Microglia contributes to remyelination in cerebral but not spinal cord ischemia.

Inflammation after injury of the central nervous system (CNS) is increasingly viewed as a therapeutic target. However, comparative studies in different CNS compartments are sparse. To date only few studies based on immunohistochemical data and all referring to mechanical injury have directly compared inflammation in different CNS compartments. These studies revealed that inflammation is more pronounced in spinal cord than in brain. Therefore, it is unclear whether concepts and treatments established in the cerebral cortex can be transferred to spinal cord lesions and vice versa or whether immunological treatments must be adapted to different CNS compartments. By use of transcriptomic and flow cytometry analysis of equally sized photothrombotically induced lesions in the cerebral cortex and the spinal cord, we could document an overall comparable inflammatory reaction and repair activity in brain and spinal cord between day 1 and day 7 after ischemia. However, remyelination was increased after cerebral versus spinal cord ischemia which is in line with increased remyelination in gray matter in previous analyses and was accompanied by microglia dominated inflammation opposed to monocytes/macrophages dominated inflammation after spinal cord ischemia. Interestingly remyelination could be reduced by microglia and not hematogenous macrophage depletion. Our results show that despite different cellular composition of the postischemic infiltrate the inflammatory response in cerebral cortex and spinal cord are comparable between day 1 and day 7. A striking difference was higher remyelination capacity in the cerebral cortex, which seems to be supported by microglia dominance.

Retinal layers and visual conductivity changes in a case series of microangiopathic ischemic stroke patients.

BACKGROUND: It is unknown whether microangiopathic ischemic strokes outside the visual pathway go along with subclinical changes of the retinal structure or the visual system. The objectives of this prospective non-interventional case series were to investigate if spectral-domain optical coherence tomography (SD-OCT) or multifocal visual evoked potentials (mfVEPs) can detect structural retinal changes or functional impairment of the visual system in patients with microangiopathic ischemic stroke. METHODS: We used SD-OCT to cross-sectionally analyze the retinal morphology of 15 patients with microangiopathic ischemic stroke according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification not affecting the visual pathway. We employed semi-automated segmentation of macular volume scans to analyze the thickness of the macular retinal layers and peripapillary ring scans to investigate the retinal morphology in comparison to a control group without stroke. Visual function was assessed by the mfVEP technique in 13 microangiopathic ischemic stroke patients. RESULTS: First peak latency of mfVEPs was significantly delayed in the microangiopathic ischemic stroke group compared to the control patients. Neither the retinal layers nor the mfVEPs' amplitude differed between the microangiopathic ischemic stroke patients and the control group. CONCLUSIONS: In conclusion, microangiopathic ischemic stroke patients presented a delayed first peak latency in mfVEPs as a sign of subclinical functional impairment of the visual pathway. However, our case series suggests no influence on retinal structure resulting from microangiopathic ischemic stroke outside the visual system. Larger and longitudinal studies are needed to confirm these mfVEP findings.

Mechanical thrombectomy in acute middle cerebral artery M2 segment occlusion with regard to vessel involvement.

BACKGROUND: Endovascular treatment (EVT) is an established procedure in patients with acute ischemic stroke due to occlusion of the proximal M1-segment of middle cerebral artery. The assessment of distal thrombectomy in daily clinical routine has not yet been sufficiently evaluated. METHODS: Patients with M2-segment-occlusions treated by EVT in the local department (January 2012-December 2017) were included (n = 57, mean National-Institutes-of-Health-Stroke-Scale of 11, range 0-20). Patients were grouped according to localization of M2-occlusion (Cohort A (n = 14): central region only, B (n = 24): central region and involvement of frontal vessels, C (n = 19): parietal, occipital, and/or temporal vessels). Differences in proximal (M2-trunk, n = 34) and distal (M2-branches, n = 23) occlusions were also examined. Reperfusion (Thrombolysis-In-Cerebral-Infarction (TICI)), early clinical outcome at discharge (modified Rankin Scale (mRS)), and complications (hemorrhage, new emboli) were noted. RESULT: Successful reperfusion (TICI2b-3) was found in 49 patients (86.0%). Favorable early clinical outcome (mRS0-2) was achieved in n = 19 (37.7%). Compared to admission, mRS at discharge improved significantly (median (admission) 5 vs. median (discharge) 4, p < 0.001). Early clinical outcome was more favorable in patients with better reperfusion (TICI2b-3: mean mRS 3 ± 1.7 vs. TICI0-2a: mean mRS 4.4 ± 1.4, p = 0.037). Six (10.5%) patients suffered from symptomatic intracranial hemorrhage during treatment or hospitalization. Four patients died (7.0%). No significant differences in favorable clinical outcome (mRS ≤ 2: Cohort A 42.9%, B 50.0%, C 16.7%, p = 0.4; χ2-test) or periinterventional complications were found with regard to vessel involvement. CONCLUSION: EVT in patients with acute M2-occlusion is safe and leads to a significant clinical improvement at discharge. No significant differences in clinical outcome or complications were found with regard to the localization of the M2-occlusion.

