Plasma Exchange versus Intravenous Immunoglobulin in Worsening Myasthenia Gravis: A Systematic Review and Meta-Analysis with Special Attention to Faster Relapse Control.

Currently used rescue interventions to prevent rapid myasthenic deterioration are plasma exchange (PLEX) and intravenous immunoglobulin (IVIG). We investigated the evidence to determine whether the two methods were interchangeable or whether one was superior to the other. This review was registered on PROSPERO (CRD42021285985). Only randomized controlled trials (RCTs) comparing the efficacy and safety of PLEX and IVIG in patients with moderate-to-severe myasthenia gravis (MG) were included. Five major databases were systematically searched (PubMed, CENTRAL, Embase, Scopus, and Web of Science). Odds ratios (OR) with 95% confidence intervals (CI) were calculated for adverse events and mean differences (MD) for changes in quantitative myasthenia gravis scores (QMG). Three RCTs met the inclusion criteria. Two investigating 114 patients in total were eligible for meta-analysis to analyze efficacy and safety. For the change in QMG score, the MD was -2.8 (95% CI: -5.614-0.113), with PLEX performing better. For adverse events, an OR of 1.04 was found (95% CI: 0.25-4.27). This study demonstrated a low risk of bias in evaluating treatment efficacy but indicated a high risk of bias in assessing procedural safety outcomes. Although the results did not show any significant difference, there was a tendency indicating faster efficacy of PLEX in the first two weeks of treatment. In such a critical clinical condition, this tendency may be clinically meaningful, but further studies should clarify this benefit.

Treatment of relapsing multiple sclerosis in Hungary - consensus recommendation from the Hungarian neuroimmunology society.

Multiple sclerosis (MS) may impact quality of life, careers and family plans of the affected individuals. The current treatments with disease modifying therapies aim to prevent people with MS (pwMS) from disability accumulation and progression. Different countries have different reimbursement policies resulting in inequalities in patient care among geographical regions. Access to anti-CD20 therapies for relapsing MS is restricted in Hungary because therapy of individual cases only is reimbursed. In the light of the latest research and national guidelines, 17 Hungarian MS experts agreed on 8 recommendations regarding relapsing pwMS using the Delphi round method. Strong agreement (> 80%) was achieved in all except one recommendation after three rounds, which generated a fourth Delphi round. The experts agreed on treatment initiation, switch, follow-up and discontinuation, as well as on special issues such as pregnancy, lactation, elderly population, and vaccination. Well-defined national consensus protocols may facilitate dialogue between policymakers and healthcare professionals and thus contribute to better patient care in the long run.

Population-based head-to-head comparison of the clinical characteristics and epidemiology of AQP4 antibody-positive NMOSD between two European countries.

BACKGROUND: Population-based clinical studies in neuromyelitis optica spectrum disorder (NMOSD) and epidemiological and clinical comparisons of White ethnicities are missing. In a large population-based international cohort, we extensively characterized aquaporin-4 antibody seropositive (AQP4-Ab+) NMOSD, and also compared the clinical, radiological and epidemiological features between two European populations residing in different areas. METHODS: Between self-reported Danish and Hungarian ethnicities, we compared the population-based clinical features, disability outcomes, and death of 134 AQP4-Ab+ NMOSD cases fulfilling the 2015 International Panel for NMO Diagnosis (IPND) criteria. For precise comparison of epidemiology, we conducted a population-based head-to-head comparative study of the age-standardized prevalence (January 1, 2014) and incidence (2007-2013) of AQP4-Ab+ NMO/NMOSD among adults (≥16 years) in Denmark (4.6 million) and Hungary (6.4 million) by applying 2015 IPND (NMOSD) criteria and 2006 Wingerchuk (NMO). RESULTS: Danes were more likely to present with transverse myelitis and were more affected by spinal cord damage on long-term disability. Hungarians presented most often with optic neuritis, although visual outcome was similar in the groups. No differences were observed in sex, disease course, relapse rate, autoimmune comorbidity, mortality, brain MRI, and treatment strategies. The age-standardized prevalence estimates of AQP4-Ab+ NMOSD (2015 IPND criteria) in Denmark vs. Hungary were 0.66 vs. 1.43 (/100,000) while incidence rates were 0.04 vs. 0.11 (/100,000 person-years); similar differences were found based on the 2006 NMO criteria. CONCLUSIONS: This head-to-head comparative study indicates different disease characteristics and epidemiology among White populations in Europe, and substantiates the need for population-based genetic and environmental studies in NMOSD.

