Motor Efficacy of Subcutaneous DIZ102, Intravenous DIZ101 or Intestinal Levodopa/Carbidopa Infusion.

BACKGROUND: It has been suggested that carbidopa at high blood concentrations may counter the therapeutic effect of levodopa in Parkinson's disease by entering the brain and blocking central levodopa conversion to dopamine. We previously demonstrated equivalent plasma levodopa concentration in patients with Parkinson's disease during 16 h of (1) intravenous carbidopa/levodopa (DIZ101) infusion, (2) subcutaneous carbidopa/levodopa (DIZ102) infusion or (3) intestinal carbidopa/levodopa gel infusion. Plasma levels of carbidopa were however approximately four times higher with DIZ101 and DIZ102 than with LCIG, and higher than those usually observed with oral levodopa/carbidopa. OBJECTIVES: To investigate if high carbidopa blood concentrations obtained with parenteral levodopa/carbidopa (ratio 8:1) counter the effect of levodopa on motor symptoms. METHODS: Eighteen patients with advanced Parkinson's disease were administered DIZ101, DIZ102, and intestinal levodopa/carbidopa gel for 16 h on different days in randomized order. Video recordings of a subset of the motor examination in the Unified Parkinson's Disease Rating Scale (UPDRS) were evaluated by raters blinded for treatment and time. Motor function was also measured using a wrist-worn device monitoring bradykinesia, dyskinesia, and tremor (Parkinson KinetiGraph). RESULTS: There was no tendency for poorer levodopa effect with DIZ101 or DIZ102 as compared to LCIG. CONCLUSION: Although DIZ101 or DIZ102 causes approximately four times higher plasma carbidopa levels than LCIG, patients responded equally well to all treatments. The results do not indicate that high plasma carbidopa levels hamper the motor efficacy of levodopa.

Noninvasive assessment of glymphatic dysfunction in idiopathic normal pressure hydrocephalus with diffusion tensor imaging.

OBJECTIVE: Diffusion tensor imaging (DTI) along the perivascular space (ALPS) (DTI-ALPS)-by calculating the ALPS index, a ratio accentuating water diffusion in the perivascular space-has been proposed as a noninvasive, indirect MRI method for assessing glymphatic function. The main aim of this study was to investigate whether DTI-ALPS would reveal glymphatic dysfunction in idiopathic normal pressure hydrocephalus (iNPH) and whether the ALPS index was associated with disease severity. METHODS: Thirty iNPH patients (13 men; median age 77 years) and 27 healthy controls (10 men; median age 73 years) underwent MRI and clinical assessment with the Timed Up and Go test (TUG) and Mini-Mental State Examination (MMSE); only the patients were evaluated with the Hellström iNPH scale. MRI data were analyzed with the DTI-ALPS method and Radscale screening tool. RESULTS: iNPH patients showed significantly lower mean ALPS index scores compared with healthy controls (median [interquartile range] 1.09 [1.00-1.15] vs 1.49 [1.36-1.59], p < 0.001). Female healthy controls showed significantly higher ALPS index scores than males in both hemispheres (e.g., right hemisphere 1.62 [1.47-1.67] vs 1.33 [1.14-1.41], p = 0.001). This sex difference was not seen in iNPH patients. The authors found a moderate exponential correlation between mean ALPS index score and motor function as measured with time required to complete TUG (r = -0.644, p < 0.001), number of steps to complete TUG (r = -0.571, p < 0.001), 10-m walk time (r = -0.637, p < 0.001), and 10-m walk steps (r = -0.588, p < 0.001). The authors also found a positive linear correlation between mean ALPS index score and MMSE score (r = 0.416, p = 0.001). Simple linear regression showed a significant effect of diagnosis (B = -0.39, p < 0.001, R2 = 0.459), female sex (B = 0.232, p = 0.002, R2 = 0.157), and Evans index (B = -4.151, p < 0.001, R2 = 0.559) on ALPS index. Multiple linear regression, including diagnosis, sex, and Evans index score, showed a higher predictive value (R2 = 0.626) than analysis of each of these factors alone. CONCLUSIONS: The ALPS index, which was significantly decreased in iNPH patients, could serve as a marker of disease severity, both clinically and in terms of neuroimaging. However, it is important to consider the significant influence of biological sex and ventriculomegaly on the ALPS index, which raises the question of whether the ALPS index solely reflects glymphatic function or if it also encompasses other types of injury. Future studies are needed to address potential confounding factors and further validate the ALPS method.

