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Background and ObjectivesMyasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG.MethodsIn this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II–Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available atclinicaltrials.gov/ct2/show/NCT02473965.ResultsThe primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated.DiscussionIn this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different.Trial Registration InformationThe trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) andclinicaltrials.gov(identifierNCT02473965).Classification of EvidenceThis study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.

Study Design: Narrative review. Objectives: To discuss the current understanding of the natural history of degenerative cervical myelopathy (DCM). Methods: Literature review summarizing current evidence pertaining to the natural history and risk factors of DCM. Results: DCM is a common condition in which progressive arthritic disease of the cervical spine leads to spinal cord compression resulting in a constellation of neurological symptoms, in particular upper extremity dysfunction and gait impairment. Anatomical factors including cord-canal mismatch, congenitally fused vertebrae and genetic factors may increase individuals’ risk for DCM development. Non-myelopathic spinal cord compression (NMSCC) is a common phenomenon with a prevalence of 24.2% in the healthy population, and 35.3% among individuals >60 years of age. Clinical radiculopathy and/or electrophysiological signs of cervical cord dysfunction appear to be risk factors for myelopathy development. Radiological progression of incidental Ossification of the Posterior Longitudinal Ligament (OPLL) is estimated at 18.3% over 81-months and development of myelopathy ranges between 0-61.5% (follow-up ranging from 40 to 124 months between studies) among studies. In patients with symptomatic DCM undergoing non-operative treatment, 20-62% will experience neurological deterioration within 3-6 years. Conclusion: Current estimates surrounding the natural history of DCM, particularly those individuals with mild or minimal impairment, lack precision. Clear predictors of clinical deterioration for those treated with non-operative care are yet to be identified. Future studies are needed on this topic to help improve treatment counseling and clinical prognostication.

Introduction The occurrence of obstructive sleep apnea (OSA) is strongly associated with obesity. Behavioral, pharmacological, and surgical interventions that promote weight reduction can reduce OSA severity and improve other common obesity related complications and quality of life. While the relationship between weight reduction and apnea-hypopnea index (AHI) improvement has been documented, it does not seem to have been quantified adequately. The objective of this analysis was to quantify the association between percent change in body weight and percent change in AHI using results from the literature. Methods A literature search identified 13 studies with AHI and weight measurements before and after weight intervention in people living with obesity and OSA; 6 studies from bariatric surgery, 4 studies from diet and exercise intervention, and 3 studies from anti-obesity medications (including 2 placebo-controlled randomized clinical trials). A polynomial and a linear meta regression model as well as 95% prediction intervals were used to assess the relationship between % weight change from baseline and % change in AHI from baseline. Results Both the polynomial and linear models show, on average, weight reduction in patients living with obesity and OSA has a clinical benefit in reducing AHI. The linear meta-regression model that we developed suggests a mean AHI decrease of 2.6% per 1% weight reduction. As the prediction intervals are relatively wide, a precise relationship could not be established. For example, based on the linear model for a patient with 20% weight reduction we expect to see a mean 52.8% reduction in AHI with a 95% prediction interval (89.8%, 15.8%) AHI reduction. Conclusion Evidence shows that intentional weight reduction in people living with obesity and OSA results in improvements in OSA severity, and this was confirmed by our meta-analysis and modeling. The model shows that the degree of AHI improvement is dependent on the magnitude of weight reduction. However, establishing a precise relationship between percent change in AHI and percent weight reduction is challenging given the sparsity of data, variability in populations studied, and variability in AHI change following weight reduction. Support (if any) Eli Lilly and Company

Introduction Weight reduction is a standard recommended component of OSA treatment in people with obesity or overweight; however, the challenge to achieve and maintain weight reduction has limited its clinical application outside of the benefit established after bariatric surgery. Currently no FDA-approved anti-obesity medication (AOM) has demonstrated clinically meaningful improvement in OSA severity and symptomology. Methods Tirzepatide is a single molecule GIP and GLP-1 receptor agonist. In SURMOUNT-1, a 72-week phase 3 clinical trial in participants with obesity or overweight, tirzepatide 15mg provided average reductions in body weight of 22.5% which occurred with beneficial effects on blood pressure, lipids, and physical functioning. In a linear meta regression model, we estimated that tirzepatide treatment would provide clinically meaningful apnea-hypopnea index decrease compared to placebo-treated participants with obesity and OSA. SURMOUNT-OSA, a placebo controlled 52-week, phase 3 trial, will investigate efficacy and safety of tirzepatide for the treatment of moderate to severe OSA (defined as AHI ≥15) in participants with obesity. SURMOUNT-OSA utilizes an umbrella master protocol and 2 Intervention-Specific Appendices (ISAs): ISA 1 includes participants with no current OSA treatment and ISA 2 includes participants using positive airway pressure therapy. Approximately 412 participants will be randomly assigned to placebo or tirzepatide across the entire master protocol, with approximately 206 participants in each ISA. While participants will receive tirzepatide or placebo based on a 1:1 randomization ratio, all participants will receive background lifestyle intervention for weight reduction. Results The primary endpoint for the individual ISAs is the difference in AHI response measured by polysomnography between tirzepatide and placebo arms at week 52. Secondary endpoints include hypoxic burden, functional outcomes and cardiometabolic biomarkers. The trial is utilizing a unique hierarchical functional outcomes endpoint based on Functional Outcomes of Sleep Questionnaire methodology. The trial employs wearables, such as home sleep testing and accelerometry to capture time to improvement as exploratory outcomes. Conclusion SURMOUNT-OSA aims to explore whether tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting an underlying etiology. Support (if any) Eli Lilly

BACKGROUND Despite the high prevalence of depression and anxiety in chronic pain conditions, current knowledge concerning emotional distress among painful diabetic polyneuropathy (pDSPN) and other diabetes mellitus (DM) sufferers is limited. METHODS This observational multicentre cohort study employed the Hospital Anxiety and Depression Scale, the Beck Depression Inventory II and the State-Trait Anxiety Inventory to assess symptoms of depression and anxiety in several groups with diabetes, as well as in a control group. The study cohort included 347 pDSPN patients aged 63.4 years (median), 55.9% males; 311 pain-free diabetic polyneuropathy (nDSPN) patients aged 63.7 years, 57.9% males; 50 diabetes mellitus (DM) patients without polyneuropathy aged 61.5 years, 44.0% males; and 71 healthy controls (HC) aged 63.0 years, 42.3% males. The roles played in emotional distress were explored in terms of the biological, the clinical (diabetes-, neuropathy- and pain-related), the socio-economic and the cognitive factors (catastrophizing). RESULTS The study disclosed a significantly higher prevalence of the symptoms of depression and anxiety not only in pDSPN (46.7% and 60.7%, respectively), but also in patients with nDSPN (24.4% and 44.4%) and DM without polyneuropathy (22.0% and 30.0%) compared with HCs (7.0% and 14.1%, p

ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

Study Design Literature Review (Narrative) Objective To propose a new framework, to support the investigation and understanding of the pathobiology of DCM, AO Spine RECODE-DCM research priority number 5. Methods Degenerative cervical myelopathy is a common and disabling spinal cord disorder. In this perspective, we review key knowledge gaps between the clinical phenotype and our biological models. We then propose a reappraisal of the key driving forces behind DCM and an individual’s susceptibility, including the proposal of a new framework. Results Present pathobiological and mechanistic knowledge does not adequately explain the disease phenotype; why only a subset of patients with visualized cord compression show clinical myelopathy, and the amount of cord compression only weakly correlates with disability. We propose that DCM is better represented as a function of several interacting mechanical forces, such as shear, tension and compression, alongside an individual’s vulnerability to spinal cord injury, influenced by factors such as age, genetics, their cardiovascular, gastrointestinal and nervous system status, and time. Conclusion Understanding the disease pathobiology is a fundamental research priority. We believe a framework of mechanical stress, vulnerability, and time may better represent the disease as a whole. Whilst this remains theoretical, we hope that at the very least it will inspire new avenues of research that better encapsulate the full spectrum of disease.

Background Serum antibodies to myelin-oligodendrocyte glycoprotein (MOG) are biomarkers of MOG-IgG-associated disorder (MOGAD), a demyelinating disease distinct from both multiple sclerosis and aquaporin-4-IgG neuromyelitis optica spectrum disorder. The phenotype of MOGAD is broad and includes optic neuritis, transverse myelitis, and acute demyelinating encephalomyelitis. Myelitis is common with MOGAD and typically results in acute and severe disability, although prospects for recovery are often favorable with prompt immunotherapy. Case presentation This contribution presents a unique case report of a young male patient exhibiting relapsing myelitis with normal spinal cord and brain magnetic resonance imaging. Comprehensive diagnostic assessment revealed myelin-oligodendrocyte glycoprotein-IgG-associated disorder. Conclusion MOGAD is one of the conditions which should be considered in MRI-negative myelitis. The diagnosis, however, may prove difficult, especially if the patient is not exhibiting other neurological symptoms of MOGAD. Conus or epiconus involvement is common in MOGAD; the patient reported herein exhibited incomplete rostral epiconus symptoms which, together with somatosensory evoked potential abnormalities, led to the diagnosis.

In this multicenter cross-sectional study, we determined sensory profiles of patients with (NL-1) and without neuropathic pain (NL-0) after nerve lesion and assessed immune-related systemic gene expression. Patients and matched healthy controls filled in questionnaires and underwent neurological examination, neurophysiological studies, quantitative sensory testing, and blood withdrawal. Neuropathic pain was present in 67/95 (71%) patients (NL-1). Tactile hyperalgesia was the most prominent clinical sign in NL-1 patients (P < 0.05). Questionnaires showed an association between neuropathic pain and the presence of depression, anxiety, and catastrophizing (P < 0.05 to P < 0.01). Neuropathic pain was frequently accompanied by other chronic pain (P < 0.05). Quantitative sensory testing showed ipsilateral signs of small and large fiber impairment compared to the respective contralateral side, with elevated thermal and mechanical detection thresholds (P < 0.001 to P < 0.05) and lowered pressure pain threshold (P < 0.05). Also, more loss of function was found in patients with NL-1 compared to NL-0. Pain intensity was associated with mechanical hyperalgesia (P < 0.05 to P < 0.01). However, quantitative sensory testing did not detect or predict neuropathic pain. Gene expression of peptidylglycine α-amidating monooxygenase was higher in NL patients compared with healthy controls (NL-1, P < 0.01; NL-0, P < 0.001). Also, gene expression of tumor necrosis factor-α was higher in NL-1 patients compared with NL-0 (P < 0.05), and interleukin-1s was higher, but IL-10 was lower in NL-1 patients compared with healthy controls (P < 0.05 each). Our study reveals that nerve lesion presents with small and large nerve fiber dysfunction, which may contribute to the presence and intensity of neuropathic pain and which is associated with a systemic proinflammatory pattern.

Complex regional pain syndrome (CRPS) typically develops after fracture or trauma. Many of the studies so far have analyzed clinical and molecular markers of CRPS in comparison with healthy or pain controls. This approach, however, neglects mechanisms occurring during physiological trauma recovery. Therefore, we compared the clinical phenotype, sensory profiles, patient-reported outcomes, and exosomal immunobarrier microRNAs (miRs) regulating barrier function and immune response between CRPS and fracture controls (FCs) not fulfilling the CRPS diagnostic criteria. We included upper-extremity FCs, acute CRPS I patients within 1 year after trauma, a second disease control group (painful diabetic polyneuropathy), and healthy controls. Fracture controls were not symptoms-free, but reported some pain, disability, anxiety, and cold pain hyperalgesia in quantitative sensory testing. Patients with CRPS had higher scores for pain, disability, and all patient-reported outcomes. In quantitative sensory testing, ipsilateral and contralateral sides differed significantly. However, on the affected side, patients with CRPS were more sensitive in only 3 parameters (pinprick pain and blunt pressure) when compared to FCs. Two principal components were identified in the cohort: pain and psychological parameters distinguishing FC and CPRS. Furthermore, the immunobarrier-protective hsa-miR-223-5p was increased in plasma exosomes in FCs with normal healing, but not in CRPS and healthy controls. Low hsa-miR-223-5p was particularly observed in subjects with edema pointing towards barrier breakdown. In summary, normal trauma healing includes some CRPS signs and symptoms. It is the combination of different factors that distinguish CRPS and FC. Fracture control as a control group can assist to discover resolution factors after trauma.

Complex regional pain syndrome (CRPS) develops after fracture. The acute CRPS phenotype resembles exaggerated inflammation, which is explained by local and systemic activation of a proinflammatory network including peptides and cytokines. Epidemiologic data suggest that inactivation of the peptidase angiotensin-converting enzyme in patients treated for hypertension increases the odds to develop CRPS. This hint leads us to investigate the serum protease network activity in patients with CRPS vs respective controls. For this purpose, we developed a dabsyl-bradykinin (DBK)-based assay and used it to investigate patients with CRPS, as well as healthy and pain (painful diabetic neuropathy [dPNP]) controls. The major result is that the degradation of DBK to fragments 1-8 and 1-5 in healthy control and dPNP is shifted to higher values for DBK1-8 and lower values for DBK1-5 at 1 hour of incubation in patients with CRPS. Using this novel reporter peptide assay, we have been able to show that the resolving protease network for mediators such as BK might be different in patients with CRPS; having a look at the clinical signs, which resemble inflammation, this resolving protease network is probably less effective in CRPS.