Differences in guidelines for patients with carotid artery stenosis in some European countries / A nyaki veroér-szukületes betegek ellátási irányelveinek különbségei Európa különbözo országaiban.

Összefoglaló. A tudomány jelenlegi állása szerint - csoportok összehasonlítására épülo matematikai-statisztikai eszközökkel - a leginkább hatékonynak és hatásosnak vélt kezelési módszerek szisztematikus elemzése mentén, a bizonyítékokon alapuló irányelveken nyugvó gyógyító munkát tekintjük követendonek. A nyaki veroérszukület ellátása esetén az utóbbi években elkészült mind a hazai, mind az európai irányelv, mindemellett a társszakmák irányelveiben is megjelentek kezelési javaslatok. Közleményünkben összehasonlítottuk a témában publikált magyar, angol, német és olasz nyelvu, valamint az európai társaságok által kiadott irányelveket. Az irányelvek alapelveikben hasonlóak, formailag és tartalmilag azonban jelentos (idonként egymásnak ellentmondani látszó) különbségeket találhatunk. Az ellentmondások három leggyakoribb oka: 1) az egyes irányelvek által kituzött célok különbözosége, 2) az aszimptomatikus és szimptomatikus betegcsoport definíciói, valamint 3) az eltéro evidenciaszintek. Az irányelvek összevetése alapján a tünetes, szignifikáns nyaki veroérszukületek sebészi ellátása evidenciának tekintheto. A szimptomatikus nyaki veroérszukület a definíció szerint ellenoldali cerebralis ischaemia okozta, tranziens vagy definitív plegia, paresis, aphasia és az azonos oldali arteria centralis retinae embolisatiója miatti amaurosis fugax. A tünetmentes nyaki veroérszukületek ellátása tekintetében az európai és a nemzeti irányelvek nem azonosak, ezen esetek terápiás döntése egyéni mérlegelést igényel. Tünetmentes, 70%-os stenosis esetén vascularteam-konzílium javasolt. Orv Hetil. 2020; 161(51): 2139-2145. Summary. The correct practice is the one that is proven to be the most effective based on systematic statistical analyses of different treatment methods, and is applied according to evidence-based principles. In recent years, not only has the European Society of Vascular Surgery created a guideline about the management of supra-aortic steno-occlusive disease, but some nations' vascular surgical societies and related disciplines have also developed their own guidance. In this paper, the guidelines by the European societies on the clinical care of patients with carotid artery luminal narrowing is compared to national guidelines published in Hungarian, English, German, and Italian. Although the fundamental points of the guidelines are similar, there are some important differences among them both in presentation and in content; as a result, they sometimes appear to be contradictory. The three main sources of inconsistency are the various goals, the discrepancy in the definition of symptomatic and asymptomatic carotid artery stenosis, and the bias arising from the use of distinct evidence levels. A comparison of guidelines suggests that the treatment of symptomatic significant carotid artery stenosis with surgery can be considered evidence. Symptomatic carotid artery stenosis is defined as transient or definite plegia, paresis, aphasia due to cerebral ischemia, and monocular blindness caused by embolism in the central retinal artery. However, in the case of asymptomatic 70% or greater carotid artery stenosis, the guidelines are quite heterogeneous, and these patients require individual consideration and a vascular team decision is recommended. Orv Hetil. 2020; 161(51): 2139-2145.

Induction of transforming growth factor beta receptors following focal ischemia in the rat brain.