Neural suppression in odor recognition memory.

Little is known about the neural basis of lower- and higher-order olfactory functions such as odor memory, compared with other sensory systems. The aim of this study was to explore neural networks and correlates associated with 3 functions: passive smelling (PS), odor encoding (OE), and in particular odor recognition memory (ORM). Twenty-six healthy participants were examined using functional magnetic resonance imaging conducted across 3 sessions, one for each function. Independent component analysis revealed a difference between sessions where a distinct ORM component incorporating hippocampus and posterior cingulate showed delayed triggering dissociated from odor stimulation and recognition. By contrasting Hit for ORM (target odors correctly recognized as old) and a combination of PS and detected odors from OE, we found significantly lower activations in amygdala, piriform cortex, insula, thalamus, and the inferior parietal lobule. Region of interest analysis including anterior insula, posterior cingulate gyrus, dentate gyrus, left middle frontal gyrus, amygdala, and piriform cortex demonstrated that Hit were associated with lower activations compared with other memory responses. In summary, our findings suggest that successful recognition of familiar odors (odor familiarity) is associated with neural suppression in the abovementioned regions of interest. Additionally, network including the hippocampus and posterior cingulate is engaged in a postrecognition process. This process may be related to incidental encoding of less familiar and more novel odors (odor novelty) and should be subject for future research.

Worldwide estimation of restless legs syndrome: a systematic review and meta-analysis of prevalence in the general adult population.

This systematic review, meta-analysis and meta-regression assessed the prevalence of restless legs syndrome (RLS) in the general adult population. Studies identified in Scopus, PubMed, Web of Science, and PsycInfo between January 2000 and February 2022 were included if they used a case-control or cross-sectional design and reported data regarding the prevalence of RLS. The protocol was pre-registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022300709). A total of 97 studies including 483,079 participants from 33 different countries met the eligibility criteria. The Newcastle Ottawa Scale was used to evaluate the methodological quality, and the fill-and-trim method was used to correct probable publication bias, while the jack-knife method was performed to assess small study effect. The corrected overall pooled prevalence of RLS was 3% (95% confidence interval [CI] 1.4%-3.8%). The pooled prevalence of RLS syndrome was affected by methodological quality (no data from non-respondents in the included studies), gender (higher among women), study design (lower prevalence in case-control versus cohort and cross-sectional studies). The figures for corrected pooled prevalence among men, women, alcohol consumers and smokers were 2.8% (95% CI 2%-3.7%); 4.7% (95% CI 3.2%-6.3%); 1.4% (95% CI 0%-4.2%); and 2.7% (95% CI 0%-5.3%), respectively. The prevalence among male and female participants was lower in community-based versus non-community-based studies. Moreover, the prevalence was higher in developed versus developing countries and among elders versus adults. In conclusion, RLS is a common disorder in the general adult population, with a higher prevalence in women; however, prevalence data are affected by study design and quality.

Living conditions, lifestyle habits and health in the general population in spring 2020 and one year into the COVID-19 pandemic in Sweden - Results from two cross-sectional studies carried out in 2020 and 2021.