Background and Objective: Short- and long-term mortality following ischemic stroke (IS) and their predictors have not been defined in the Czech population, and studies on long-term mortality are largely missing for the populations of Central Europe. Methods: Using the National Register of Hospitalized Patients and the Czech National Mortality Registry, we analyzed data on 1-month, 1-year, and 3-year all-cause mortality for patients admitted with IS to any of the 4 hospitals with a certified stroke unit in Brno, Czech Republic, in 2011. We reviewed discharge summaries and recorded potential factors impacting mortality after the index stroke event. Using univariate and multivariable analyses, we identified predictors of mortality at all 3 time points. Results: In our multivariable model, statin use (odds ratio [OR] 0.095, p < 0.0001), age at stroke (OR 1.03, p = 0.0445), and admission National Institutes of Health Stroke Scale (NIHSS) score (OR 1.16, p < 0.0001) predicted 1-month mortality, while statin use (OR 0.43, p = 0.0004), history of cardiac failure (OR 2.17, p = 0.0137), age at stroke (OR 1.07, p < 0.0001), and admission NIHSS score (OR 1.14, p < 0.0001) predicted 1-year mortality. Statin use (OR 0.54, p = 0.0051), history of cardiac failure (OR 2.13, p = 0.0206), age at stroke (OR 1.07, p < 0.0001), and admission NIHSS score (OR 1.11, p < 0.0001) also predicted 3-year mortality. Conclusions: Our study is the first to report data on short- and long-term mortality rates and their predictors in patients hospitalized with IS in the Czech population. Our results indicate that mortality rates and predictors of mortality are consistent with those reported in studies from other populations throughout the world.

Impaired gait is one of the cardinal symptoms of degenerative cervical myelopathy (DCM) and frequently its initial presentation. Quantitative gait analysis is therefore a promising objective tool in the disclosure of early cervical cord impairment in patients with degenerative cervical compression. The aim of this cross-sectional observational cohort study was to verify whether an objective and easily-used walk and run test is capable of detecting early gait impairment in a practical proportion of non-myelopathic degenerative cervical cord compression (NMDCC) patients and of revealing any correlation with severity of disability in DCM. The study group consisted of 45 DCM patients (median age 58 years), 126 NMDCC subjects (59 years), and 100 healthy controls (HC) (55.5 years), all of whom performed a standardized 10-m walk and run test. Walking/running time/velocity, number of steps and cadence of walking/running were recorded, analysis disclosed abnormalities in 66.7% of NMDCC subjects. The DCM group exhibited significantly more pronounced abnormalities in all walk/run parameters when compared with the NMDCC group. These were apparent in 84.4% of the DCM group and correlated closely with disability as quantified by the modified Japanese Orthopaedic Association scale. A standardized 10-m walk/run test has the capacity to disclose locomotion abnormalities in NMDCC subjects who lack other clear myelopathic signs and may provide a means of classifying DCM patients according to their degree of disability.

Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p

Natalizumab is an effective therapy in the treatment of relapsing-remitting multiple sclerosis; it induces lymphocytosis (NIL, natalizumab-induced lymphocytosis) and changes the peripheral lymphocyte pattern. This study aims to evaluate NIL, peripheral blood lymphocyte subsets, CD4/CD8 ratio, and their impacts on JCV index and clinical data—No Evidence of Disease Activity (NEDA-3) and annualized relapse rate (ARR) in patients treated with natalizumab. Forty-one patients (33 women) were included in the study. The mean duration of follow-up on natalizumab treatment was 6.7 ± 3.2 years. Significant increases in relative lymphocytosis after 1 month, with a median of 40.4% (− 34.1 to + 145.5%) (p

Some muscular dystrophies may have a negative impact on fertility. A decreased ovarian reserve is 1 of the factors assumed to be involved in fertility impairment. AMH (anti-Müllerian hormone) is currently considered the best measure of ovarian reserve. A total of 21 females with myotonic dystrophy type 1 (MD1), 25 females with myotonic dystrophy type 2 (MD2), 12 females with facioscapulohumeral muscular dystrophy (FSHD), 12 female carriers of Duchenne muscular dystrophy mutations (cDMD) and 86 age-matched healthy controls of reproductive age (range 18 – 44 years) were included in this case control study. An enzymatically amplified 2-site immunoassay was used to measure serum AMH level. The MD1 group shows a significant decrease of AMH values (median 0.7 ng/mL; range 0 – 4.9 ng/mL) compared with age-matched healthy controls (P

Background Central neuropathic extremity pain (CNEP) is the most frequent type of pain in multiple sclerosis (MS). The aim of the present study was to evaluate sensory and pain modulation profiles in MS patients with CNEP. Methods In a single-centre observational study, a group of 56 CNEP MS patients was compared with 63 pain-free MS patients and with a sex- and age-adjusted control group. Standardized quantitative sensory testing (QST) and dynamic QST (dQST) protocols comprising temporal summation and conditioned pain modulation tests were used to compare sensory profiles. Results Loss-type QST abnormalities in both thermal and mechanical QST modalities prevailed in both MS subgroups and correlated significantly with higher degree of disability expressed as Expanded Disability Status Scale (EDSS). Comparison of sensory phenotypes disclosed a higher frequency of the 'sensory loss' prototypic sensory phenotype in the CNEP subgroup (30%) compared with pain-free MS patients (6%; p = .003). Conclusion The role of aging process and higher lesion load in the spinothalamocortical pathway might be possible explanation for pain development in this particular 'deafferentation' subtype of central neuropathic pain in MS. We were unable to support the role of central sensitization or endogenous facilitatory and inhibitory mechanisms in the development of CNEP in MS. Significance This article presents higher prevalence of the 'sensory loss' prototypic sensory phenotype in multiple sclerosis patients with central extremity neuropathic pain compared to pain-free patients. Higher degree of disability underlines the possible role of higher lesion load in the somatosensory pathways in this particular 'deafferentation' type of central neuropathic pain.

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

Background This retrospective cross-sectional study reports 1 month and 1 year intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) case fatality rates and their temporal trends in the Czech Republic between 1998 and 2015. Methods Utilizing the National Register of Hospitalized Patients, we randomly selected 600 patients hospitalized for ICH and 600 patients hospitalized for SAH for each year from 1998 to 2015, and identified those who died, regardless of cause, using the Czech National Mortality Registry. We calculated crude and age-adjusted 1 month and 1 year case fatality rates for ICH and SAH. Long-term trends of the crude rates were analyzed using a one-sided Cochran Armitage test. Results A total of 21,600 cases hospitalized for SAH and ICH (10,800 for each) between 1998 and 2015 were randomly selected for analysis. One month case fatality of SAH overall and in women has decreased by 0.2% (P = .006) and 0.3% per year (P = .04), respectively. Overall 1 year case fatality of SAH has decreased by 0.2% per year (P = .03). One month case fatality rate of ICH overall and in men has decreased by 0.2% (p=0.01) and 0.4% (P = .0007), respectively. One year case fatality of ICH in men has decreased by 0.2% per year (P = .047). Conclusions One month and 1 year case fatality rates for SAH and ICH have been decreasing in the Czech Republic between 1998 and 2015, and are similar or lower than those reported from other developed European countries.

