Background and purpose
Approximately, 50% of myasthenia gravis (MG) patients initially present with purely ocular symptoms. Of these, about 60% will develop secondary generalized MG, typically within ...2 years. Risk factors for secondary generalization are still controversial. In this study, we reviewed clinical parameters, thymic pathologies and medical treatments of MG patients with purely ocular symptoms at onset to investigate risk factors for secondary generalization.
Methods
In this monocentric retrospective study, we reviewed consecutive patients who underwent robotic thymectomy between January 2003 and October 2017 in Charite Universitaetsmedizin Berlin. We used univariate and multivariate Cox proportional hazards regression models to identify factors associated with secondary generalization. Survival curves were plotted using Kaplan–Meier method and log-rank tests were performed to analyze the association between corticosteroids use and secondary generalization in subgroups defined by anti-AChR antibody status and thymic pathology.
Results
One hundred and eighty of 572 MG patients who underwent robotic thymectomy were eligible for inclusion, of whom 110 (61.1%) developed a secondary generalized MG over a mean follow-up time of 23.6 months. The presence of a thymoma (HR 1.659, 95% CI (1.52–2.617),
P
= 0.029) was the only risk factor for secondary generalization in our series. Treating with corticosteroids was associated with a lower conversion rate in ocular myasthenia patients with thymic hyperplasia (
n
= 55,
P
= 0.028), but not with other thymic pathologies including thymoma and normal or atrophic thymus.
Conclusions
The conversion rate in ocular myasthenia was high in our series, predicted by the presence of a thymoma. Our findings suggest that corticosteroids can prevent secondary generalization in ocular myasthenia patients with thymic hyperplasia, which requires further research.
We aimed to investigate several blood-based biomarkers related to inflammation, immunity, and stress response in a cohort of patients without stroke-associated infections regarding their predictive ...abilities for functional outcome and explore whether they correlate with MRI markers, such as infarct size or location.
We combined the clinical and radiological data of patients participating in two observational acute stroke cohorts: the PREDICT and 1000Plus studies. The following blood-based biomarkers were measured in these patients: monocytic HLA-DR, IL-6, IL-8, IL-10, LBP, MRproANP, MRproADM, CTproET, Copeptin, and PCT. Multiparametric stroke MRI was performed including T2
, DWI, FLAIR, TOF-MRA, and perfusion imaging. Standard descriptive sum statistics were used to describe the sample. Associations were analyzed using Fischer's exact test, independent samples
test and Spearmans correlation, where appropriate.
Demographics and stroke characteristics were as follows: 94 patients without infections, mean age 68 years (SD 10.5), 32.2% of subjects were female, median NIHSS score at admission 3 (IQR 2-5), median mRS 3 months after stroke 1 (IQR 0-2), mean volume of DWI lesion at admission 5.7 ml (SD 12.8), mean FLAIR final infarct volume 10 ml (SD 14.9), cortical affection in 61% of infarctions. Acute DWI lesion volume on admission MRI was moderately correlated to admission/maximum IL-6 as well as maximum LBP. Extent of perfusion deficit and mismatch were moderately correlated to admission/maximum IL-6 levels. Final lesion volume on FLAIR was moderately correlated to admission IL-6 levels.
We found IL-6 to be associated with several parameters from acute stroke MRI (acute DWI lesion, perfusion deficit, final infarct size, and affection of cortex) in a cohort of patients not influenced by infections.
www.ClinicalTrials.gov, identifiers NCT01079728 and NCT00715533.
Background:
In chronic inflammatory demyelinating polyneuropathy (CIDP), there is an urgent need for biomarkers to monitor ongoing disease activity. Serum calprotectin (CLP) induces signaling ...pathways involved in inflammatory processes and has been shown to correlate with markers of disease activity in other autoimmune disorders. Thus, we wanted to study the potential value of CLP in comparison to serum neurofilament light chain (sNfl) to monitor disease activity.
Materials and Methods:
Sera from 63 typical and atypical CIDP and 6 MMN patients with varying degrees of disease activity were analyzed in comparison with 40 healthy controls (HC) in a cross-sectional design. Association of CLP and sNfl levels with socio-demographics, disease duration, CIDP disease activity scale (CDAS), and impairment status medical research council-sum score (MRC-SS), the inflammatory neuropathy cause and treatment disability score (INCAT-DS), grip strength, and maximum walking distance, patient-reported outcome (PRO) parameters SF-36 questionnaire, Beck's depression index (BDI), and fatigue severity scale (FSS), as well as treatment regime were investigated using uni- and multivariate analysis.