The aim of the study was to investigate mental and physical health as well as living conditions and lifestyle habits in the adult general population in spring 2020 and one year into the COVID-19 pandemic in Sweden comparing results from two cross-sectional studies carried out in February-May 2020 and 2021. The study population comprises 2,273 persons in 2020 and 2,216 persons in 2021 who responded to the national public health survey sent to random population samples in one county in Sweden. The age group was 16-84 years, and the response rates were 45% and 44%, respectively. Differences in living conditions (economic difficulties, social support and worrying about losing one's job), lifestyle habits (physical activity, daily smoking, sitting duration and alcohol use), and health (self-rated health, pain in shoulders or neck, sleeping difficulties, anxiety or worry, and obesity) between years 2020 and 2021 were analysed using multiple binary logistic regression in men and women, adjusting for age group and educational level. Very few statistically significant differences were observed between 2020 and 2021 regarding living conditions, lifestyle factors and health. The main finding was that the prevalence of anxiety and worry increased among women. Surveillance of the long-term public health consequences of the pandemic in the general population using robust data and methods, is important for planning and targeting preventive activities.

Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis: The RINOMAX Randomized Clinical Trial.

Importance: Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown. Objective: To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids. Interventions: Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo. Main Outcomes and Measures: Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment. Results: Of 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 [95% CI, 1.20-5.11]). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event. Conclusions and Relevance: A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02950155.

Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease.

BACKGROUND AND OBJECTIVES: Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson's disease. The primary objectives of this trial were to investigate if continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady state plasma concentrations of levodopa that are equivalent in magnitude, and non-inferior in variability, to those obtained with LCIG in patients with advanced Parkinson's disease. METHODS: A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved intestinal levodopa/carbidopa gel (LCIG) in a randomized, 3-period cross-over, open-label multicenter trial. Formulations were infused for 16h to patients with Parkinson's disease who were using LCIG as their regular treatment. Patients were recruited at several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and non-inferior variability of DIZ101 and DIZ102 versus LCIG with respect to levodopa plasma concentrations. RESULTS: With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits when compared to LCIG in the 18 participants that received all treatments. While the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Due to poor uptake with LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n=20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient. DISCUSSION: It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa containing solution. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03419806. Registration first posted 5 Feb 2018, first patient enrolled 16 Feb 2018. Link to registration.

Impact of Ankle Brachial Index Calculations on Peripheral Arterial Disease Prevalence and as a Predictor of Cardiovascular Risk.

OBJECTIVE: The aim of this study was to estimate the prevalence and predictive accuracy for cardiovascular (CV) morbidity by using different ankle brachial index (ABI) calculation methods in the general population. METHODS: ABI measurements and questionnaire data were collected from 5 080 randomly selected citizens aged 60 - 90 years. A 10 year follow up with data from Swedish national health registries was carried out. ABI was calculated using as numerator the highest (ABI-HI) or the lowest (ABI-LO) ankle BP obtained in each leg. Subjects were defined as references or having peripheral arterial disease (PAD) based on ABI-LO (Group 1) or ABI-HI (Group 2). Prevalence, mortality, CV events and risk were then analysed for these three groups, and their predictive power by using the area under the curve (AUC). RESULTS: A total of 4 909 inhabitants were included in the cohort (References: 83.8%, Group 1: 6.7% and Group 2: 9.6%). The prevalence of PAD was 16% using ABI-LO, and 9.6% using ABI-HI. The 10 year all cause mortality for references and Groups 1 and 2 was 27.6%, 48.8%, and 67.2%, respectively. The overall age adjusted hazard ratio (95% confidence interval) for the composite outcome of CV mortality and a non-fatal CV event was 1.25 (1.06 - 1.49) for Group 1 and 2.11 (1.85 - 2.39) for Group 2. The prediction accuracy for ABI < 0.9 in predicting CV event measured with AUC was 0.60 for ABI-HI and 0.62 for ABI-LO. CONCLUSION: An ABI < 0.9 should be considered a strong risk marker for future CV morbidity. Applying the traditional ABI calculation method of using the highest measured ankle BP, a group of subjects with high CV risk may be overlooked for intervention, and this why the lowest ankle BP should be the preferred for risk stratification. However, as a single predictive tool an ABI < 0.9 cannot adequately discriminate which individual will have a future CV event regardless of calculation method used.

