Quality measurement of out-patient neuropsychological therapy after stroke in Germany: definition of indicators and retrospective pilot study.

BACKGROUND: In contrast to the hospital setting, today little work has been directed to the definition, measurement, and improvement of the quality of out-patient medical and therapeutic care. We developed a set of indicators to measure the quality of out-patient neuropsychological therapy after stroke. METHODS: The indicators cover core and interdisciplinary aspects of out-patient neuropsychological work such as mediation of patients into social care in case of need. Selection of the quality-indicators was done together with a consensus group of out-patient therapists and supported by evidence, validity, reliability as well as estimated relevance and variability with the quality of care. The set of indicators was further tested in a retrospective cohort study. Anonymous data of 104 patients were collected from out-patient clinical records of five clinics between November 2017 and April 2018. Associations between process and outcome quality were estimated exploitatively. RESULTS: Results allowed for the identification of areas with greater variability in the quality of process care and indicated that attention training as recommended by current guidelines had the lowest overall rate for meeting the quality-aim (met in 44% of the cases). This was followed by time < 1 month until the start of therapy (63% met) and mediation into social care in case of need (65% met). We further observed that overall quality and involving relatives in the therapy was associated with higher rates of professional reintegration (p-value = 0.03). However, the need for mediation into social care was associated with a reduced chance for successful professional reintegration (p-value = 0.009). CONCLUSION: In conclusion, we describe a first set of quality indicators which cover different aspects of out-patient neuropsychological therapy and sufficient variability with care. First data further suggests that meeting the specified quality aims may indeed have relevant effects on outcomes.

Movement disorders after hypoxic brain injury following cardiac arrest in adults.

BACKGROUND AND PURPOSE: Post-hypoxic movement disorders and chronic post-hypoxic myoclonus are rare complications after cardiac arrest in adults. Our study investigates the clinical spectrum, neuroimaging results, therapy and prognosis of these debilitating post-hypoxic sequelae. METHODS: This retrospective study included 72 patients from the neurological intensive care unit at a university hospital, who were diagnosed with hypoxic-ischaemic encephalopathy after cardiac arrest between January 2007 and September 2018. Clinical records were screened for occurrence of post-hypoxic movement disorders and chronic post-hypoxic myoclonus. Affected patients were further analysed for applied neuroprognostic tests, administered therapy and treatment response, and the outcome of these movement disorders and neurological function. RESULTS: Nineteen out of 72 screened patients exhibited post-hypoxic motor symptoms. Basal ganglia injury was the most likely neuroanatomical correlate of movement disorders as indicated by T1 hyperintensities and hypometabolism of this region in magnetic resonance imaging and positron emission tomography computed tomography. Levomepromazine and intrathecal baclofen showed first promising and mostly prompt responses to control these post-hypoxic movement disorders and even hyperkinetic storms. In contrast, chronic post-hypoxic myoclonus best responded to co-application of clonazepam, levetiracetam and primidone. Remission rates of post-hypoxic movement disorders and chronic post-hypoxic myoclonus were 58% and 50%, respectively. Affected patients seemed to present a rather good recovery of cognitive functions in contrast to the often more severe physical deficits. CONCLUSIONS: Post-hypoxic movement disorders associated with pronounced basal ganglia dysfunction might be efficiently controlled by levomepromazine or intrathecal baclofen. Their occurrence might be an indicator for a more unfavourable, but often not devastating, neurological outcome.

A spontaneous missense mutation in the chromodomain helicase DNA-binding protein 8 (CHD8) gene: a novel association with congenital myasthenic syndrome.

AIMS: Congenital myasthenic syndromes (CMS) are characterized by muscle weakness, ptosis and episodic apnoea. Mutations affect integral protein components of the neuromuscular junction (NMJ). Here we searched for the genetic basis of CMS in female monozygotic twins. METHODS: We employed whole-exome sequencing for mutation detection and Sanger sequencing for segregation analysis. Immunohistology was done with antibodies against CHD8, rapsyn, ß-catenin (ßCAT) and golgin on fi-bro-blasts, human and mouse muscle. We recorded superresolution images of the NMJ using 3D-structured illumination microscopy. RESULTS: We discovered a spontaneous missense mutation in CHD8 [chr14:g.21,884,051G>A, GRCh37.p11 | c.1732C>T, NM_00117062 | p.(R578C)], the gene encoding chromodomain helicase DNA-binding protein 8. This is the first missense mutation affecting Duplin, the short 110 kDa isoform of CHD8. It is known that CHD8/Duplin negatively regulates ßCAT signalling in the WNT pathway and plays a role in chromatin remodelling. Inactivating CHD8 mutations are associated with autism spectrum disorder and intellectual disability in combination with facial dysmorphism, overgrowth and macrocephalus. No muscle-specific phenotype has been reported to date. Co-immunostaining with rapsyn on human and mouse muscle revealed a strong presence of CHD8 at the NMJ being located towards the sarcoplasmic side of the rapsyn cluster, where it co-localizes with ßCAT. CONCLUSION: We hypothesize CHD8 to have a role in the maintenance of the structural integrity and function of the NMJ. Both patients benefited from treatment with 3,4-diaminopyridine, a reversible blocker of voltage-gated potassium channels at the nerve terminal that prolongs the action potential and increases acetylcholine release.