Transforming growth factor-ßs (TGF-ßs) regulate cellular proliferation, differentiation, and survival. TGF-ßs bind to type I (TGF-ßRI) and II receptors (TGF-ßRII), which are transmembrane kinase receptors, and an accessory type III receptor (TGF-ßRIII). TGF-ß may utilize another type I receptor, activin-like kinase receptor (Alk1). TGF-ß is neuroprotective in the middle cerebral artery occlusion (MCAO) model of stroke. Recently, we reported the expression pattern of TGF-ß1-3 after MCAO. To establish how TGF-ßs exert their actions following MCAO, the present study describes the induction of TGF-ßRI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-ßRI had significant expression: neurons in cortical layer IV contained TGF-ßRI. At 24 h after the occlusion, no TGF-ß receptors showed induction. At 72 h following MCAO, all four types of TGF-ß receptors were induced in the infarct area, while TGF-ßRI and RII also appeared in the penumbra. Most cells with elevated TGF-ßRI mRNA levels were microglia. TGF-ßRII co-localized with both microglial and endothelial markers while TGF-ßRIII and Alk1 were present predominantly in endothels. All four TGF-ß receptors were induced within the lesion 1 mo after the occlusion. In particular, TGF-ßRIII was further induced as compared to 72 h after MCAO. At this time point, TGF-ßRIII signal was predominantly not associated with blood vessels suggesting its microglial location. These data suggest that TGF-ß receptors are induced after MCAO in a timely and spatially regulated fashion. TGF-ß receptor expression is preceded by increased TGF-ß expression. TGF-ßRI and RII are likely to be co-expressed in microglial cells while Alk1, TGF-ßRII, and RIII in endothels within the infarct where TGF-ß1 may be their ligand. At later time points, TGF-ßRIII may also appear in glial cells to potentially affect signal transduction via TGF-ßRI and RII.

Cerebral iodized lipid embolization via a pulmonary arteriovenous shunt: rare complication of transcatheter arterial embolization for hepatocellular carcinoma.

We report the first European case of cerebral iodized lipid embolism post transcatheter arterial embolization for hepatocellular carcinoma. Lipiodol emboli and corresponding multifocal brain ischemia were documented with computed tomography (CT) and magnetic resonance (MR) in the acutely symptomatic patient. Transcranial Doppler sonography with contrast indicated a right-to-left shunt, while on a follow-up CT scan lipiodol embolization was detected in both lungs. Dilated pulmonary vessels and thick vascular channels were seen in the vicinity of the right diaphragm suggestive of pulmonary arteriovenous shunt. The patient symptoms regressed with supportive care alone, but he died 5 months later due to hepatic failure unrelated to the procedure.

Time course, distribution and cell types of induction of transforming growth factor betas following middle cerebral artery occlusion in the rat brain.

Transforming growth factor-ßs (TGF-ß1-3) are cytokines that regulate the proliferation, differentiation, and survival of various cell types. The present study describes the induction of TGF-ß1-3 in the rat after focal ischemia at 3 h, 24 h, 72 h and 1 month after transient (1 h) or permanent (24 h) middle cerebral artery occlusion (MCAO) using in situ hybridization histochemistry and quantitative analysis. Double labeling with different markers was used to identify the localization of TGF-ß mRNA relative to the penumbra and glial scar, and the types of cells expressing TGF-ßs. TGF-ß1 expression increased 3 h after MCAO in the penumbra and was further elevated 24 h after MCAO. TGF-ß1 was present mostly in microglial cells but also in some astrocytes. By 72 h and 1 month after the occlusion, TGF-ß1 mRNA-expressing cells also appeared in microglia within the ischemic core and in the glial scar. In contrast, TGF-ß2 mRNA level was increased in neurons but not in astrocytes or microglial cells in layers II, III, and V of the ipsilateral cerebral cortex 24 h after MCAO. TGF-ß3 was not induced in cells around the penumbra. Its expression increased in only a few cells in layer II of the cerebral cortex 24 h after MCAO. The levels of TGF-ß2 and -ß3 decreased at subsequent time points. Permanent MCAO further elevated the levels of all 3 subtypes of TGF-ßs suggesting that reperfusion is not a major factor in their induction. TGF-ß1 did not co-localize with either Fos or ATF-3, while the co-localization of TGF-ß2 with Fos but not with ATF-3 suggests that cortical spreading depolarization, but not damage to neural processes, might be the mechanism of induction for TGF-ß2. The results imply that endogenous TGF-ßs are induced by different mechanisms following an ischemic attack in the brain suggesting that they are involved in distinct spatially and temporally regulated inflammatory and neuroprotective processes.

The neuroprotective functions of transforming growth factor beta proteins.