Results:
CLP and sNfl levels were significantly higher in all CIDP patients compared to HC (
p
= 0.0009). Multivariate analysis adjusted for age and gender revealed that CLP acts as an independent predictor for CIDP and MMN. CLP was significantly associated with active disease course according to CDAS and correlated with MRC-SS, whereas sNfl correlated with parameters of disease impairment. There was no correlation with PRO, except for sNfl and the mental health composite score. Subgroup analysis revealed no differences between typical CIDP and atypical variants.
Conclusions:
CLP was elevated in CIDP and variants and was associated with active disease course, whereas sNfl shows further potential as biomarker of axonal degeneration. Thus, CLP might be a suitable additive biomarker for measurement of ongoing inflammation, which is greatly needed to guide better patient care in CIDP.
This study aimed to evaluate the association of neurofilament light chain (Nfl) with neuromuscular destruction and disease severity in the serum of patients with myasthenia gravis (MG).
Sera from 134 ...patients with MG with varying degrees of disease severity and autoantibody (Abs) status were analyzed and compared to controls in a cross-sectional design. Prospectively, we additionally measured serum NfL (sNfl) levels in patients with MG longitudinally for up to 3 years. Based on linear regression, differences between patients and controls were assessed. With correlation coefficients and mixed linear regression, the association among sNfl levels, socio-demographics, disease activity (Quantitative Myasthenia Gravis (QMG) score and Myasthenia Gravis Activities of Daily Living (MG-ADL) scale), Abs-status (acetylcholine receptor antibody (AChR-Abs), muscle-specific receptor tyrosine kinase antibody (MuSK-Abs), lipoprotein-related protein 4 (LRP4), and seronegative), Abs titer, treatment regime (pyridostigmine, steroids, and immunosuppressive therapies), and thymectomy were investigated.
sNfl levels were higher in patients with MG compared to controls (median: 11.2 vs. 7.88), where sNfl levels were highest in anti-AChR-Abs positive patients (median 12.6), followed by anti-MuSK-Abs positive, anti-LRP4-Abs positive, and seronegative patients. Adjusting for age and sex, sNfl levels of patients with MG were on average 35% higher compared to controls (35.1, 95% CI: 8.4;68.3) and highest for patients with seronegative MG (44.35; 95% CI 16.47; 78.90). We found no relevant relationship between individual changes in sNfl and changes in QMG and MG-ADL scores.
sNfl levels are higher in patients with MG than in controls but were not consistently associated with clinical severity. Thus, sNfl is not a suitable biomarker to monitor individual disease progression in patients with MG.
Clinical trials are the hallmark of evidence-based medicine, but recruitment is often challenging, especially in stroke trials investigating patients not being able to give informed consent. In some ...nations, ethics committees will not approve of inclusion in a clinical study via consent of a legal representative. The ethical dilemma of including or excluding those patients has not been properly addressed, as there is little data on the effect of stroke characteristics on the ability to give informed consent.
To examine differences between patients able and unable to consent at inclusion to an acute stroke trial, we conducted a post-hoc analysis of monitoring records from a multicentric interventional trial. These records listed patients who gave informed consent by themselves and those who needed a legal representative to do so. This exemplary STRAWINSKI trial aimed at improving stroke outcome by biomarker-guided antibiotic treatment of stroke associated pneumonia and included patients within 40 h after stroke onset, suffering from MCA infarctions with an NIHSS score > 9 at admission. Standard descriptive and associative statistics were calculated to compare baseline characteristics and outcome measures between patients who were able to consent and those who were not.
We identified the person giving consent in 228 out of 229 subjects. Patients with inability to consent were older (p < 0.01), suffered from more left-hemispheric (p < 0.01) and more severe strokes (NIHSS, p < 0.01), were more likely to die during hospitalisation (p < 0.01) or have unfavourable outcome at discharge (mRS, p < 0.01), to develop fever (p < 0.01) and tended to be more susceptible to infections (p = 0.06) during the acute course of the disorder.
Demographics, stroke characteristics and outcomes significantly affect stroke patients in their ability to consent. Where selection criteria and primary outcome measures of a trial are significantly affected by ability to consent, excluding patients unable to consent might be unethical.