Presence of asymptomatic Peripheral Arterial Disease in combination with common risk factors elevates the cardiovascular risk Substantially.

Background and aims: This study evaluates the risks for adverse cardiovascular (CV) events in Asymptomatic Peripheral Arterial Disease (APAD) combined with different traditional CV risk factors. Methods: A population-based observational study of 8000 subjects, identified 559 subjects as having APAD through ankle-brachial index (ABI) measurements and questionnaires regarding limb symptoms. This cohort and subgroups classified by presence of different traditional CV risk factors at baseline were assessed for 10 years on CV outcome. The recorded endpoints were all-cause mortality, CV mortality and non-fatal CV events. Results: Before subdividing the APAD subjects, the CV mortality incidence was 28.5 deaths per 1000 person-years as compared to 8.7 deaths for references without APAD. For subjects with hypertension at baseline the CV mortality incidence was 35.4 when combined with APAD and 11.7 without. In women with hypertension but without other risk factors, presence of APAD increased the age-adjusted Hazard Ratio (HR) for fatal and non-fatal CV events by 1.86 [CI 1.54,2.24, p < 0.001]. Conclusions: ABI measurements should be considered an important indication for aggressive multifactorial risk factor reduction in populations with any other prevalent CV risk factor. In hypertension, diabetes mellitus and a smoking history, coexisting APAD contributes significantly to the increased age-adjusted CV risk.

Physical Capacity and Activity in Patients With Idiopathic Normal Pressure Hydrocephalus.

Introduction: Most patients with idiopathic normal pressure hydrocephalus (iNPH) improve gait after surgery. However, knowledge on physical capacity and activity after shunt surgery is limited. One of the aims of this study was to evaluate the effect of shunt surgery in patients with iNPH on short-distance walking, functional exercise capacity, functional strength, and variables of activity and sleep, 3 and 6 months postoperatively. Another aim was to evaluate the effect of a physical exercise program. Additionally, we studied how changes in short-distance walking were correlated with functional exercise capacity and voluntary walking. Methods: In total, 127 patients were consecutively included and randomized to the exercise group (n = 62) or the control group (n = 65). Participants in the exercise group underwent the supervision of a 12-week exercise program. All patients were assessed before surgery, at 3 and 6 months postoperatively with the 10-m walk test (10MWT), the 6-min walk test (6MWT), 30-s chair stand test (30sCST), and with the actigraphic recordings of activity variables measured for a total of 24 h/day for at least 3 days. Results: All patients improved at 3 months postoperatively in the 10MWT (p < 0.001), 6MWT (p < 0.001), and 30sCST (p < 0.001). These results were maintained after 6 months. Actigraphic recordings for voluntary walking (steps per minute) were improved and nighttime sleep (%) increased after 6 months (p = 0.01, p = 0.04). There were no significant differences between the exercise group and the control group, except for the postoperative change in the proportion of daytime sleep after 3 months, which was slightly more reduced compared to baseline in the exercise group (p = 0.04). Changes after 3 months in the 10MWT and 6MWT were moderately correlated (ρ= -0.49, p = 0.01) whereas the correlation between the 10MWT and voluntary walking was weak (ρ = -0.34, p = 0.01). Conclusion: Shunt surgery improved short-distance walking, functional exercise capacity, functional strength, and voluntary walking. An exercise program did not affect these outcomes. Short-distance walking was weakly correlated with voluntary walking, indicating improved physical capacity does not directly translate to increased physical activity. Further research should address how interventions should be tailored to promote physical activity after shunt surgery. Trial Registration: clinicaltrials.gov, Id: NCT02659111.

The demography of idiopathic normal pressure hydrocephalus: data on 3000 consecutive, surgically treated patients and a systematic review of the literature.