Transforming growth factor beta (TGF-ß) proteins are multifunctional cytokines whose neural functions are increasingly recognized. The machinery of TGF-ß signaling, including the serine kinase type transmembrane receptors, is present in the central nervous system. However, the 3 mammalian TGF-ß subtypes have distinct distributions in the brain suggesting different neural functions. Evidence of their involvement in the development and plasticity of the nervous system as well as their functions in peripheral organs suggested that they also exhibit neuroprotective functions. Indeed, TGF-ß expression is induced following a variety of types of brain tissue injury. The neuroprotective function of TGF-ßs is most established following brain ischemia. Damage in experimental animal models of global and focal ischemia was shown to be attenuated by TGF-ßs. In addition, support for their neuroprotective actions following trauma, sclerosis multiplex, neurodegenerative diseases, infections, and brain tumors is also accumulating. The review will also describe the potential mechanisms of neuroprotection exerted by TGF-ßs including anti-inflammatory, -apoptotic, -excitotoxic actions as well as the promotion of scar formation, angiogenesis, and neuroregeneration. The participation of these mechanisms in the neuroprotective effects of TGF-ßs during different brain lesions will also be discussed.

The genetic signature of perineuronal oligodendrocytes reveals their unique phenotype.

Oligodendrocytes--best known for assembling central nervous system myelin--can be categorized as precursors, myelin-forming cells and non-myelinating perineuronal cells. Perineuronal oligodendrocytes have been well characterized morphologically and ultrastructurally, but knowledge about their function remains scanty. It has been proposed that perineuronal oligodendrocytes support neurons and, following injury, transform into myelin-synthesizing cells. Recent findings implicating perineuronal oligodendrocytes in cytoarchitectural abnormalities in the prefrontal cortex of schizophrenia and other psychiatric disorders shed new light on these cells. We have obtained the genetic signature of perineuronal oligodendrocytes by identifying gene expression differences between oligodendrocyte subpopulations using cell-specific tags, microarray technology, quantitative time-resolved polymerase chain reaction and bioinformatics tools. We show that perineuronal cells are the progeny of oligodendrocyte progenitors and, hence, are members of the oligodendrocyte lineage. Physiologically they exhibit a novel phenotype. Their expression of PDGFR-αß and its growth factor ligand PDGF-CC sets them apart from members of their lineage as this receptor precludes their response to the same growth factors that act on myelinating cells. Their coordinate expression and context-specific usage of transcription factors Olig2, Ascl1 and Pax6, together with the prominent presence of transcription factors Pea3, Lhx2 and Otx2--not hitherto linked to the oligodendrocyte lineage--suggested a cell with features that blur the boundary between a neuron and a glial cell. But they also maintain a reservoir of untranslated transcripts encoding major myelin proteins presumably for a demyelinating episode. This first molecular characterization of perineuronal oligodendrocytes revealed the striking difference between the myelinating and non-myelinating phenotypes.

[Therapy for anti-MuSK antibody positive myasthenia gravis]. / A MuSK-ellenes antitest pozitív myasthenia gravis kezelése.

The authors report the case of a 27-year-old woman with muscle-specific receptor tyrosine kinase antibody positive myasthenia with predominantly ocular and bulbar symptoms. Both edrophonium and low dose (4×30 mg/day) pyridostigmin resulted in cholinergic side effects including fasciculation mainly in the facial and neck muscles, and excessive salivation. The patient responded well to a relatively high dose of chronic corticosteroid treatment (methyprednisolone 64mg/day), but the decrease of the corticosteroid dose below 16 mg/day induced exacerbation of the clinical symptoms. Immunosuppression with azathioprine and methotrexate failed to maintain the clinical improvement. However, plasma exchange was always very effective, and all clinical symptoms improved significantly. The authors conclude that patients with muscle-specific receptor tyrosine kinase antibody positive myasthenia gravis should have an individual treatment protocol differing from those used in patients who do not have this antibody but are positive for acetylcholine-receptor antibody. Identification of the pathogenic antibody in the early stage of myasthenia gravis may help to develop the optimal, individualized treatment strategy, to avoid severe side effects, and to achieve fast improvement.

Distribution of mRNAs encoding transforming growth factors-beta1, -2, and -3 in the intact rat brain and after experimentally induced focal ischemia.