Background It is not known if risk factors differ between ischemic stroke (IS) subtypes in Central and Eastern Europe. Aims We performed a community-based analysis of risk factors in patients admitted with IS over a 1 year period in Brno, the second largest city in the Czech Republic (CR). Methods Based on the National Register of Hospitalized Patients, all patients with IS admitted in Brno in 2011 were identified. Comprehensive discharge summaries from hospital admissions were collected and reviewed. IS subtype and relevant risk factors were ascertained for all patients. The age- and sex-adjusted association of risk factors with IS subtypes was determined. Results Overall, 682 patients with IS were admitted in 2011 to Brno hospitals. The distribution of IS subtypes was: 35% cardioembolism, 28% large-artery atherosclerosis, 23% small-artery occlusion, 7% stroke of undetermined etiology, 7% stroke of other determined etiology. Several of the risk factors showed high prevalence in the overall sample – e.g. hypertension (84%) and hyperlipidemia (61%). Cardioembolism as compared to other subtypes was positively associated with a history of myocardial infarction, cardiac failure, and atrial fibrillation. Small-artery occlusion was positively associated with history of dementia. No significant association was found between IS subtypes and history of IS, hypertension, diabetes, obesity, alcohol abuse or smoking. Conclusions We found high frequency of stroke risk factors in all IS subtypes. These findings have implications for stroke prevention strategies in the CR and across Central Europe.

Background Cervical vertigo (CV) is a grossly over-diagnosed entity although, in all probability, it does not exist. The aim of this study was to test following hypothesis: that even in patients with one of the most severe forms of cervical spondylosis, degenerative cervical myelopathy (DCM), stimulation of the cervical proprioceptors does not provoke or increase vertigo Methods The study was performed in a cohort of 38 patients with DCM confirmed by clinical manifestation and MRI-detected degenerative cervical cord compression. The incidental presence of vertigo in these patients was investigated by means of a questionnaire and a clinical neurological examination. The cervical torsion test (to stimulate cervical proprioceptors), and ultrasound examinations of the extracerebral carotid and vertebral arteries (to exclude impaired blood circulation in the cervical region) were performed. All patients with vertigo underwent a diagnostic work-up designed to reveal its cause. Results: Subjective symptoms of vertigo occurring in the six months previous to examination were reported by 18 patients (47%). None of these patients responded positively to the cervical torsion test, while highly probable explanations involving an etiology for vertigo other than from the cervical region were found in all patients suffering from it. No patient exhibited significant stenosis of the vertebral arteries. Conclusions: There were no clear signs of CV in the cohort of patients with DCM. If patients with cervical spondylosis suffer from vertigo, its cause may, more easily be explained by common and treatable etiologies that do not lie in the cervical region.

Supplemental Digital Content is available in the text, The aim of this observational, cross-sectional study was to analyse lumbar magnetic resonance imaging (MRI) findings in patients with non-specific chronic low back pain (CLBP), and to evaluate any correlation with pain intensity and their capacity to predict neuropathic pain (NP) in these patients. Fifty-two patients with non-specific CLBP, between 21 and 62 years of age, 50% men, were investigated. Lumbar MRI was employed to assess disc degeneration, endplate changes, Modic changes, disc displacement, facet degeneration, foraminal stenosis and central lumbar spinal stenosis. The characteristics of pain were evaluated and patients were divided into 2 subgroups: with NP (24 patients) and without NP (28 patients), based on the results of a DN4-interview. Correlations between particular MRI changes and their relations to the intensity of pain were evaluated. Logistic regression was used to disclose predictors of NP. Lumbar spine degenerative features were frequent in patients with non-specific CLBP, with L4/5 the most affected level. A significant correlation emerged between the severity of degenerative changes in particular lumbar spine structures (correlation coefficient ranging between 0.325 and 0.573), while no correlation was found between severity of degenerative changes and pain. Multivariate logistic regression revealed only 2 independent predictors of NP – female sex (odds ratio [OR] = 11.9) and a mean pain intensity of ≥4.5 in the previous 4 weeks (OR = 13.1). Degenerative changes in the lumbar spine are frequent MRI findings, but do not correlate with the intensity of pain and do not predict NP. However, female sex and pain intensity do predict NP.

(1) Background: Cervical vertigo (CV) represents a controversial entity, with a prevalence ranging from reported high frequency to negation of CV existence. (2) Objectives: To assess the prevalence and cause of vertigo in patients with a manifest form of severe cervical spondylosis–degenerative cervical myelopathy (DCM) with special focus on CV. (3) Methods: The study included 38 DCM patients. The presence and character of vertigo were explored with a dedicated questionnaire. The cervical torsion test was used to verify the role of neck proprioceptors, and ultrasound examinations of vertebral arteries to assess the role of arteriosclerotic stenotic changes as hypothetical mechanisms of CV. All patients with vertigo underwent a detailed diagnostic work-up to investigate the cause of vertigo. (4) Results: Symptoms of vertigo were described by 18 patients (47%). Causes of vertigo included: orthostatic dizziness in eight (22%), hypertension in five (14%), benign paroxysmal positional vertigo in four (11%) and psychogenic dizziness in one patient (3%). No patient responded positively to the cervical torsion test or showed significant stenosis of vertebral arteries. (5) Conclusions: Despite the high prevalence of vertigo in patients with DCM, the aetiology in all cases could be attributed to causes outside cervical spine and related nerve structures, thus confirming the assumption that CV is over-diagnosed.

Study Design.Cross-sectional population-based observational study.Objective.To estimate the prevalence of nonmyelopathic spondylotic cervical cord compression (NMSCCC) and cervical spondylotic myelopathy (CSM) in a population older than 40 years and to evaluate the magnetic resonance imaging (MRI) characteristics of these conditions.Summary of Background Data.The prevalence of neither NMSCCC nor CSM is known and there exists no commonly accepted quantitative MRI definition of cervical cord compression.Methods.A group of 183 randomly recruited volunteers, 93 women, median age 66 years, range 40-80 years, underwent MRI examination of the cervical spine and spinal cord on a 1.5 T device using conventional sequences from disc levels C2/C3 to C6/C7. The imaging criterion for cervical cord compression was defined as a change in spinal cord contour at the level of an intervertebral disc on axial or sagittal MRI scan.Results.MRI signs of cervical cord compression were found in 108 individuals (59.0%; 95% CI: 51.5%-66.2%); their numbers increased with age from 31.6% in the fifth decade to 66.8% in the eighth. Clinical signs of symptomatic CSM were found in two cases (1.1%), and 75 cases (41.0%) were without compression. An anteroposterior cervical canal diameter at the level of intervertebral disc (CDdisc) of less than 9.9 mm was associated with the highest probability of NMSCCCodds ratio (OR)=32.5, followed by a compression ratio of 0.5: OR=11.1.Conclusion.The prevalence of NMSCCC in a population older than 40 years is higher than previously reported and increases with age. CDdisc and compression ratio had the highest capacity to discriminate between subjects with and without asymptomatic compression, and their cut-off values could be used to objectify criteria for cervical cord compression.