OBJECTIVE: The objective of this study was to describe the demographic characteristics of patients with idiopathic normal pressure hydrocephalus (iNPH) through an analysis of 3000 consecutive, surgically treated Swedish patients and a systematic review of the literature. METHODS: Data on age, sex, comorbidities, diagnostic delay, initial symptoms, and severity of symptoms at diagnosis were extracted from the Swedish Hydrocephalus Quality Registry. In addition, a systematic PRISMA-based review of the literature published from database inception until August 2019 was performed using the PubMed, Cochrane, and Scopus databases on the basis of two concepts: normal pressure hydrocephalus and demography and their association with related terms. Of 1020 unique articles, 16 were eligible for study inclusion and were assessed for quality using the Newcastle-Ottawa Scale. Mean and weighted mean values were calculated. RESULTS: The mean patient age at the time of surgery was 74.4 years, 79% of patients were in their 70s, and 60% of the patients were men. Almost 50% of the patients had symptoms from four main domains (i.e., balance, gait, cognition, and urinary dysfunction) at disease onset. Patients aged < 60 years (2%) reported more headaches and fewer balance problems than those aged ≥ 60. Women were more impaired in function than men at the time of diagnosis. Dementia (Mini-Mental State Examination score < 25) was found in 47% of the patients. Men had more diabetes, heart disease, hypertension, and stroke than women, and comorbidity correlated with increased impairment. The incidence of surgery for iNPH was 20%-40% of the disease incidence according to survey and operation-based studies. CONCLUSIONS: Most iNPH patients undergo surgery in their 70s. Those aged < 60 years show slightly different symptomatology and probably present with a specific disease entity, indicating that the lower age limit for iNPH should be 60 years. iNPH patients have severe impairment preceded by a long diagnostic delay. Even though the included study designs differed, the systematic review showed that the disorder has a very low treatment incidence. The importance of diagnosing and treating iNPH is further emphasized by the fact that iNPH may account for a considerable part of all cases of dementia.

The a' velocity by tissue-Doppler echocardiography correlates to invasive mean left atrial pressure in patients with normal ejection fraction.

OBJECTIVES: To evaluate the correlation of a' velocity by tissue-Doppler measurements with invasively measured mean left atrial pressure in patients with normal ejection fraction. DESIGN: In this retrospective study, we evaluated the septal a', lateral a' and average a' velocity by tissue-Doppler echocardiography, in 125 in-hospital patients, 1-12 h before an elective pulmonary vein isolation due to intermittent atrial fibrillation, and compared to invasively measured mean left atrial pressure (LAP) during the invasive procedure. The patients, aged 35-81 years, had to be in sinus rhythm at both examinations, no atrial fibrillation during two procedures, no or mild valve disease and normal ejection fraction (>50%). RESULTS: Invasively measured mean LAP correlated well to septal a' (r = -0.435), lateral a' (r = -0.473) and average a' velocity (r = -0.491). Normal mean LAP (≤12 mmHg) was found in 95 patients and elevated mean LAP (>12 mmHg) in 30 patients. The patients with elevated mean LAP had a lower septal a' velocity (6.5 ± 2.7 vs 8.6 ± 2.3 cm/s; p < .01), lateral a' velocity (5.9 ± 2.3 vs 8.6 ± 2.1 cm/s; p < .01) and average a' velocity (6.2 ± 2.4 vs 8.8 ± 2.1 cm/s; p < .01) compared to patients with normal mean LAP. Septal a', lateral a' and average a' velocity were good predictors of elevated mean LAP with AUC of 0.78, 0.83 and 0.82. Average a' velocity with cut-off < 7.25 cm/s had a sensitivity of 83% and a specificity of 77% to predict elevated mean LAP. CONCLUSION: The a' velocity is a good indicator of mean LAP and might be considered in the evaluation of left ventricle filling pressure in patients with normal ejection fraction.

The timed up and go test in idiopathic normal pressure hydrocephalus: a Nationwide Study of 1300 patients.