Biomarkers of immune capacity, infection and inflammation are associated with poor outcome and mortality after stroke - the PREDICT study.

BACKGROUND: Almost 40% of stroke patients have a poor outcome at 3 months after the index event. Predictors for stroke outcome in the early acute phase may help to tailor stroke treatment. Infection and inflammation are considered to influence stroke outcome. METHODS: In a prospective multicenter study in Germany and Spain, including 486 patients with acute ischemic stroke, we used multivariable regression analysis to investigate the association of poor outcome with monocytic HLA-DR (mHLA-DR) expression, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide-binding protein (LBP) as markers for immunodepression, inflammation and infection. Outcome was assessed at 3 months after stroke via a structured telephone interview using the modified Rankin Scale (mRS). Poor outcome was defined as a mRS score of 3 or higher which included death. Furthermore, a time-to-event analysis for death within 3 months was performed. RESULTS: Three-month outcome data was available for 391 patients. Female sex, older age, diabetes mellitus, atrial fibrillation, stroke-associated pneumonia (SAP) and higher National Institute of Health Stroke Scale (NIHSS) score as well as lower mHLA-DR levels, higher IL-6 and LBP-levels at day 1 were associated with poor outcome at 3 months in bivariate analysis. Furthermore, multivariable analysis revealed that lower mHLA-DR expression was associated with poor outcome. Female sex, older age, atrial fibrillation, SAP, higher NIHSS score, lower mHLA-DR expression and higher IL-6 levels were associated with shorter survival time in bivariate analysis. In multivariable analysis, SAP and higher IL-6 levels on day 1 were associated with shorter survival time. CONCLUSIONS: SAP, lower mHLA-DR-expression and higher IL-6 levels on day one are associated with poor outcome and shorter survival time at 3 months after stroke onset. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01079728 , March 3, 2010.

Differences in peripheral myelin antigen-specific T cell responses and T memory subsets in atypical versus typical CIDP.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is presented by a large heterogeneity of clinical phenotypes. Around 50% of patients suffer from typical CIDP and show better therapy response than atypical variants. The goal of our study was to search for cellular immunological differences in typical versus atypical CIDP in comparison to controls. METHODS: We evaluated 26 (9 typical, 17 atypical) patients with mainly active-unstable CIDP using clinical and immunological examinations (enzyme-linked immunospot assay ELISPOT, fluorescence-activated cell sorting FACS) in comparison to 28 healthy, age-matched controls (HC). Typical or atypical CIDP measurements were compared with HC using Kruskal-Wallis test. RESULTS: Atypical CIDP patients showed increased frequencies of T cell subsets, especially CD4+ effector memory T cells (TEM) and CD4+ central memory T cells (TCM) as well as a tendency of higher T cell responses against the peripheral myelin antigens of PMP-22, P2, P0 and MBP peptides compared to typical CIDP. Searching for novel auto-antigens, we found that T cell responses against P0 180-199 as well as MBP 82-100 were significantly elevated in atypical CIDP patients vs. HC. CONCLUSIONS: Our results indicate differences in underlying T cell responses between atypical and typical CIDP characterized by a higher peripheral myelin antigen-specific T cell responses as well as a specific altered CD4+ memory compartment in atypical CIDP. Larger multi-center studies study are warranted in order to characterize T cell auto-reactivity in atypical CIDP subgroups in order to establish immunological markers as a diagnostic tool.

Glucocorticoids in myasthenia gravis - if, when, how, and how much?

Glucocorticoids (GC) are the most commonly used immune-directed therapy in myasthenia gravis (MG). However, to date, GC have not proven their effectiveness in the setting of a randomized clinical trial that complies with currently accepted standards. The rationale for the use of GC in MG is the autoimmune nature of the disease, which is supported by consistent positive results from retrospective studies. Well-defined recommendations for treatment of MG with GC are lacking and further hampered by inter- and intra-individual differences in the disease course and responses to GC treatment. Uncertainties concerning GC treatment in MG encompass the indication for treatment initiation, exact dosage, dose adjustment in specific conditions (e.g., pregnancy, thymectomy), mode of tapering, and surveillance of adverse events (AE). This review illustrates the mode of action of GC in the treatment for MG, presents the currently available data on GC treatment in MG, and attempts to translate the currently available information into clinical recommendations.