Background and Purpose Administration of evidence-based pharmacotherapy improves stroke outcome while the use of non–evidence-based medications may not be of benefit and leads to unnecessary patient care costs. The aim of our study was to determine the frequency of guideline-approved and guideline-disapproved pharmacotherapy use in acute stroke management in the Czech Republic (CR). Methods Using the ICD-10 codes, 500 stroke and transient ischemic attack (TIA) patients were randomly selected (random selection of 10 hospitals and then 50 patients from each hospital) from the National Registry of Hospitalized Patients for strokes occurring in 2011. Discharge summaries were reviewed for medications prescribed during hospitalization and at discharge. Results Of the 500 requested discharge summaries, 484 were available for review (response rate 97%). Up to 479 (96%) summaries were sufficient for evaluation and of these, 393 were confirmed to have a stroke or TIA diagnosis. Brain imaging (computed tomography or magnetic resonance imaging) was performed in 97% of the 393 cases. Intravenous thrombolysis was administered to 7% of patients with ischemic stroke (rate was 0%-25% in different hospitals). Up to 97% of patients with ischemic events (TIA or ischemic stroke) were treated with antiplatelets or anticoagulants. At least 1 non–evidence-based medication was administered to 28% of the 393 patients (rate was 5%-89% in different hospitals). Conclusions Guideline-disapproved pharmacotherapy is common in stroke and TIA patients in the CR and processes should be put into place to lessen the frequency of their use. The use of guideline-approved medications is also high and should be further promoted.

This contribution reports the case of a young female patient with a cytotoxic T-lymphocyte antigen 4 (CTLA-4) heterozygous missense mutation giving rise to a broad range of autoimmune diseases, including central nervous system inflammation presenting as disseminated intramedullary and infiltrating brain lesions on MRI. Multiple sclerosis was one of the diagnoses considered. CTLA-4 is a negative immune regulator essential for the function of regulatory T-cells, themselves responsible for maintaining self-tolerance and immune homeostasis. Heterozygous germline mutations in CTLA-4 may lead to an autosomal dominant immune dysregulation syndrome with highly variable phenotype, including various immunodeficiency and autoimmune diseases, along with neurological manifestations.

Natalizumab-related progressive multifocal leukoencephalopathy (PML) is associated with the presence of anti-John Cunningham virus (JCV) antibodies. The aim of this investigation was to evaluate the long-term stability of anti-JCV antibody serum levels and their relation to various demographic, clinical and radiological characteristics in patients suffering from multiple sclerosis (MS).Seventy-eight relapsing-remitting MS patients treated with natalizumab and evaluated for the presence of serum anti-JCV antibodies over a time period of 1-6 years (3-11 samples) were included in the study. Anti-JCV antibody levels and their changes were correlated with various demographic, clinical and radiological findings.Median follow-up time was 43.5 months, with a median of 5.3 samples available per patient. At baseline, 46 (59%) of the patients were seropositive. During follow-up, anti-JCV antibody status changed from negative to positive or vice versa in 23% of patients. Baseline anti-JCV antibody index correlated positively with age (p = 0.03).with stable positive anti-JCV antibody index had more T2 hyperintensities (20.2 vs. 13.1; p 0.007) on cerebral magnetic resonance imaging (MRI) and were also older than the stable negative anti-JCV antibody index group of patients (45.2.vs. 40.3 years; p 0.01). No significant increase in T2 hyperintensities after seroconversion was revealed. Average duration from beginning of natalizumab therapy to seroconversion (n = 13) was 33 months. Annual seroconversion rate of anti-JCV antibody status was 6.5%. A baseline anti-JCV antibody index of0.90 (n = 33) predicted stable seropositivity (100%), while baseline anti-JCV antibody index0.20 did not predicted stable seronegativity (59%). PML was not diagnosed in any of the patients studied during the follow-up.A positive baseline anti-JCV antibody index of0.90 predicts stable positive JCV serostatus, in contrast with a baseline anti-JCV antibody index of0.20, which remained negative in 59% of cases. Stable positive anti-JCV index patients have more MRI T2 hyperintensities and are older compared with stable negative anti-JCV index patients.

Objectives: Assessment of neuropathic pain in chronic low back syndromes is important. However, there is currently no gold standard for its diagnosis. The aim of this observational cross-sectional study was to assess the neuropathic component of pain in various chronic low back pain syndromes using a range of diagnostic tests. Materials and Methods: Included in this study were 63 patients with chronic axial low back pain (ALBP), 48 patients with chronic radicular syndromes (CRS) comprising 23 with discogenic compression (CDRS) and 25 with lumbar spinal stenosis (LSS), and 74 controls. PainDETECT questionnaire (PDQ), quantitative sensory testing (QST), and skin biopsy with evaluation of intraepidermal nerve fiber density (IENFD) were used to assess the neuropathic pain component. Results: Positive PDQ (>= 19) was obtained more frequently in patients with CDRS and LSS (26.1% and 12.0%, respectively) compared with patients with ALBP (1.6%, P

Study design This was an observational cross-sectional study. Objective The purpose of this study was to evaluate whether the degree of stenosis on magnetic resonance imaging (MRI) relates to the severity of clinical symptoms, disability, or neurological deficit in patients with symptomatic central lumbar spinal stenosis (LSS). Summary of background data The relationship between radiologic findings and the clinical manifestations of LSS remains unclear. Materials and methods A total of 84 patients (42 men, median age 70 y) with neurogenic claudication and central degenerative LSS were included in the study. The MRI parameters describing severity (anteroposterior diameter of dural sac, cross-sectional area of the dural sac, stenosis ratio, and Schizas qualitative morphologic classification were evaluated at maximum stenotic level) and the extent of stenosis (the number of central stenotic levels) were correlated to symptoms (pain intensity, walking capacity), functional disability (measured in terms of the Oswestry Disability Index), and neurological signs of LSS (neurological status was evaluated and scored by Neurological Impairment Score in LSS). Results A statistically significant correlation emerged only between the Neurological Impairment Score in LSS and Schizas morphologic classification (P=0.006). Pain intensity, walking capacity, and functional disability displayed no correlation with the MRI parameters of LSS. Conclusions LSS is a clinicoradiologic syndrome with complex relationships between degree of radiologic stenosis disclosed by MRI and clinical manifestations. Neurological impairment in the lower extremities reflects the degree of morphologic LSS on MRI. This study did not identify any association between the degree of stenosis and functional disability, pain intensity, or walking capacity. Level of evidence Level II.