One-year single-center experience with the Aperio thrombectomy device in large vessel occlusion in the anterior circulation: safety, efficacy, and clinical outcome.

BACKGROUND AND PURPOSE: The Aperio thrombectomy device (Aperio) is a stent retriever designed to achieve rapid and substantial flow restoration in acute ischemic stroke due to large-vessel occlusions (LVOs). We evaluated the safety and efficacy of the Aperio device and compared it with published data of established stent retrievers. METHODS: We retrospectively analyzed institutional data of consecutive stroke procedures in patients with LVO in the anterior circulation that were treated between January 2017 and December 2017 with the Aperio. Reperfusion rate regarding to the extended thrombolysis in cerebral infarction scale (eTICI), procedural times, early clinical outcome, and complications were documented. RESULTS: Eighty-two patients were treated by using the Aperio in LVO in the anterior circulation. Median age was 77 (± 12) years (w = 59.8%). Median Baseline National Institutes of Health Stroke Scale (NIHSS) score was 14. Fifty-three (64.6%) patients received intravenous thrombolysis. Successful recanalization (eTICI≥2b) was achieved in 85.3%. Mean time from groin puncture to final recanalization was 52.3 ± 34.8 min. Embolization to new territories occurred in one case. Symptomatic intracranial hemorrhage within 24 h was observed in six patients (7.3%). Twenty-eight (41.2%) out of 68 patients available for assessment of functional outcome at 3 months achieved favorable outcome (mRS 0-2). CONCLUSION: The Aperio stent retriever mechanical thrombectomy device demonstrated high rates of successful reperfusion and a good safety profile in patients with acute ischemic stroke due to LVO in the anterior circulation.

A Retrospective Single-Center Case Series of Direct Aspiration Thrombectomy as First-Line Approach in Ischemic Stroke and Review of the Literature.

INTRODUCTION: The benefit of the direct aspiration thrombectomy (ADAPT) technique for the treatment of ischemic stroke due to large vessel occlusion are challenged after publishing of the ASTER trial that failed to show superiority of ADAPT compared to stent retriever. Aim of the present single-center study was a retrospective evaluation of the ADAPT technique comparing our results with literature. MATERIAL/METHODS: We retrospectively analyzed institutional data of stroke procedures in patients with mainstem occlusion of the middle cerebral artery treated between November 2016 and December 2017 with an initial attempt of manual thrombaspiration. Reperfusion rate (thrombolysis in cerebral infarction), procedural times, early clinical outcome and complications were recorded. RESULTS: Forty patients were treated by using direct thrombaspiration in middle cerebral artery mainstem occlusion. Median age was 67.5 (±17.8) years (m = 27.5%). Median Baseline National Institutes of Health Stroke Scale score was 12 (IQR 7) preintervention and 3 (IQR 11) postintervention. Twenty-eight (70%) patients received intravenous thrombolysis. Successful recanalization (modified thrombolysis in cerebral infarction ≥ 2b) could be achieved in 85% with direct aspiration alone. Mean time from groin puncture to recanalization was 25.2 ± 14.3 minutes. Embolization to new territories occurred in 1 of 40 (2.5%) cases and symptomatic intracranial hemorrhage in 3 of 40 (7.5%). Nineteen of 40 (47.5%) patients achieved favorable outcome (modified Rankin scale 0-2) at discharge. CONCLUSIONS: The ADAPT technique presented as a safe and efficient first-line recanalization strategy with good clinical outcome for treatment of acute ischemic stroke resulting from large vessel occlusions in this single-center study and review of the literature. However, the concept of ADAPT as an equivalent first-line approach to stent retriever thrombectomy has to be proven by future randomized studies.