[Thymectomy in myasthenia and/or thymoma]. / Thymektomie bei Myasthenie und/oder Thymom.

Thymectomy, the surgical removal of the thymic gland, is essential in cases of thymoma. The majority of cases of a myasthenia gravis (MG) represent a relative indication for thymectomy which requires cooperation with specialized neurologists. Patients with MG may present with a tumor of the thymic gland. In case of suspicious thymoma, the resectability of the tumor has to be evaluated in the preoperative diagnostic. The clinical condition of patients with MG has to be stabilized preoperatively. The aim of thymectomy is the radical removal of thymoma and/or maximal improvement of MG symptoms. This requires the complete extirpation of the thymic gland including all ectopic thymic tissue in the anterior mediastinum. There is a variety of surgical techniques for performing a complete thymectomy. In addition to the conventional techniques with sternotomy, the significance of minimally-invasive approaches is increasing rapidly. Despite the ongoing scarcity of data of higher evidence concerning the procedure of thymectomy an increasing number of equivalent results with minimally-invasive operation techniques for MG and for thymoma are available. The successful surgical performance of a thymectomy is part of an interdisciplinary cooperation in the perioperative treatment of MG as well as the postoperative long-term care for patients with MG and/or thymoma.

Predicting post-stroke pneumonia: the PANTHERIS score.

OBJECTIVES: Stroke-associated pneumonia (SAP) is a common complication with a known negative impact on neurological outcome. We developed a score to identify patients at highest risk of SAP in order to promote prophylactic measures. MATERIALS AND METHODS: We conducted a cohort study on a neurological intensive care unit in patients suffering from acute ischemic MCA infarction. Association of predefined demographics, comorbidities, and clinical characteristics with SAP was investigated using logistic regression analysis. RESULTS: Between 2003 and 2010, a total of 335 patients were included in this analysis. Frequency of SAP was 31.3%. A 12-point scoring system was developed based on the following factors: Glasgow Coma Scale (GCS) [GCS < 9 = 5, GCS 9-12 = 2, GCS > 12 = 0], age [<60 = 0, 60-80 = 1, >80 = 2], increase in systolic arterial blood pressure >200 mmHg within the first 24 h after admission [no = 0, yes = 2], and white blood cell count >11.000/µl [no = 0, yes = 3]. The score revealed excellent discrimination (AUC = 0.85) and calibration (Nagelkerke's R² = 0.46) properties. Predictive properties were reproduced in an internal validation group. CONCLUSIONS: The PANTHERIS score is a simple scoring system for the prediction of SAP based on easy-to-assess parameters. By identifying patients at high risk, it may guide intense monitoring or prophylactic measures. This score needs to be validated within external datasets.

[Dysphagia diagnostics and therapy of acute stroke: federal survey of certified stroke units]. / Dysphagiediagnostik und -therapie des akuten Schlaganfalls : Eine bundesweite Erhebung auf zertifizierten Stroke-Units.

BACKGROUND: Due to malnutrition and aspiration pneumonia dysphagia is associated with increased morbidity and mortality in acute stroke patients. Early detection of patients at risk of dysphagia leading to timely treatment improves the outcome. METHODS: A survey concerning the current state of dysphagia diagnostics and therapy was carried out among certified stoke units in Germany. RESULTS: Of the 163 invited hospitals 51% participated in the study. A standardized dysphagia program lying mainly within the responsibility of speech language therapists (64%) is established in 94%. Main elements are swallowing assessments carried out by nurses (72%) and the clinical swallowing examination (93%). Instrumental diagnostics are available in 55% with videoendoscopy (52%) being more widely used than videofluoroscopy (17%). In the acute stage nutrition with texture modified diets is the primary therapeutic strategy. CONCLUSIONS: Structured programs for the diagnosis and treatment of dysphagia have generally been established but individual strategies differ and differences in the quality of care are obvious.

Nonviral gene delivery of erythropoietin by mesenchymal stromal cells.