Aims This paper aims to investigate whether intraepidermal nerve-fibre density (IENFD) may be used as a marker of the course of neuropathy in patients with Type2 diabetes mellitus. Methods Skin biopsies from the distal leg were serially evaluated in a group of 30 patients with Type2 diabetes mellitus (median age 60years, 17 men) with a short duration of diabetes (2years (median 33.8months). Eighteen patients with Type2 diabetes mellitus had symptoms or signs of distal symmetrical diabetic polyneuropathy, 12 had no neuropathy. Results At first skin biopsy, IENFD was normal in all controls and in patients without neuropathy (mean 9.5 and 7.9fibres/mm, respectively) compared with abnormal IENFD in 77.8% in patients with polyneuropathy (mean 3.4fibres/mm). The annual rate of intraepidermal nerve-fibre (IENF) loss expressed as a percentage of the first IENFD value in patients with diabetic polyneuropathy was significantly higher [mean (se), 11.95 (3.82)%] compared with controls [1.92 (1.81)%, P

Background Stroke is a common cause of mortality and morbidity in Eastern Europe. However, detailed epidemiological data are not available. The National Registry of Hospitalized Patients (NRHOSP) is a nationwide registry of prospectively collected data regarding each hospitalization in the Czech Republic since 1998. As a first step in the evaluation of stroke epidemiology in the Czech Republic, we validated stroke cases in NRHOSP. Methods Any hospital in the Czech Republic with a sufficient number of cases was included. We randomly selected 10 of all 72 hospitals and then 50 patients from each hospital in 2011 stratified according to stroke diagnosis (International Classification of Diseases Tenth Revision [ICD-10] cerebrovascular codes I60, I61, I63, I64, and G45). Discharge summaries from hospitalization were reviewed independently by 2 reviewers and compared with NRHOSP for accuracy of discharge diagnosis. Any disagreements were adjudicated by a third reviewer. Results Of 500 requested discharge summaries, 484 (97%) were available. Validators confirmed diagnosis in NRHOSP as follows: transient ischemic attack (TIA) or any stroke type in 82% (95% confidence interval [CI], 79-86), any stroke type in 85% (95% CI, 81-88), I63/cerebral infarction in 82% (95% CI, 74-89), I60/subarachnoid hemorrhage in 91% (95% CI, 85-97), I61/intracerebral hemorrhage in 91% (95% CI, 85-96), and G45/TIA in 49% (95% CI, 39-58). The most important reason for disagreement was use of I64/stroke, not specified for patients with I63. Conclusions The accuracy of coding of the stroke ICD-10 codes for subarachnoid hemorrhage (I60) and intracerebral hemorrhage (I61) included in a Czech Republic national registry was high. The accuracy of coding for I63/cerebral infarction was somewhat lower than for ICH and SAH.

The aim of this prospective cross-sectional observational comparative study was to determine the prevalence of spondylotic cervical cord compression (SCCC) and symptomatic cervical spondylotic myelopathy (CSM) in patients with symptomatic lumbar spinal stenosis (LSS) in comparison with a general population sample and to seek to identify predictors for the development of CSM. A group of 78 patients with LSS (48 men, median age 66 years) was compared with a randomly selected age- and sex-matched group of 78 volunteers (38 men, median age 66 years). We evaluated magnetic resonance imaging findings from the cervical spine and neurological examination. The presence of SCCC was demonstrated in 84.6 % of patients with LSS, but also in 57.7 % of a sample of volunteers randomly recruited from the general population. Clinically symptomatic CSM was found in 16.7 % of LSS patients in comparison with 1.3 % of volunteers (p = 0.001). Multivariable logistic regression proposed the Oswestry Disability Index of 43 % or more as the only independent predictor of symptomatic CSM in LSS patients (OR 9.41, p = 0.008). The presence of symptomatic LSS increases the risk of SCCC; the prevalence of SCCC is higher in patients with symptomatic LSS in comparison with the general population, with an evident predominance of more serious types of MRI-detected compression and a clinically symptomatic form (CSM). Symptomatic CSM is more likely in LSS patients with higher disability as assessed by the Oswestry Disability Index.

Introduction: Small fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in critical care survivors. Methods: Eleven adult ischemic stroke patients in a neurocritical care unit were enrolled in an observational cohort study. Intraepidermal never fiber density (IENFD) in the distal leg was assessed on admission to the intensive care unit and 10-14 days later, together with electrophysiological testing. Results: Of the 11 patients recruited, 9 (82%) had sepsis or multiple organ failure. Median IENFD on admission (5.05 fibers/mm) decreased significantly to 2.18 fibers/mm (P

Different sensory profiles in diabetic distal symmetrical sensory-motor polyneuropathy (DSPN) may be associated with pain and the responsiveness to analgesia. We aimed to characterize sensory phenotypes of patients with painful and painless diabetic neuropathy and to assess demographic, clinical, metabolic, and electrophysiological parameters related to the presence of neuropathic pain in a large cohort of well-defined DSPN subjects. This observational cross-sectional multi-center cohort study (performed as part of the ncRNAPain EU consortium) of 232 subjects with nonpainful (n = 74) and painful (n = 158) DSPN associated with diabetes mellitus of type 1 and 2 (median age 63 years, range 21-87 years; 92 women) comprised detailed history taking, laboratory tests, neurological examination, quantitative sensory testing, nerve conduction studies, and neuropathy severity scores. All parameters were analyzed with regard to the presence and severity of neuropathic pain. Neuropathic pain was positively correlated with the severity of neuropathy and thermal hyposensitivity (P < 0.001). A minority of patients with painful DSPN (14.6%) had a sensory profile, indicating thermal hypersensitivity that was associated with less severe neuropathy. Neuropathic pain was further linked to female sex and higher cognitive appraisal of pain as assessed by the pain catastrophizing scale (P < 0.001), while parameters related to diabetes showed no influence on neuropathic pain with the exception of laboratory signs of nephropathy. This study confirms the value of comprehensive DSPN phenotyping and underlines the importance of the severity of neuropathy for the presence of pain. Different sensory phenotypes might be useful for stratification of patients with painful DSPN for analgesic treatment and drug trials.