Protective features of peripheral monocytes/macrophages in stroke.

Hematogenous recruitment of monocytes and macrophages has traditionally been viewed as a harmful process causing exacerbation of brain injury after stroke. However, emerging findings suggest equally important protective features. Inflammatory monocytes are rapidly recruited to ischemic brain via a CCR2-dependent pathway and undergo secondary differentiation in the target tissue towards non-inflammatory macrophages, mediating neuroprotection and repair of the ischemic neurovascular unit. In contrast, independent recruitment of non-inflammatory monocytes via CX3CR1 does not occur. Thus, protective features of hematogenous macrophages mainly depend on initial CCR2-dependent cell recruitment. Under therapeutic considerations, specific modulation of monocyte-derived macrophages will therefore be more appropriate than non-selectively blocking their hematogenous recruitment. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

Coagulation Testing in Acute Ischemic Stroke Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants.

BACKGROUND AND PURPOSE: In patients who present with acute ischemic stroke while on treatment with non-vitamin K antagonist oral anticoagulants (NOACs), coagulation testing is necessary to confirm the eligibility for thrombolytic therapy. We evaluated the current use of coagulation testing in routine clinical practice in patients who were on NOAC treatment at the time of acute ischemic stroke. METHODS: Prospective multicenter observational RASUNOA registry (Registry of Acute Stroke Under New Oral Anticoagulants; February 2012-2015). Results of locally performed nonspecific (international normalized ratio, activated partial thromboplastin time, and thrombin time) and specific (antifactor Xa tests, hemoclot assay) coagulation tests were documented. The implications of test results for thrombolysis decision-making were explored. RESULTS: In the 290 patients enrolled, nonspecific coagulation tests were performed in ≥95% and specific coagulation tests in 26.9% of patients. Normal values of activated partial thromboplastin time and international normalized ratio did not reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11%-44% [95% confidence interval 1%-69%]). Twelve percent of patients apparently failed to take the prescribed NOAC prior to the acute event. Only 5.7% (9/159) of patients in the 4.5-hour time window received thrombolysis, and NOAC treatment was documented as main reason for not administering thrombolysis in 52.7% (79/150) of patients. CONCLUSIONS: NOAC treatment currently poses a significant barrier to thrombolysis in ischemic stroke. Because nonspecific coagulation test results within normal range have a high false-negative rate for detection of relevant drug concentrations, rapid drug-specific tests for thrombolysis decision-making should be established. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797.

Mechanical recanalization in basilar artery occlusion: the ENDOSTROKE study.

OBJECTIVE: A study was undertaken to evaluate clinical and procedural factors associated with outcome and recanalization in endovascular stroke treatment (EVT) of basilar artery (BA) occlusion. METHODS: ENDOSTROKE is an investigator-initiated multicenter registry for patients undergoing EVT. This analysis includes 148 consecutive patients with BA occlusion, with 59% having received intravenous thrombolysis prior to EVT. Recanalization (defined as Thrombolysis in Cerebral Infarction [TICI] score 2b-3) and collateral status (using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral grading system) were assessed by a blinded core laboratory. Good (moderate) outcome was defined as a modified Rankin Scale score of 0 to 2 (0-3) assessed after at least 3 months (median time to follow-up = 120 days). RESULTS: Thirty-four percent had good and 42% had moderate clinical outcome; mortality was 35%. TICI 2b-3 recanalization was achieved by 79%. Age, hypertension, National Institutes of Health Stroke Scale scores, collateral status, and the use of magnetic resonance imaging prior to EVT predicted clinical outcome, the latter 3 remaining independent predictors in multivariate analysis. Independent predictors of recanalization were better collateral status and the use of a stent retriever. However, recanalization did not significantly predict clinical outcome. INTERPRETATION: Beside initial stroke severity, the collateral status predicts clinical outcome and recanalization in BA occlusion. Our data suggest that the use of a stent retriever is associated with high recanalization rates, but recanalization on its own does not predict outcome. The role of other modifiable factors, including the choice of pretreatment imaging modality and time issues, warrants further investigation.