Erythropoietin (EPO) acts on erythroblasts in the bone marrow (BM) to stimulate the formation of red blood cells. In this study, we wanted to determine whether BM-derived mesenchymal stromal cells (MSCs) can be used as cellular vehicles to deliver EPO in mice without the use of viral vectors. After isolation and characterization of murine MSCs (mMSCs), different transient transfection procedures were compared for their efficacy of gene transfer of the pEGFP-N2 plasmid. Nucleofection outperformed magnetofection and lipofection. Stably transfected mMSCs were generated by selection with G418-disulfate and single-cell-colony-forming unit (sc-CFU) assays without changes in their proliferation capacity and osteogenic/adipogenic differentiation potential. Next, murine EPO was stably introduced into mMSCs by nucleofection of a plasmid encoding the epo and egfp genes. Intraperitoneal transplantation of EPO-expressing mMSCs increased serum EPO levels, hematocrit and hemoglobin of C57BL/6 mice within 1 week. The hematocrit remained elevated for 5 weeks, but production of antibodies against both transgenes was detected in the hosts and serum EPO levels normalized. Our results suggest that nonviral gene delivery into MSCs can be used to enhance the known beneficial effects MSCs by additional production of therapeutic factors like EPO in vivo.

[Course and treatment of myasthenia gravis during pregnancy]. / Verlauf und Behandlung der Myasthenia gravis in der Schwangerschaft.

Pregnancy and family planning issues are frequent concerns in the medical care of patients with myasthenia gravis since disease onset often coincides with the life period which is decisive in this respect. Although pregnancy, delivery and breastfeeding represent special circumstances in these patients, they are not associated with higher risks of complications compared to normal pregnancy, delivery and postpartum period. Frequently asked questions regard the course of pregnancy as well as the impact of the disease and particularly medical treatment on pregnancy and the foetus or neonate. Great significance is attached to the mode of delivery since it is still widely accepted that patients with myasthenia gravis have to deliver per elective caesarean section. This paper gives an overview and provides a basis for the medical care and individual counselling of patients with myasthenia gravis who want to start a family or are already pregnant.

Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial.

UNLABELLED: Infections are a leading cause of death in patients with acute CNS injury such as stroke. Recent experimental evidence indicated that stroke leads to suppression of innate and adaptive peripheral immune responses which predisposes to infection. However, less is known on phenotypic and functional immune alterations in correlation with the occurrence of infectious complications in patients with acute stroke. EXPERIMENTAL PROCEDURES: In the recently completed randomized, double blind, placebo-controlled Preventive Antibacterial Therapy in Stroke (PANTHERIS) trial on the efficacy of short-term antibacterial therapy to prevent the development of post-stroke infections, we assessed longitudinal changes in lymphocyte subpopulations and mitogen-induced lymphocytic interferon gamma (IFN)-gamma production using flow cytometry in 80 patients with acute severe stroke at days 1, 3, 8, 90 and 180 after clinical onset. Plasma interleukin (IL)-6 and IL-10 concentration as well as urinary levels of norepinephrine and cortisol was assessed within the first 8 days after stroke. Patients of the placebo and verum (moxifloxacin) treatment groups who did or did not develop infections within 11 days after stroke were compared to identify immunological changes associated with the occurrence of post-stroke infections. RESULTS: Rapid T-lymphopenia and long-lasting suppression of lymphocytic IFN-gamma production were observed in all stroke patients. Patients of the placebo group who developed infections showed a trend toward greater decline of CD4+ Th cell counts and higher urinary levels of norepinephrine early after stroke than patients without infections. Onset of infections was accompanied with higher plasma IL-6 levels in the placebo group but not in the moxifloxacin group. In addition, an early rise in plasma IL-10 was detected in patients who developed infections despite preventive antibacterial treatment. CONCLUSION: A rapid loss and functional deactivation of T cells are common changes in stroke patients consistent with immunodepression after brain ischemia. A stronger decrease in cellular immune responses and an increased sympathetic activity after stroke are associated with a higher risk of infections. Increased plasma levels of the anti-inflammatory cytokine IL-10 early after stroke may identify patients who will not respond to preventive antibacterial therapy with moxifloxacin.

[Minimally invasive thymus surgery]. / Minimal-invasive Chirurgie des Thymus.

There are absolute and relative indications for complete removal of the thymus gland. In the complex therapy of autoimmune-related myasthenia gravis, thymectomy plays a central role and is performed with relative indication. In case of thymoma with or without myasthenia, thymectomy is absolutely indicated. Thymus resection is further necessary for cases of hyperparathyroidism with ectopic intrathymic parathyroids or with certain forms of multiple endocrine neoplasia. The transcervical operation technique traditionally reflected the well-founded desire for minimal invasiveness for thymectomy. Due to the requirement of radicality however, most of these operations were performed using sternotomy. With the evolution of therapeutic thoracoscopy in thoracic surgery, several pure or extended minimally invasive operation techniques for thymectomy have been developed. At present uni- or bilateral, subxiphoid, and modified transcervical single or combination thoracoscopic techniques are in use. Recently a very precise new level of thoracoscopic operation technique was developed using robotic-assisted surgery. There are special advantages of this technique for thymectomy. An overview of the development and experiences with minimally invasive thymectomy is presented, including data from the largest series published so far.