Purpose The aim of this prospective observational cohort study was to evaluate long-term outcomes in patients with mild-to-moderate lumbar spinal stenosis (LSS) and to analyse the predictors of clinical outcomes. Methods A group of 53 patients were re-examined after a median period of 139 months. Evaluations were made of subjective clinical outcome, objective clinical outcome and its predictors, any correlation between subjective and objective outcome, and the development of changes in radiological and electrophysiological parameters after 12 years. Results Satisfactory objective and subjective clinical outcomes were recorded in 54.7 and 43.4 % of patients, respectively. No statistically significant correlation between objective and subjective clinical outcome was found (Spearman coefficient = 0.225, p = 0.132). Patients with isolated unsatisfactory subjective outcome exhibited the highest Functional Comorbidity Index of all subgroups. Electrophysiological and radiological findings did not demonstrate statistically significant changes after 12-year follow-up. Multivariate logistic regression confirmed only the lowest transverse diameter of spinal canal ^13.6 mm as an independent predictor of unsatisfactory clinical outcome (OR = 5.51). Conclusions Satisfactory objective and subjective clinical outcomes were disclosed in about half of the patients with mild-to-moderate LSS in a 12-year follow-up. The number of comorbid diseases had an unfavourable effect on subjective evaluation of clinical outcome. The lowest transverse diameter of spinal canal proved to be the only independent predictor of deterioration of clinical status in LSS patients.

Background Contemporary stroke incidence data are not available in some countries and regions, including in Eastern Europe. Based on previous validation of the accuracy of the National Registry of Hospitalized Patients (NRHOSP), we report the incidence of hospitalized stroke in the Czech Republic (CR) using the NRHOSP. Methods The results of the prior validation study assessing the accuracy of coding of stroke diagnoses in the NRHOSP were applied, and we calculated (1) the overall incidence of hospitalized stroke and (2) the incidence rates of hospitalized stroke for the three main stroke types: cerebral infarction (International Classification of Diseases Tenth Revision, CI I63), subarachnoid hemorrhage (SAH I60), and intracerebral hemorrhage (ICH I61). We calculated the average annual age- and sex-standardized incidence. Results The overall incidence of hospitalized stroke was 241 out of 100,000 individuals. The incidence of hospitalized stroke for the main stroke types was 8.2 cases in SAH, 29.5 in ICH, and 211 in CI per 100,000 individuals. The standardized annual stroke incidence adjusted to the 2000 World Health Organization population for overall stroke incidence of hospitalized stroke was 131 per 100,000 individuals. Standardized stroke incidence for stroke subtypes was 5.7 cases in SAH, 16.7 in ICH, and 113 in CI per 100,000 individuals. Conclusions These studies provide an initial assessment of the burden of stroke in this part of the world. The estimates of hospitalized stroke in the CR and Eastern Europe suggest that ICH is about three times more common than SAH, and hemorrhagic stroke makes up about 18% of strokes.

The growth-associated protein 43 (GAP-43) is known as a marker of regenerating nerve fibers and their continuous remodeling in the adult human skin. The purpose of this pilot study was to investigate a possible role for GAP-43 in the detection of the early stages of small-fiber neuropathy in patients with type 2 diabetes mellitus (DM2) as compared with a well- established and validated parameter – intra-epidermal nerve fiber density (IENFD) of protein gene product 9.5 (PGP 9.5) immunoreactive intra-epidermal C fibers. In a group of 21 patients with DM2 within three years of diagnosis (13 men, 8 women; mean age 53.9 +- 12.8; range 30 – 74) and a group of 17 healthy volunteers (8 men, 9 women; mean age 55.8 +- 8.5; range 45 – 70 years), skin punch biopsies were taken from a distal calf and double immunostained with both PGP 9.5 and GAP-43. In healthy controls, 96.8% of 629 PGP 9.5 immunoreactive fibers were immunostained with GAP-43; the proportion of PGP 9.5 intra-epidermal nerve fibers immunoreactive for GAP-43 in control subjects ranged from 86.5 to 100%. In DM2 patients, IENFD was significantly lower compared to controls (median, 1.5 vs. 11.2/mm; p

To describe the epidemiology and time spectrum of delirium using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and to validate a tool for delirium assessment in patients in the acute poststroke period.A prospective observational cohort study.The stroke unit of a university hospital.A consecutive series of 129 patients with stroke (with infarction or intracerebral hemorrhage, 57 women and 72 men; mean age, 72.5 yrs; age range, 35-93 yrs) admitted to the stroke unit of a university hospital were evaluated for delirium incidence.None.Criterion validity and overall accuracy of the Czech version of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) were determined using serial daily delirium assessments with CAM-ICU by a junior physician compared with delirium diagnosis by delirium experts using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria that began the first day after stroke onset and continued for at least 7 days. Cox regression models using time-dependent covariate analysis adjusting for age, gender, prestroke dementia, National Institutes of Stroke Health Care at admission, first-day Sequential Organ Failure Assessment, and asphasia were used to understand the relationships between delirium and clinical outcomes. An episode of delirium based on reference Diagnostic and Statistical Manual assessment was detected in 55 patients with stroke (42.6%). In 37 of these (67.3%), delirium began within the first day and in all of them within 5 days of stroke onset. A total of 1003 paired CAM-ICU/Diagnostic and Statistical Manual of Mental Disorders daily assessments were completed. Compared with the reference standard for diagnosing delirium, the CAM-ICU demonstrated a sensitivity of 76% (95% confidence interval [CI] 55% to 91%), a specificity of 98% (95% CI 93% to 100%), an overall accuracy of 94% (95% CI 88% to 97%), and high interrater reliability (κ = 0.94; 95% CI 0.83-1.0). The likelihood ratio of the CAM-ICU in the diagnosis of delirium was 47 (95% CI 27-83). Delirium was an independent predictor of increased length of hospital stay (hazard ratio 1.63; 95% CI 1.11-2.38; p = .013).Poststroke delirium may frequently be detected provided that the testing algorithm is appropriate to the time profile of poststroke delirium. Early (first day after stroke onset) and serial screening for delirium is recommended. CAM-ICU is a valid instrument for the diagnosis of delirium and should be considered an aid in delirium screening and assessment in future epidemiologic and interventional studies in patients with stroke.

Study design A prospective study evaluating a cohort of patients with spondylotic cervical spine compression. Objective To analyze the potential of diffusion tensor imaging (DTI) of the cervical spinal cord in the detection of changes associated with spondylotic myelopathy, with particular reference to clinical and electrophysiological findings. Summary of background data Conventional magnetic resonance imaging (MRI) may provide confusing findings because of a frequent disproportion between the degree of the spinal cord compression and clinical symptoms. The DTI is known to be more sensitive to subtle pathological changes of the spinal cord compared with conventional MRI. Methods The DTI of the cervical spinal cord was performed within a group of 52 patients with spondylotic spinal cord compression and 13 healthy volunteers on a 1.5-T MRI scanner. All patients underwent clinical examination that differentiated between asymptomatic and symptomatic myelopathy subgroups, and 45 patients underwent electrophysiological examination. We measured the apparent diffusion coefficient and fractional anisotropy of the spinal cord at C2/C3 level without compression and at the maximal compression level (MCL). Sagittal spinal canal diameter, cross-sectional spinal cord area, and presence of T2 hyperintensity at the MCL were also recorded. Nonparametric statistical testing was used for comparison of controls with subgroups of patients. Results Significant differences in both the DTI parameters measured at the MCL, between patients with compression and control group, were found, while no difference was observed at the noncompression level. Moreover, fractional anisotropy values were lower and apparent diffusion coefficient values were higher at the MCL in the symptomatic patients than in the asymptomatic patients. The DTI showed higher potential to discriminate between clinical subgroups in comparison with standard MRI parameters and electrophysiological findings. Conclusion The DTI appears to be a promising imaging modality in patients with spondylotic spinal cord compression. It reflects the presence of symptomatic myelopathy and shows considerable potential for discriminating between symptomatic and asymptomatic patients.