BACKGROUND: The aim of this study was to describe the outcome measure timed up and go (TUG) in a large, nationwide cohort of patients with idiopathic normal pressure hydrocephalus (iNPH) pre- and post-operatively. Furthermore, to compare the TUG test to the 10-m walk test (10MWT), the iNPH scale, the modified Rankin scale (mRS) and the Mini Mental State Examination (MMSE), which are commonly applied in clinical assessment of iNPH. METHODS: Patients with iNPH (n = 1300), registered in the Swedish Hydrocephalus Quality Registry (SHQR), were included. All data were retrieved from the SHQR except the 10MWT, which was collected from patient medical records. Clinical scales were examined pre- and 3 months post-operatively. Data were dichotomised by sex, age, and preoperative TUG time. RESULTS: Preoperative TUG values were 19.0 [14.0-26.0] s (median [IQR]) and 23 [18-30] steps. Post-operatively, significant improvements to 14.0 [11.0-20.0] s and 19 [15-25] steps were seen. TUG time and steps were higher in women compared to men (p < 0.001) but there was no sex difference in improvement rate. Worse preoperative TUG and younger age favoured improvement. TUG was highly correlated to the 10MWT, but correlations of post-operative changes were only low to moderate between all scales (r = 0.22-0.61). CONCLUSIONS: This study establishes the distribution of TUG in iNPH patients and shows that the test captures important clinical features that improve after surgery independent of sex and in all age groups, confirming the clinical value of the TUG test. TUG performance is associated with performance on the 10MWT pre- and post-operatively. However, the weak correlations in post-operative change to the 10MWT and other established outcome measures indicate an additional value of TUG when assessing the effects of shunt surgery.

Physical exercise and goal attainment after shunt surgery in idiopathic normal pressure hydrocephalus: a randomised clinical trial.

BACKGROUND: Rehabilitation in iNPH is suggested to be an important factor to improve patients' functions but there are lack of clinical trials evaluating the effect of rehabilitation interventions after shunt surgery in iNPH. The objective of this study was to evaluate the effect of a physical exercise programme and goal attainment for patients with idiopathic normal pressure hydrocephalus (iNPH) after surgery compared to a control group. METHODS: This was a dual centre randomised controlled trial with assessor blinding, intention-to-treat (ITT) and per protocol (PP) analysis. Individuals diagnosed with iNPH scheduled to undergo shunt surgery at the Linköping University Hospital in Linköping and Sahlgrenska University Hospital in Gothenburg, Sweden were consecutively eligible for inclusion. Inclusion was conducted between January 2016 and June 2018. The patients were randomised 1:1 using sequentially numbered sealed envelopes to receive either written exercise information (control group) or written information and an additional supervised high-intensity, functional exercise programme (HIFE) executed twice weekly over 12 weeks (exercise group). Preoperatively, the patients set individual goals. The primary outcome was change from baseline in the total iNPH scale score at the post-intervention follow-up. Secondary outcomes were goal attainment, and change in the separate scores of gait, balance, neuropsychology and continence and in the total score after 6 months. RESULTS: In total, 127 participants were randomised to the exercise group (n = 62) and to the control group (n = 65). In the ITT population (exercise group, n = 50; control group, n = 59), there were no between-group differences in the primary outcome, but the attrition rate in the exercise group was high. The exercise group improved more than the control group in the balance domain scores after 6 months. Post-intervention, the PP exercise population achieved their set goals to a greater extent than the controls. CONCLUSIONS: An additional effect of the 12-week HIFE-programme on the overall improvement according to the iNPH-scale after shunt surgery in iNPH was not shown. This could be due to high attrition rate. However, the long-term effect on balance and higher goal achievement indicate beneficial influences of supervised physical exercise. Trial registration clinicaltrials.gov, NCT02659111. Registered 20 January 2016, https://clinicaltrials.gov/ct2/show/NCT02659111.

Higher rate of SARS-CoV-2 IgG seropositivity in hospital-based healthcare workers compared to elderly care staff in a Swedish low-prevalence region: a cross-sectional study.