Macrophage-derived osteopontin induces reactive astrocyte polarization and promotes re-establishment of the blood brain barrier after ischemic stroke.

Infarcted regions of the brain after stroke are segregated from the intact brain by scar tissue comprising both fibrous and glial components. The extent and quality of scarring is influenced by inflammation. The matricellular glycoprotein osteopontin (OPN) is strongly induced in myeloid cells after stroke and may contribute to repair of ischemic brain lesions. To elucidate the role of OPN in scar formation, we induced photothrombotic brain infarction, characterized by circumscribed cortical infarctions with a well-defined border zone toward the intact brain parenchyma. The cellular source and functional role of OPN was addressed by studies in OPN null (OPN(-/-) ) mice, wild-type mice depleted of hematogenous monocytes/macrophages by clodronate-filled liposome treatment, and CCR2(-/-) bone marrow chimeric mice characterized by impaired hematogenous macrophage influx into the infarctions. OPN was mainly produced by hematogenous macrophages infiltrating into the inner border zone of the infarcts whereas astrocyte activation occurred in the outer border zone. In OPN(-/-) as well as macrophage-depleted mice, reactive astrocytes failed to properly extend processes from the periphery toward the center of the infarctions. This was associated with incomplete coverage of neovessels by astrocytic endfeet and persistent leakiness of the damaged blood brain barrier. In conclusion, OPN produced by hematogenous macrophages induces astrocyte process extension toward the infarct border zone, which may contribute to repair of the ischemic neurovascular unit.

Hyperglycemia and PPARγ Antagonistically Influence Macrophage Polarization and Infarct Healing After Ischemic Stroke.

BACKGROUND AND PURPOSE: Secondary intracerebral hemorrhage (sICH) is a potentially serious complication of ischemic stroke, in particular under concomitant oral anticoagulation. Previous studies in murine stroke models defined a novel vascular repair function of hematogenous monocytes/macrophages (MO/MP), which proved essential for the prevention of oral anticoagulation-associated sICH. Here, we addressed the question whether hyperglycemia as a clinically relevant prohemorrhagic risk factor and peroxisome proliferator-activated receptor gamma (PPARγ) activation affect MO/MP differentiation and the risk of sICH after ischemic stroke. METHODS: Oral anticoagulation-associated sICH was induced by phenprocoumon feeding to mice undergoing transient middle cerebral artery occlusion. Hyperglycemia was induced by streptozotocin treatment. The role of PPARγ-dependent MO/MP differentiation was addressed in mice with myeloid cell-specific PPARγ-knockout (LysM-PPARγ(KO)). Pharmacological PPARγ activation via pioglitazone was tested as a treatment option. RESULTS: Hyperglycemic mice and normoglycemic LysM-PPARγ(KO) mice exhibited abnormal proinflammatory skewing of their hematogenous MO/MP response and abnormal vascular remodeling in the infarct border zone, leading to an increased rate of oral anticoagulation-associated sICH. Pharmacological PPARγ activation in hyperglycemic mice corrected the inflammatory response toward an anti-inflammatory profile, stabilized neovessels in the infarct border zone, and reduced the rate of sICH. This preventive effect was dependent on the presence of macrophages, but independent from effects on blood glucose levels. CONCLUSIONS: Hyperglycemia and macrophage-specific PPARγ activation exert opposing effects on MO/MP polarization in ischemic stroke lesions and, thereby, critically determine the risk of hemorrhagic infarct transformation.

Macrophages prevent hemorrhagic infarct transformation in murine stroke models.