URL http://www.clinicaltrials.gov . Unique identifier: NCT01264549 .
Stroke patients are often affected by long-term disabilities with needs concerning social issues. There is relatively little consideration of social recovery of patients and the support required to ...return to work, receive social benefits, participate in daily life activities, maintain contact with family and friends and to organize financial affairs. In our study we aimed to investigate if existing tools record social needs adequately. We analyzed the current provision of social support provided in long-term care after stroke and whether unmet social needs were associated with quality of life, caregiver burden, overall function and degree of disability.
Our analysis is part of the Managing Aftercare of Stroke study (MAS-I), a cross-sectional exploratory study of patient needs 2-3 years after initial stroke. Assessment tools included the Nikolaus-score (social situation), the EuroQoL (quality of life), the German Burden Scale for Family Caregivers (caregiver burden), the modified Rankin Scale (disability / dependence), Stroke Impact Scale (function and degree of disability) and the Stroke Survivor Needs Questionnaire (unmet needs).
Overall 57 patients were included in MAS-I, with ten patients classified in urgent need of socio-economic support according to the Nikolaus-score. Patients with lower than normal Nikolaus-score had a higher degree of disability. Thirty percent of all patients had never received professional social support. Social worker contact happened mostly during the stay in acute hospital or rehabilitation institution. Only four patients (11%) reported long-term support after discharge. Apart from social worker contact during acute care, 43% of patients had unmet needs in the long-term aftercare. Forty percent of all patients included in MAS-I were recommended for social work intervention after an in-depth analysis of their situation. Finally, we saw that unmet social needs were associated with lower quality of life and higher caregiver burden.
Our data suggest significant unmet needs in social care in long-term stroke patients. Screening tools for unmet social needs such as the Nikolaus-score do not holistically report patients' needs.
Clinicaltrials.Gov NCT02320994 . Registered 19 December 2014 (retrospectively registered).
Myasthenia gravis (MG) is the most common autoimmune disease affecting the neuromuscular junction by specific autoantibodies. The etiology of MG and its heterogeneity in clinical courses are poorly ...understood, although it was recently shown that gut microbial dysbiosis plays a critical role. Since levels of Calprotectin (CLP) seem to correlate with level of dysbiosis, we hypothesize that CLP may serve as potential disease activity biomarker in MG. Sera from 251 patients with MG and 90 controls were analyzed in an explorative, cross-sectional design. Prospectively, we tested CLP levels in MG patients up to 3 years. Association of CLP levels with socio-demographics, disease activity (quantitative myasthenia gravis (QMG) score, myasthenia gravis-specific Activities of Daily Living scale (MG-ADL)), antibody (Abs) status, history of myasthenic crisis, treatment regime, and history of thymectomy were investigated using univariate analysis. Mean baseline serum levels of CLP were significantly higher in MG patients compared to controls (4.3 μg/ml vs. 2.1 μg/ml; p < 0.0001). Higher levels of CLP were associated with a higher clinical disease severity measured by MGFA classification and QMG score. Nevertheless, the only weak correlation of CLP with clinical outcome parameters needs confirmation in future studies. Currently, there are no validated blood biomarkers for MG. The significantly elevated CLP and mild correlation with parameters of disease activity suggests that CLP holds promise as a biomarker for measurement of individual disease severity.
•The etiology of myasthenia gravis (MG) is still poorly understood, although gut microbial dysbiosis plays a critical role.•Levels of Calprotectin (CLP) seem to correlate with level of gut dysbiosis.•CLP levels are elevated in MG patients correlating with markers of disease severity.•CLP might be a promising biomarker for measuring MG disease activity.
In order to select patients most likely to benefit for thrombolysis and to predict patient outcome in acute ischemic stroke, the volumetric assessment of the infarcted tissue is used. However, ...infarct volume estimation on Diffusion weighted imaging (DWI) has moderate interrater variability despite the excellent contrast between ischemic lesion and healthy tissue. In this study, we compared volumetric measurements of DWI hyperintensity to a simple maximum orthogonal diameter approach to identify thresholds indicating infarct size >70 ml and >100 ml.