BACKGROUND: Previous seroprevalence studies have demonstrated higher anti-SARS-CoV-2 IgG seroprevalence in healthcare workers (HCWs) than in the background population during the first phase of the 2020 COVID-19 pandemic. These studies, however, focussed mainly on hospital employees. AIM: To perform a cross-sectional study comparing the seroprevalence of hospital-based HCWs with those employed in elderly care (home care and nursing homes). METHODS: Employees (n = 4955) in the county of Värmland, Sweden, were recruited between weeks 27 and 42 and tested for IgG antibodies against SARS-CoV-2. Serological results were combined with self-reported questionnaire data. FINDINGS: IgG seroprevalence was 5.7% in the total group of HCWs, and was higher among those employed in hospital-based healthcare than among those working in elderly care (8.4% vs. 3.7%, p < .001). Being employed as an assistant nurse, working in a COVID-19 unit, and being exposed via co-workers or private acquaintances were all associated with IgG seropositivity. CONCLUSION: The difference in seroprevalence between HCWs in the two settings suggests that not only the profession but also factors in the workplace environment may be of importance. As all studied exposures were associated with IgG seropositivity, and asymptomatic infection was detected in 7.5% of participants, preventing outbreaks among HCWs is challenging. Adequate use of personal protective equipment when working with patients regardless of COVID-19 status, source control in situations with co-workers in which distancing is not possible, and routines enabling symptomatic staff to isolate pending PCR results are required to prevent healthcare-associated outbreaks of COVID-19.

Patient-Reported Symptom Severity in a Nationwide Myasthenia Gravis Cohort: Cross-sectional Analysis of the Swedish GEMG Study.

OBJECTIVES: To describe Myasthenia Gravis-Activities of Daily Living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort. METHODS: In a cross-sectional prevalent cohort study, the Genes and Environment in Myasthenia Gravis study (GEMG), performed November 2018 - August 2019, Myasthenia gravis (MG) patients were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early onset MG (EOMG, <50 years), late onset MG (LOMG, ≥50 years) or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sex and different MG-ADL scores. RESULTS: A total of 1077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n=1035) ranged from 0-18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity and diagnostic delay (OR=1.62, 1.72 and 1.69, P adj=0.017, 0.013 and 0.008) and inversely correlated with high educational attainment (OR=0.59, P adj=0.02), but not with age at inclusion, disease subtype nor disease duration. Almost half the population (47%) reported MG-ADL ≥3p, corresponding to an unsatisfactory symptom state. CONCLUSIONS: In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, we observe that almost half of patients report current disease symptoms associated to an unsatisfactory symptom state, indicating the need for improved treatment options.

Evaluating the cerebrospinal fluid tap test with the Hellström iNPH scale for patients with idiopathic normal pressure hydrocephalus.

BACKGROUND: The cerebrospinal fluid tap test (CSF TT) is used for selecting shunt surgery candidates among patients with idiopathic normal pressure hydrocephalus (iNPH). We aimed to evaluate the predictive value of the CSF TT, by using the Hellström iNPH scale for shunted iNPH patients with a standardized method. METHODS: One hundred and sixteen shunt-operated iNPH patients were retrospectively included in this study. The gait and balance domains in the iNPH scale were used as outcome measures for the CSF TT and the total iNPH scale score as the postoperative outcome. A positive response to CSF TT was defined as a change of ≥ 5 points in the gait domain and ≥ 16 points in the balance domain. Differences between CSF TT responders and non-responders, sensitivity, specificity, positive and negative predictive values, accuracy, and correlations between changes from baseline to post CSF TT and from baseline to the postoperative follow-up, were calculated. RESULTS: In the CSF TT there were 63.8% responders in the gait domain and correspondingly 44.3% in the balance domain. CSF TT responders had a significantly better postoperative outcome in the total scale score (gait P ≤ 0.001, balance P ≤ 0.012) and gait CSF TT responders improved more in gait (P ≤ 0.001) and balance CSF TT responders in balance (P ≤ 0.001). No differences between CSF TT gait or balance responders could be found in neuropsychological or urinary continence assessments postoperatively. The sensitivity and specificity of the CSF TT and the outcome of the total iNPH scale score postoperatively were 68.1% and 52.0% for gait and 47.8% and 68.0% for balance, respectively. CONCLUSIONS: The CSF TT, with the Hellström iNPH scale as the outcome measure, has clear limitations in predicting postoperative results. The gait domain may be used to predict outcomes for gait, but the balance domain is too insensitive.