OBJECTIVE: Inflammation is increasingly viewed as a new therapeutic target in subacute stages of brain infarction. However, apart from causing secondary damage, inflammation could equally promote beneficial lesion remodeling and repair. Distinct subpopulations of monocytes/macrophages (MOs/MPs) may critically determine the outcome of lesion-associated inflammation. METHODS: We addressed the role of bone marrow-derived MOs/MPs in 2 different mouse models of ischemic stroke using a combined cell-specific depletion, chemokine receptor knockout, bone marrow chimeric, and pharmacological approach. RESULTS: Starting within 24 hours of stroke onset, immature Ly6c(hi) monocytes infiltrated into the infarct border zone and differentiated into mature Ly6c(lo) phagocytes within the lesion compartment. MO/MP infiltration was CCR2-dependent, whereas we did not obtain evidence for additional recruitment via CX3CR1. Depletion of circulating MOs/MPs or selective targeting of CCR2 in bone marrow-derived cells caused delayed clinical deterioration and hemorrhagic conversion of the infarctions. Bleeding frequently occurred around thin-walled, dilated neovessels in the infarct border zone and was accompanied by decreased expression of transforming growth factor (TGF)-ß1 and collagen-4, along with diminished activation of Smad2. Injection of TGF-ß1 into the lesion border zone greatly reduced infarct bleeding in MO/MP-depleted mice. INTERPRETATION: Bone marrow-derived MOs/MPs recruited via CCR2 and acting via TGF-ß1 are essential for maintaining integrity of the neurovascular unit following brain ischemia. Future therapies should be aimed at enhancing physiological repair functions of CCR2(+) MOs/MPs rather than blocking their hematogenous recruitment.

Age dependency of successful recanalization in anterior circulation stroke: the ENDOSTROKE study.

BACKGROUND: Clinical outcome after endovascular stroke therapy (EVT) for proximal anterior circulation stroke is often disappointing despite high recanalization rates. The ENDOSTROKE study aims to determine predictors of clinical outcome in patients undergoing EVT. Here we focus on the impact of age and recanalization on proximal middle cerebral artery (M1-MCA) or carotid T occlusion. METHODS: ENDOSTROKE is an investigator-initiated, industrially independent multicenter registry launched in January, 2011, for consecutive patients undergoing EVT for large-vessel stroke. This analysis focuses on patients treated in 11 academic and nonacademic stroke centers with angiographically proven M1-MCA (n = 259) or carotid T occlusion (n = 103). Recanalization was defined as Thrombolysis in Myocardial Infarction (TIMI) score 2 or 3, and in patients with available Thrombolysis in Cerebral Ischemia (TICI) data (n = 309) as TICI scores 2b-3. Good outcome was defined as modified Rankin Scale (mRS) score of 0-2 assessed after 3 months or later. RESULTS: The median age was 68 years (25th and 75th percentiles: 56, 76 years), and the median National Institutes of Health Stroke Scale (NIHSS) score at admission was 16 (13, 19); 41% of the patients had a favorable (mRS scores 0-2), and 59% had an unfavorable (mRS scores 3-6) outcome; 83% reached TIMI 2-3 flow. Independent predictors of good outcome were younger age, lower initial NIHSS scores, TIMI 2/3 recanalization and lower serum glucose levels. Outcome was highly dependent on patients' age: 60% of the patients within the lowest age quartile (range: 18-56 years) experienced good clinical outcome, decreasing stepwise over 47% (57-68 years) and 37% (69-76 years) to 17% in the highest age quartile (77-94 years). The proportion of patients with poor clinical outcome despite TIMI 2/3 recanalization ('futile recanalization') increased dramatically from only 29% in the lowest age quartile over 34% and 40% (2nd and 3rd age quartiles) up to 53% in the highest age quartile. Results were similar in patients with available TICI scores, with 'futile recanalization' rates increasing from 24% to 46% (lowest to highest age quartile). CONCLUSIONS: This study emphasizes the dramatic impact of patients' age on outcome in EVT for M1-MCA or carotid T occlusion, even in the presence of recanalization. Reasons for this age-related decrease in clinically successful recanalization rates urgently need clarification and may comprise patient-related factors (age-related increase in cardioembolic strokes, collateral status, comorbidities) as well as periprocedural issues (tortuous vessel anatomy in the elderly, age-dependent negative impact of general anesthesia in EVT).

Periprocedural aspects in mechanical recanalization for acute stroke: data from the ENDOSTROKE registry.

