percentage (quartiles) of lesions in MS participants with CVS was 88 (81, 100) compared to 19 (11, 54) in migraine (P = 0.004). This difference was not identified in juxtacortical, periventricular, or infratentorial regions. INTERPRETATION: Identification of CVS using FLAIR* on 3T MRI helps differentiate MS from migraine, particularly in the subcortical and deep white matter.

Mining and Visualizing Family History Associations in the Electronic Health Record: A Case Study for Pediatric Asthma.

Asthma is the most common chronic childhood disease and has seen increasing prevalence worldwide. While there is existing evidence of familial and other risk factors for pediatric asthma, there is a need for further studies to explore and understand interactions among these risk factors. The goal of this study was to develop an approach for mining, visualizing, and evaluating association rules representing pairwise interactions among potential familial risk factors based on information documented as part of a patient's family history in the electronic health record. As a case study, 10,260 structured family history entries for a cohort of 1,531 pediatric asthma patients were extracted and analyzed to generate family history associations at different levels of granularity. The preliminary results highlight the potential of this approach for validating known knowledge and suggesting opportunities for further investigation that may contribute to improving prediction of asthma risk in children.

Cognitive outcome after spinal anesthesia and surgery during infancy.

BACKGROUND: Observational studies on pediatric anesthesia neurotoxicity have been unable to distinguish long-term effects of general anesthesia (GA) from factors associated with the need for surgery. A recent study on elementary school children who had received a single GA during the first year of life demonstrated an association in otherwise healthy children between the duration of anesthesia and diminished test scores and also revealed a subgroup of children with "very poor academic achievement" (VPAA), scoring below the fifth percentile on standardized testing. Analysis of postoperative cognitive function in a similar cohort of children anesthetized with an alternative to GA may help to begin to separate the effects of anesthesia from other confounders. METHODS: We used a novel methodology to construct a combined medical and educational database to search for these effects in a similar cohort of children receiving spinal anesthesia (SA) for the same procedures. We compared former patients with a control population of students matched by grade, gender, year of testing, and socioeconomic status. RESULTS: Vermont Department of Education records were analyzed for 265 students who had a single exposure to SA during infancy for circumcision, pyloromyotomy, or inguinal hernia repair. Exposure to SA and surgery had no significant effect on the odds of children having VPAA. (mathematics: P = 0.18; odds ratio 1.50, confidence interval (CI), 0.83-2.68; reading: P = 0.55; odds ratio = 1.19, CI, 0.67-2.1). There was no relationship between duration of exposure to SA and surgery and performance on mathematics (P = 0.73) or reading (P = 0.57) standardized testing. There was a small but statistically significant decrease in reading and math scores in the exposed group (mathematics: P = 0.03; reading: P = 0.02). CONCLUSIONS: We found no link between duration of surgery with infant SA and scores on academic achievement testing in elementary school. We also found no relationship between infant SA and surgery with VPAA on elementary school testing, although the CIs were wide.

Utility of spine bone mineral density in fracture prediction within FRAX.

Predicting individuals at risk for fracturing and modifying that risk are important in preventative health. Our aim was to quantify the impact of spine bone mineral density (BMD) on fracture risk prediction and determine the positive predictive value of fracture prediction using the lowest BMD value at the femoral neck, total hip, or lumbar spine. A retrospective cross-sectional analysis of 15,033 women was performed, assessing the contribution of age, body mass index, number of clinical risk factors, T-score, and osteoporosis category to the presence of fracture. In patients whose lumbar spine T-scores are 1 or 2 osteoporosis categories lower than femoral neck, there is an approximately 30% increased risk of fracture compared with the femoral neck alone. For patients younger than 60 years, the odds ratio of having a fracture based on the presence of lumbar spine osteoporosis was greater than that based on femoral neck osteoporosis. Osteoporosis at the total hip correlated best with the presence of fracture. When using FRAX, we recommend that the 10-yr fracture prediction be adjusted when lumbar spine T-score is 1-2 osteoporosis categories lower than the femoral neck T-score or when lumbar spine T-score is ≥1 standard deviation less than femoral neck T-score.

Neurodevelopmental outcome of extremely low birth weight infants from the Vermont Oxford network: 1998-2003.