Patients presenting with ischemic stroke with an NIHSS of ≥ 8 were examined with stroke MRI within 24 h after symptom onset. For assessment of the orthogonal DWI lesion diameters (od-values) the image with the largest lesion appearance was chosen. The maximal diameter of the lesion was determined and a second diameter was measured perpendicular. Both diameters were multiplied. Od-values were compared to volumetric measurement and od-value thresholds identifying a lesion size of > 70 ml and > 100 ml were determined. In a selected dataset with an even distribution of lesion sizes we compared the results of the od value thresholds with results of the ABC/2 and estimations of lesion volumes made by two resident physicians.
For 108 included patients (53 female, mean age 71.36 years) with a median infarct volume of 13.4 ml we found an excellent correlation between volumetric measures and od-values (r2 = 0.951). Infarct volume >100 ml corresponds to an od-value cut off of 42; > 70 ml corresponds to an od-value of 32. In the compiled dataset (n = 50) od-value thresholds identified infarcts > 100 ml / > 70 ml with a sensitivity of 90%/ 93% and with a specificity of 98%/ 89%. The od-value offered a higher accuracy in identifying large infarctions compared to both visual estimations and the ABC/2 method.
The simple od-value enables identification of large DWI lesions in acute stroke. The cutoff of 42 is useful to identify large infarctions with volume larger than 100 ml. Further studies can analyze the therapeutic utility of this new method.
ClinicalTrials.org NCT00715533.
The mismatch between diffusion weighted imaging (DWI) lesion and perfusion imaging (PI) deficit volumes has been used as a surrogate of ischemic penumbra. This pathophysiology-orientated patient ...selection criterion for acute stroke treatment may have the potential to replace a fixed time window. Two recent trials - DEFUSE and EPITHET - investigated the mismatch concept in a multicenter prospective approach. Both studies randomized highly selected patients (n = 74/n = 100) and therefore confirmation in a large consecutive cohort is desirable. We here present a single-center approach with a 3T MR tomograph next door to the stroke unit, serving as a bridge from the ER to the stroke unit to screen all TIA and stroke patients. Our primary hypothesis is that the prognostic value of the mismatch concept is depending on the vessel status. Primary endpoint of the study is infarct growth determined by imaging, secondary endpoints are neurological deficit on day 5-7 and functional outcome after 3 months.
1000Plus is a prospective, single centre observational study with 1200 patients to be recruited. All patients admitted to the ER with the clinical diagnosis of an acute cerebrovascular event within 24 hours after symptom onset are screened. Examinations are performed on day 1, 2 and 5-7 with neurological examination including National Institute of Health Stroke Scale (NIHSS) scoring and stroke MRI including T2*, DWI, TOF-MRA, FLAIR and PI. PI is conducted as dynamic susceptibility-enhanced contrast imaging with a fixed dosage of 5 ml 1 M Gadobutrol. For post-processing of PI, mean transit time (MTT) parametric images are determined by deconvolution of the arterial input function (AIF) which is automatically identified. Lesion volumes and mismatch are measured and calculated by using the perfusion mismatch analyzer (PMA) software from ASIST-Japan. Primary endpoint is the change of infarct size between baseline examination and day 5-7 follow up.
The aim of this study is to describe the incidence of mismatch and the predictive value of PI for final lesion size and functional outcome depending on delay of imaging and vascular recanalization. It is crucial to standardize PI for future randomized clinical trials as for individual therapeutic decisions and we expect to contribute to this challenging task.
clinicaltrials.gov NCT00715533.
In perfusion magnetic resonance imaging a manual approach to delineation of regions of interest is, due to rater bias and time intensive operator input, clinically less favorable than an automated ...approach would be. The goal of our study was to compare the performances of these approaches.
Using Stroketool, PMA and Perfscape/Neuroscape perfusion maps of cerebral blood flow, mean transit time and Tmax were created for 145 patients with acute ischemic stroke. Volumes of hypoperfused tissue were calculated using both a manual and an automated protocol, and the results compared between methods.
The median difference between the automatically and manually derived volumes was up to 210 ml in Perfscape/Neuroscape, 123 ml in PMA and 135 ml in Stroketool. Correlation coefficients between perfusion volumes and radiological and clinical outcome were much lower for the automatic volumes than for the manually derived ones.
The agreement of the two methods was very poor, with the automated use producing falsely exaggerated volumes of hypoperfused tissue. Software improvements are necessary to enable highly automated protocols to credibly assess perfusion deficits.
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