INTRODUCTION: The ENDOSTROKE registry aims to accompany the spreading use of endovascular stroke treatment (EVT) in academic and non-academic hospitals. This analysis focuses on preprocedural imaging, patient handling and referral, as well as on different treatment modalities in mechanical recanalization. METHODS: Data for this study were from observational registry study in 12 stroke centers in Germany and Austria with online assessment of prespecified variables concerning endovascular stroke therapy. RESULTS: Data from 734 patients undergoing EVT were analyzed. Preferred imaging modality prior to EVT was CT (83 %) and CTA (78 %). In 95 %, EVT was performed under general anesthesia. In 55 % of patients, a combination of intravenous (IV) thrombolysis and EVT was used, followed by pure EVT (25 %), intra-arterial (IA) thrombolysis plus EVT (13 %) and IV + IA thrombolysis plus EVT (7 %). Intrahospital time delay until start of EVT was 91 and 99 min in anterior and vertebrobasilar circulation stroke, respectively. Average duration of EVT was 60 min. Overall thrombolysis in myocardial infarction grade 2/3 recanalization rate was 85 %. Stent retrievers were used in 75 %, being associated with higher recanalization rates than non-stent retrievers. Hemorrhagic complications (symptomatic and asymptomatic) occurred in 12 %. Overall vessel occlusion time was approximately 60 min longer in patients being referred from a primary care hospital for EVT. CONCLUSION: This study gives an overview of procedure-related factors in current EVT practice. It gives estimates on preprocedural imaging modalities, periprocedural handling, and treatment combinations used for EVT. Patient referral for EVT from primary care hospitals is associated with longer vessel occlusion times.

Mothership vs. drip-and-ship: evaluation of initial treatment strategies for acute ischemic stroke in a well-developed network of specialized hospitals.

PURPOSE: Two strategies of initial patient care exist in endovascular thrombectomy (ET) depending on the site of initial admission: the mothership (MS) and drip-and-ship (DnS) principles. This study compares both strategies in regard to patient outcome in a local network of specialized hospitals. METHODS: Two-hundred-and-two patients undergoing ET in anterior circulation ischemic stroke between June 2016 and May 2018 were enrolled. Ninety two patients were directly admitted to our local facility (MS), One-hundred-and-ten were secondarily referred to our facility. Group comparisons between admission strategies in three-months modified Rankin Scale (mRS), Maas Score and Alberta-Stroke-Program-Early-computed-tomography-score (ASPECTS), National-Institutes-of-Health-Stroke-Scale (NIHSS), age and onset-to-recanalization-time were performed. Correlation between admission strategy and mRS was calculated. A binary logistic regression model was computed including mRS as dependent variable. RESULTS: There were neither significant group differences in three-months mRS between MS and DnS nor significant correlations. Patients tended to achieve a better outcome with DnS. Collateralization status differed between MS and DnS (p = 0.003) with better collateralization in DnS. There were no significant group differences in NIHSS or ASPECTS but in onset-to-recanalization-time (p < 0.001) between MS and DnS. Binary logistic regression showed a high explanation of variance of mRS but no significant results for admission strategy. CONCLUSIONS: Functional outcome in patients treated with ET is comparable between the MS and DnS principles. Tendentially better outcome in the DnS subgroup may be explained by selection bias due to a higher willingness to apply ET in patients with worse baseline conditions (e.g. worse collateralization), if patients undergoing MS are already on site.

Guideline for the management of myasthenic syndromes.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

Secondary intracerebral hemorrhage due to early initiation of oral anticoagulation after ischemic stroke: an experimental study in mice.

BACKGROUND AND PURPOSE: The uncertain risk of secondary intracerebral hemorrhage (sICH) frequently keeps clinicians from initiating oral anticoagulation (OAC) early after ischemic cardioembolic stroke. The goal of this experimental study was to determine the risk of sICH depending on the timing of OAC initiation relative to stroke onset and to address the role of hematogenous macrophages for repair processes preventing OAC-associated sICH. METHODS: C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Subgroups were treated with either the vitamin K antagonist (VKA) phenprocoumon or the direct thrombin inhibitor dabigatran etexilate. Hematogenous macrophages were depleted using intraperitoneal injections of clodronate-filled liposomes. RESULTS: Time to therapeutic OAC was 48 hours with VKA and 0.5 hours with dabigatran etexilate treatment. In VKA-treated mice, the risk of sICH was high if effective OAC was already present at stroke onset or achieved within 48 hours after ischemia. With more delayed OAC, the risk of sICH rapidly decreased. Compared with VKA treatment, effective anticoagulation with dabigatran etexilate was associated with a significantly reduced extent of sICH, either if present at stroke onset or if achieved 48 hours later. Partial depletion of macrophages greatly increased the extent of OAC-associated sICH in the subacute stage of 3 to 4 days after ischemia. CONCLUSIONS: Our findings suggest that repair mechanisms involving hematogenous macrophages rapidly decrease the risk of OAC-associated sICH in the first days after ischemic stroke. The lower risk of sICH under dabigatran etexilate compared with VKA treatment may facilitate early initiation of OAC after cardioembolic stroke.

Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod.

In this report we describe a multiple sclerosis patient who developed a relapse with magnetic resonance imaging (MRI) features of tumefactive demyelination after switching therapy from natalizumab to fingolimod. Tumefactive lesions emerged 16 weeks after stopping natalizumab and eight weeks after commencing fingolimod therapy but had been absent at the time of diagnosis and throughout the preceding course of the disease. Thus, the first-time occurrence of atypical lesion features may have been caused by the change in immunotherapy. The possible relevance of natalizumab withdrawal vs fingolimod introduction is discussed against the background of recently published case studies.

An emboligenic pulmonary abscess leading to ischemic stroke and secondary brain abscess.

BACKGROUND: Ischemic stroke by septic embolism occurs primarily in the context of infective endocarditis or in patients with a right-to-left shunt and formation of a secondary cerebral abscess is a rare event. Erosion of pulmonary veins by a pulmonary abscess can lead to transcardiac septic embolism but to our knowledge no case of septic embolic ischemic stroke from a pulmonary abscess with secondary transformation into a brain abscess has been reported to date. CASE PRESENTATION: We report the case of a patient with a pulmonary abscess causing a septic embolic cerebral infarction which then transformed into a cerebral abscess. After antibiotic therapy and drainage of the abscess the patient could be rehabilitated and presented an impressive improvement of symptoms. CONCLUSION: Septic embolism should be considered as cause of ischemic stroke in patients with pulmonary abscess and can be followed by formation of a secondary cerebral abscess. Early antibiotic treatment and repeated cranial CT-scans for detection of a secondary abscess should be performed.

p57kip2 is dynamically regulated in experimental autoimmune encephalomyelitis and interferes with oligodendroglial maturation.

The mechanisms preventing efficient remyelination in the adult mammalian central nervous system after demyelinating inflammatory diseases, such as multiple sclerosis, are largely unknown. Partial remyelination occurs in early disease stages, but repair capacity diminishes over time and with disease progression. We describe a potent candidate for the negative regulation of oligodendroglial differentiation that may underlie failure to remyelinate. The p57kip2 gene is dynamically regulated in the spinal cord during MOG-induced experimental autoimmune encephalomyelitis. Transient down-regulation indicated that it is a negative regulator of post-mitotic oligodendroglial differentiation. We then applied short hairpin RNA-mediated gene suppression to cultured oligodendroglial precursor cells and demonstrated that down-regulation of p57kip2 accelerates morphological maturation and promotes myelin expression. We also provide evidence that p57kip2 interacts with LIMK-1, implying that p57kip2 affects cytoskeletal dynamics during oligodendroglial maturation. These data suggest that sustained down-regulation of p57kip2 is important for oligodendroglial maturation and open perspectives for future therapeutic approaches to overcome the endogenous remyelination blockade in multiple sclerosis.

Energy transfer from CdSe/CdS nanorods to amorphous carbon.

Semiconductor nanocrystals placed nearby a metal film significantly change their optical properties. In this work, we examine the change in fluorescence intensity, lifetime, and blinking behavior of individual CdSe/CdS nanorods close to a 9 nm thick amorphous carbon film. Energy transfer between the donor and acceptor was investigated in detail yielding a R(-4) distance dependence for the nanorod-carbon system. The Förster critical distance was determined to be R0=24.9 nm, which is nearly identical with the theoretical value of 24.8 nm predicted by the classical approach. Additionally, antibunching measurements were performed in order to prove the presence of single isolated emitters.