BACKGROUND: Physicians and parents face significant uncertainties when making care decisions for extremely low birth weight (ELBW) infants. Many published estimates of death and developmental outcome are from well-funded university programs and may not reflect outcomes of infants from a variety of settings. The best estimates of the probabilities of death and severe disability combine local experience and published data. OBJECTIVE: To describe the neurodevelopmental outcome of ELBW infants from centers of the ELBW Infant Follow-Up Group of the Vermont Oxford Network (VON) and to identify characteristics associated with severe disability. METHODS: Predefined measures of living situation, health and developmental outcome were collected at 18-24 months' corrected age for infants born from July 1, 1998 to December 31, 2003 with birth weights of 401-1,000 g at 33 North American VON centers. Logistic regression was used to identify characteristics associated with severe disability. RESULTS: 6,198 ELBW infants were born and survived until hospital discharge; by the time of follow-up, 88 infants (1.4%) had died. Of the remaining 6,110 infants, 3,567 (58.4%) were evaluated. Severe disability occurred in 34% of the assessed infants. Multivariate logistic regression suggested cystic periventricular leukomalacia, congenital malformation and severe intraventricular hemorrhage were the characteristics most highly associated with severe disability. There were marked variations among the follow-up clinics in the attrition rate. CONCLUSION: ELBW infants completing evaluation were at a high risk for severe disability. There are considerable differences among participating centers in attrition at follow-up. Further resources will be needed to study the effect of follow-up care for this group of infants.

An Update Survey of Bulk Tank Milk Quality in Vermont.

Quality of Vermont bulk tank milk was first surveyed in 1985 as part of a statewide milk quality enhancement program. In a second survey conducted in 1990, bulk tank milk from 1,971 farms was sampled and tested for standard plate count, bacterial type and species distribution, and somatic cell count. Test results from 1,203 duplicate bulk tank milk samples were compared between five Vermont milk processors and the University of Vermont Quality Milk Research Laboratory. Arithmetic mean standard plate count conducted by processors was 2.3 × 104 CFU/ml in 1990 compared with 3.0 × 104 CFU/ml in 1985 (Geometric mean went from 1.3 × 104 CFU/ml in 1985 to 1.1 × 104 CFU/ml in 1990). Trypticase blood-esculin agar was used at the Quality Milk Research Laboratory to determine distribution of bacteria types and species. Comparison of results with a 1985 survey appeared to demonstrate a reduction in the percentage of farms with Streptococcus agalactiae from 47% to 32%. Frequency of other organisms increased with the majority being environmental organisms. Arithmetic mean total raw bacteria count on blood agar was 1.9 × 104 CFU/ml. Correlation between standard plate count and blood agar raw bacteria count was low. Arithmetic mean somatic cell count appeared to decline from 5.4 × 105 cells/ml in 1985 to 3.4 × 105 cells/ml in 1990 (Geometric mean went from 4.1 × 105 cells/ml in 1985 to 2.9 × 105 cells/ml in 1990). Correlation between somatic cell counts conducted by milk processors and the Quality Milk Research Laboratory was high.

Comparison of Infectious Dose of Listeria monocytogenes F5817 as Determined for Normal Versus Compromised C57B1/6J Mice.

The infectious dose of Listeria monocytogenes F5817, a serotype 4b human patient isolate, was determined following oral challenge in normal and compromised C57B1/6J mice. In an attempt to mimic human populations previously shown to be at risk to ingestion of L. monocytogenes , groups of mice used in this study consisted of the following: mice pretreated with hydrocortisone acetate or cimetidine; pregnant mice (12-14 d gestation); or beige mutants of C57B1/6J mice (deficient in lysosome production within monocytes and granulocytes). Mice were gavaged with varying levels of L. monocytogenes suspended in sterile 11% non-fat milk solids (NFMS). Upon expiration, the spleen, liver, lung, and brain were aseptically removed from mice. Organs were plated on LPM agar, and colonies were enumerated and biochemically confirmed as L. monocytogenes . Mice were considered infected if L. monocytogenes was recovered from at least one of the examined organs. In normal resistant C57B1/6J mice, the infectious dose 50 (ID50) ranged from 3.24-4.55 log10 CFU. In comparison, the ID50 for mice treated with 2.5 mg hydrocortisone acetate/day for 3d prior to infection decreased to 0.41 log10 CFU (range -1.91-2.74 log10 CFU). Administration of 0.25 mg hydrocortisone acetate/day for 3d prior to infection resulted in an ID50 similar to that calculated for normal mice. The ID50 calculated for pregnant mice was 2.48 log10 CFU, a value not significantly different from that of normal control mice. The response of beige mutants and cimetidine treated mice was comparable to that of normal controls, with ID50 values of 4.00 and 3.30 log10 CFU, respectively.