Multiple sclerosis (MS) is characterized by autoimmune attack leading to demyelination of the white matter in the central nervous system with devastating clinical consequences. Several immune-mediated destruction mechanisms were previously proposed including different T-cell subsets but complex view on immune system function in patients with MS is missing. In the present study, T-lymphocyte populations and pro-inflammatory as well as suppressive cytokine profiles were evaluated in detail in previously untreated patients with relapsing-remitting MS (RRMS). CD4(+) and CD8(+) naïve, central memory (Tcm), effector memory (Tem), terminal effector memory (Ttem), CD4(+) regulatory T-cells (Treg) and CD8(+) T-suppressor cells (Ts) were analysed using flow cytometry, and levels of ten plasma cytokines were determined using fluorescent bead-based immunoassay. We evaluated two groups of RRMS with minor (n=33) and major (n=25) clinical impairment and compared them with healthy controls (n=40) in order to detect any correlation between severity of MS clinical symptoms and immune disturbances. Significant differences were noted in CD4(+)CD45RA(+)CCR7(+) naïve T-cells, CD4(+)CD45RO(+)CCR7(-) and CD8(+)CD45RO(+)CCR7(-) Tem cells, while no differences were recognized in Tcm, Ttem, Treg and Ts cells in RRMS patients. Nine out of ten studied cytokines were disturbed in plasma samples of patients with RRMS. In conclusion, we demonstrate complex immune dysbalances in untreated MS patients.

The aim of this study was to evaluate the etiology in a group of 84 patients with painful sensory neuropathy with predominant small-fiber dysfunction (54 men and 30 women, median: 58; range: 25-83 years) recruited from a population of the South Moravian region of the Czech Republic. Involvement of small nerve fibers was verified by abnormal thermal thresholds and/or reduced intraepidermal nerve fiber densities. Motor signs or symptoms or significant clinical signs of sensory large-fiber involvement were exclusionary; 33 patients, however, had sensory nerve conduction abnormalities. For comparison, the prevalence of risk factors was assessed in a group of 47 asymptomatic age- and sex-matched controls (30 men and 17 women, median: 59; range: 29-85 years). The multivariate regression model disclosed that diabetes mellitus (odds ratio [OR] = 4.08), chronic alcoholism (OR = 5.31), and serum cholesterol levels (OR = 4.51) were the only parameters independently associated with small-fiber involvement. No possible etiology was detected in 19 patients (22.6%). In conclusion, the spectrum of risk factors and proportion of idiopathic cases in geographically defined small-fiber polyneuropathy sample is similar to that referred in large-fiber polyneuropathy.

In this prospective study, intraepidermal nerve fiber densities (IENFD) and subepidermal nerve plexus densities (SENPD) were quantified by immunostaining in skin punch biopsies from the distal calf in 99 patients with clinical symptoms of painful sensory neuropathy and from 37 age-matched healthy volunteers. The clinical diagnosis was based on history and abnormal thermal thresholds on quantitative sensory testing (QST). In patients with neuropathy, IENFD and SENPD were reduced to about 50% of controls. Elevated warm detection thresholds on QST correlated with IENFD but not with SENPD. Using receiver-operating characteristic (ROC) curve analysis of IENFD values, the diagnostic sensitivity for detecting neuropathy was 0.80 and the specificity 0.82. For SENPD, sensitivity was 0.81 and specificity 0.88. With ROC analysis of both IENFD and SENPD together, the diagnostic sensitivity was further improved to 0.92. The combined examination of IENFD and SENPD is a highly sensitive and specific diagnostic tool in patients suspected to suffer from painful sensory neuropathies but with normal values on clinical neurophysiological studies.

Summary Background Neuromuscular weakness in paediatric patients with sepsis and multiple organ dysfunction is increasingly reported. However, many aspects of neuromuscular involvement in critically ill children are not completely understood. As more patients survive the critical illness, an understanding of the long-term outcomes of this condition is needed. Aims To describe clinical and electrophysiological features and evaluate the long-term outcomes in critically ill paediatric patients with neuromuscular complications. Methods A case series of five critically ill children was observed prospectively for a 1-month period. Selected clinical and laboratory parameters were evaluated. Electrophysiological studies were performed during the first week and then 1 month later in order to detect signs of critical illness polyneuromyopathy (CIPM). Patients with neuromuscular involvement completed a 1-year follow-up. Results Electrophysiological abnormalities were detected in two patients. Flaccid quadriplegia was a clinical presentation. Both children had electromyographic evidence of chronic partial denervation at follow-up, findings indicative of a preceding axonal neuropathy. Marked but incomplete recovery within 1 year after the onset of the disease occured in both patients. With a mild residual functional handicap the health-related quality of life was not significantly impaired (Barthel Index>80). Conclusions In both our patients with CIPM, the long-term clinical outcome is markedly better than we expected when electromyography in the 1-year follow-up demonstrated a persistent severe chronic partial denervation. These findings can have important implications for the management and rehabilitation of paediatric intensive care survivors.

We aimed to confirm usefulness of intraepidermal nerve fiber density (IENFD) as a marker of progression of diabetic polyneuropathy (DPN) in patients with early type 2 diabetes mellitus (DM2). In a group of 23 healthy subjects (median age 57 years, 14 men) and 30 DM2 patients (median age 60 years, 17 men) we serially evaluated skin biopsies from distal leg. Eighteen DM2 patients complied with the criteria of symptomatic diabetic polyneuropathy (DPN) and 12 had no neuropathy (nDPN). Time interval between biopsies were >2 years (median, range: 29.6, 24.7–58.4, and 33.8, 25.5–54.1 months in controls and DM2 patients, respectively). At first skin biopsy, the IENFD was normal in all controls and nDPN patients compared to abnormal IENFD in 77.8% of DPN patients. Drop in IENFD expressed as a proportion of the 1st IENFD value in % per year in both painful and painless DPN patients was significantly higher (11.95[3.82]%/year, p In conclusion, decrease in IENFD values in early DM2 patients is about 12% of the initial IENFD value irrespective of symptoms and/or signs of DPN at initial evaluation and several times quicker compared to healthy subjects.