Optical Coherence Tomography Revealing Ganglion Cell Loss in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Although there may theoretically be a disturbance in the eye or the visual pathways due to abnormal cerebrospinal fluid (CSF) dynamics in idiopathic normal pressure hydrocephalus (iNPH), it has not been studied systemically. Optical coherence tomography (OCT) is a noninvasive, reproducible procedure for quantitative and qualitative analysis of retinal morphology. METHODS: OCT was used to study the eye fundus before and after a CSF tap test in patients with iNPH compared with healthy individuals (HIs). Twelve patients with iNPH (6 females and 6 males) with a median age of 76 years (64-84 years) and 21 HIs (11 females and 10 males) with a median age of 73 years (64-79 years) were included. The patients underwent neurological, cognitive, and physiotherapeutic evaluation. Brain magnetic resonance imaging, CSF tap test via lumbar puncture, and subsequently CSF analysis were performed. OCT was performed before and after CSF removal. HIs underwent OCT once. RESULTS: The patients had significantly reduced retinal ganglion cell layer thickness 71 µm (56-81 µm) compared with the HIs, 79.5 µm (72-90 µm) (P = 0.001), but no significant changes were observed before or after the CSF tap test. All patients improved in motor function in a 10-m walk test after the CSF tap test. The median CSF pressure was 15 and 1 cm H2O, respectively, before and after lumbar puncture with removal of median 43.5 mL CSF. CONCLUSIONS: This pilot study shows OCT findings that differ from HIs and implies a rational for becoming a valuable tool in the diagnosis of iNPH. Further studies are warranted to elucidate the pathology of the retina in iNPH.

Publisher Correction: Indication of Thalamo-Cortical Circuit Dysfunction in Idiopathic Normal Pressure Hydrocephalus: A Diffusion Tensor Imaging Study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Indication of Thalamo-Cortical Circuit Dysfunction in Idiopathic Normal Pressure Hydrocephalus: A Tensor Imaging Study.

Idiopathic normal pressure hydrocephalus (iNPH) is a disorder with unclear pathophysiology. The diagnosis of iNPH is challenging due to its radiological similarity with other neurodegenerative diseases and ischemic subcortical white matter changes. By using Diffusion Tensor Imaging (DTI) we explored differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in iNPH patients (before and after a shunt surgery) and healthy individuals (HI) and we correlated the clinical results with DTI parameters. Thirteen consecutive iNPH-patients underwent a pre- and post-operative clinical work-up: 10 m walk time (w10mt) steps (w10ms), TUG-time (TUGt) and steps (TUGs); for cognitive function MMSE. Nine HI were included. DTI was performed before and 3 months after surgery, HI underwent DTI once. DTI differences analyzed by manually placing 12 regions-of-interest. In patients motor and balance function improved significantly after surgery (p = 0.01, p = 0.025). Higher nearly significant FA values found in the patients vs HI pre-operatively in the thalamus (p = 0.07) accompanied by an almost significant lower ADC (p = 0.08). Significantly FA and ADC-values were found between patients and HI in FWM (p = 0.02, p = 0.001) and almost significant (p = 0.057) pre- vs postoperatively. Postoperatively we found a trend towards the HIs FA values and a strong significant negative correlation between FA changes vs. gait results in the FWM (r = -0.7, p = 0.008). Our study gives a clear indication of an ongoing pathological process in the periventricular white matter, especially in the thalamus and in the frontal white matter supporting the hypothesis of a shunt reversible thalamo-cortical circuit dysfunction in iNPH.