Transforming growth factors-beta1 (TGF-beta1), -2, and -3 form a small group of related proteins involved in the regulation of proliferation, differentiation, and survival of various cell types. Recently, TGF-betas were also demonstrated to be neuroprotective. In the present study, we investigated their distribution in the rat brain as well as their expression following middle cerebral artery occlusion. Probes were produced for all types of TGF-betas, and in situ hybridization was performed. We demonstrated high TGF-beta1 expression in cerebral cortex, hippocampus, central amygdaloid nucleus, medial preoptic area, hypothalamic paraventricular nucleus, substantia nigra, brainstem reticular formation and motoneurons, and area postrema. In contrast, TGF-beta2 was abundantly expressed in deep cortical layers, dentate gyrus, midline thalamic nuclei, posterior hypothalamic area and mamillary body, superior olive, areas of monoaminergic neurons, spinal trigeminal nucleus, dorsal vagal complex, cerebellum, and choroid plexus, and a high level of TGF-beta3 mRNA was found in cerebral cortex, hippocampus, basal amygdaloid nuclei, lateral septal nucleus, several thalamic nuclei, arcuate and supramamillary nuclei, superior colliculus, superior olive, brainstem reticular formation and motoneurons, area postrema, and inferior olive. Focal brain ischemia induced TGF-betas with markedly different expression patterns. TGF-beta1 was induced in the penumbral region of cortex and striatum, whereas TGF-beta2 and -beta3 were induced in different layers of the ipsilateral cortex. The expression of the subtypes of TGF-betas in different brain regions suggests that they are involved in the regulation of different neurons and bind to different latent TGF-beta binding proteins. Furthermore, they might have subtype-specific functions following ischemic attack.

Coexisting huntingtin and SCA8 repeat expansion: case report of a severe complex neurodegenerative syndrome.

We report the case of a 29 year old woman with a complex movement disorder syndrome due to the combination of coexisting pathological triplet repeat expansions of huntingtin and ATXN8 genes. The disease course was characterized by mental disturbances including cognitive decline and changes in personality starting at the age of 12 years, followed by twisting motions, intentional tremor and gait ataxia. Later Parkinsonian symptoms of micrographia, bradykinesia, muscle rigidity and mental decline became dominant. Brain MRI showed hypoplasia of the nucleus caudatus and generalized atrophy; MR spectroscopy revealed a decrease of all typical metabolites except for an increased level of lactate and acetate. Therapeutic trials with pramipexole, ropinirole and tetrabenazine showed no benefit, while levetiracetam caused agitation and hallucinations. We discuss phenotype-genotype correlation and the rule of triplet repeat expansions of gene ATXN8.

Expression of a catalytically inactive transmembrane protein tyrosine phosphatase epsilon (tm-PTP epsilon) delays optic nerve myelination.

Reversible tyrosine phosphorylation is integral to the process of oligodendrocyte differentiation. To interfere with the subset of the phosphorylation cycle overseen by protein tyrosine phosphatase epsilon (PTP epsilon) in oligodendrocytes, we applied a substrate-trapping approach in the development of transgenic mice overexpressing a catalytically inactive, transmembrane PTP epsilon-hemaglutinin (tm-PTP epsilon-HA) from the dual promoter element of the gene encoding the myelin protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). Transgene expression peaked during the active myelinating period, at 2-3 weeks postnatal. Two tyrosine phosphoproteins, alpha-enolase and beta-actin, were phosphorylated to a greater degree in transgenic mice. Despite a high degree of tm-PTP epsilon-HA expression, myelin was grossly normal in nearly all axonal tracts. Phenotypic abnormalities were limited to optic nerve, where a decrease in the degree of myelination was reflected by reduced levels of myelin proteins on postnatal day 21 (PND21), as well as a decrease in the density of differentiated oligodendrocytes. The optic chiasm was reduced in thickness in transgenic mice; optic nerves similarly exhibited a reduction in transverse width. Further analyses of the optic pathway demonstrated that transgenic protein was unexpectedly present in retinal ganglion cells, whose axons are the targets of myelination by optic nerve oligodendrocytes. On PND28, transgenic protein declined dramatically in both oligodendrocytes and retinal ganglion cells contributing to the recovery of optic nerve myelination. Thus, delayed myelination arises only when tm-PTP epsilon-HA is simultaneously expressed in myelin-forming glia and their neuronal targets. While tm-PTP epsilon related signaling pathways may figure in axon-glial interactions, interfering with tm-PTP epsilon activity does not perceptibly affect the development or myelinating capacity of most oligodendrocytes.