The cuprizone model of toxic demyelination in the central nervous system is commonly used to investigate the pathobiology of remyelination in the corpus callosum. However, in human demyelinating ...diseases such as multiple sclerosis, recent evidence indicates a considerable amount of cortical demyelination in addition to white matter damage. Therefore, we have investigated cortical demyelination in the murine cuprizone model. To induce demyelination, C57BL/6 mice were challenged with 0.2% cuprizone feeding for 6 weeks followed by a recovery phase of 6 weeks with a cuprizone-free diet. In addition to the expected demyelination in the corpus callosum, the cortex of C57BL/6 mice was completely demyelinated after 6 weeks of cuprizone feeding. After withdrawal of cuprizone the cortex showed complete remyelination similar to that in the corpus callosum. When C57BL/6 mice were fed cuprizone for a prolonged period of 12 weeks, cortical remyelination was significantly delayed. Because interstrain differences have been described, we also investigated the effects of cuprizone on cortical demyelination in BALB/cJ mice. In these mice, cortical demyelination was only partial. Moreover, cortical microglia accumulation was markedly increased in BALB/cJ mice, whereas microglia were absent in the cortex of C57BL/6 mice. In summary, our results show that cuprizone feeding is an excellent model in which to study cortical demyelination and remyelination, including contributing genetic factors represented by strain differences.
Neuroborreliosis represents a relevant infectious disease and can cause a variety of neurological manifestations. Different stages and syndromes are described and atypical symptoms can result in ...diagnostic delay or misdiagnosis. The aim of this retrospective study was to define the pivotal neurological deficits in patients with neuroborreliosis that were the reason for admission in a hospital.
We retrospectively evaluated data of patients with neuroborreliosis. Only patients who fulfilled the diagnostic criteria of an intrathecal antibody production against Borrelia burgdorferi were included in the study.
Sixty-eight patients were identified with neuroborreliosis. Cranial nerve palsy was the most frequent deficit (50%) which caused admission to a hospital followed by painful radiculitis (25%), encephalitis (12%), myelitis (7%), and meningitis/headache (6%). In patients with a combination of deficits, back pain was the first symptom, followed by headache, and finally by cranial nerve palsy. Indeed, signs of meningitis were often found in patients with neuroborreliosis, but usually did not cause admission to a hospital. Unusual cases included patients with sudden onset paresis that were initially misdiagnosed as stroke and one patient with acute delirium. Cerebrospinal fluid (CSF) analysis revealed typical changes including elevated CSF cell count in all but one patient, a blood-CSF barrier dysfunction (87%), CSF oligoclonal bands (90%), and quantitative intrathecal synthesis of immunoglobulins (IgM in 74%, IgG in 47%, and IgA in 32% patients). Importantly, 6% of patients did not show Borrelia specific antibodies in the blood.
In conclusion, the majority of patients presented with typical neurological deficits. However, unusual cases such as acute delirium indicate that neuroborreliosis has to be considered in a wide spectrum of neurological diseases. CSF analysis is essential for a reliable diagnosis of neuroborreliosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The clinical implications of the presence of anti-N-methyl-D-aspartate receptor (NMDAR)-specific intrathecal immunoglobulin G synthesis and whether it determines the diagnosis of anti-NMDAR ...encephalitis have not been thoroughly investigated yet. Thus, the aim of this study was to investigate whether the detection of intrathecal anti-NMDAR-specific IgG synthesis contributes to the diagnostic confirmation of anti-NMDAR encephalitis, to disease severity, and to prognosis in patients with positive serum anti-NMDAR-IgG. In this study, patients with detectable anti-NMDAR IgG in serum and/or cerebrospinal fluid (CSF) were included and separated into two groups that either met the 2016 criteria by Graus et al. of definite anti-NMDAR encephalitis (n = 27) or did not (n = 15). In a total, of 80 paired CSF/serum samples, antibody titers were titrated manually and end-point titer levels were carefully determined in a blinded manner to the subgroup attribution. The disease course was assessed via the modified Rankin Scale (mRS) and prognosis was estimated by the anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. With respect to whether the diagnostic Graus criteria for definite anti-NMDAR encephalitis were fulfilled, a significantly unequal distribution of intrathecal anti-NMDAR antibody-specific synthesis could be shown with a high negative predictive value in case of a negative anti-NMDAR antibody-specific index (NMDAR AI, p = .008. OR = 23.9, sensitivity = 1.0, specificity = 0.4, negative predictive value = 1). A weak correlation was found between the CSF antibody titer and mRS value at the time of sample collection (r
= .37, p = .008, 95% CI .09, .59). During the disease course a higher delta-mRS value formed of the mRS at initial presentation minus that at the last recorded presentation correlated with a higher NMDAR AI at first lumbar puncture (r
= - .56, p = .017, 95% CI - .83, - .11). No association with the prognostic NEOS score was found. In conclusion, a negative antibody-specific index for anti-NMDAR IgG antibodies has a highly negative predictive value for the diagnosis of anti-NMDAR encephalitis. Yet, a positive NMDAR AI alone does not allow the diagnosis of anti-NMDAR encephalitis.
Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there ...is an unmet therapeutic demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned male mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.
The latest revision of the McDonald criteria of 2017 considers the evidence of an intrathecal immunoglobulin (IgG) synthesis as a diagnostic criterion for dissemination in time in multiple sclerosis. ...While the detection of oligoclonal bands is considered as the gold standard, determination of kappa free light chains might be a promising tool as a less technically demanding and cost saving method. However, data on the direct comparison between kappa free light chains and oligoclonal bands are limited and no study to date has used the highly sensitive method of polyacrylamide gels with consecutive silver staining for the demonstration of oligoclonal bands. Furthermore, the impact of the revised McDonald criteria of 2017 on the role of kappa free light chains as a biomarker has not been investigated. Nephelometry was used to determine kappa free light chains in cerebrospinal fluid (CSF) and serum from 149 patients with their first demyelinating event between 2010 and 2015. Clinical data, kappa free light chains, and oligoclonal band status were compared at the time of initial diagnosis and after follow-up to identify converters from clinically isolated syndrome to multiple sclerosis. An elevated kappa free light chain index (>5.9) was found in 79/83 patients (95%) with multiple sclerosis diagnosed at baseline, slightly less frequent than oligoclonal bands (98.8%). 18/25 (72%) patients who converted from clinically isolated syndrome to multiple sclerosis showed an elevated kappa free light chain index compared to 20/25 (80%) patients with positive oligoclonal bands. In patients with stable clinically isolated syndrome 7/41 (17%) displayed an elevated kappa free light chain index against 11/41 (27%) oligoclonal band positive patients. Only two patients with stable clinically isolated syndrome showed an elevated kappa free light chain index but were oligoclonal bands negative. In conclusion, determination of the kappa free light chain index is a promising diagnostic approach to assess intrathecal immunoglobulin synthesis in multiple sclerosis. Nevertheless, oligoclonal bands are highly prevalent in multiple sclerosis and can detect an intrathecal synthesis of IgG even when the kappa free light chain index is below the threshold. We consider sequential use of both methods as reasonable.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is a challenge for all participants in the healthcare system. At the beginning of the pandemic, many physicians asked ...themselves what risk their patients, especially those with chronic diseases, were exposed to. We present an overview of all patients with multiple sclerosis (MS) and SARS-CoV-2 infection published in the literature so far. In total, there are publications on 873 SARS-CoV-2 positive MS patients and information on the outcome can be given for 700 patients. With regard to the different disease modifying therapies (DMTs), by far the most cases were described under anti-CD20 treatment (
= 317). The mortality rate of all MS patients was 4% and a further 3% required invasive or non-invasive ventilation. When looking at the severe and fatal cases, it is particularly noticeable that patients without DMTs, with previous cardiovascular diseases, or with a severe degree of disability are at risk. Immunosuppressive therapy itself does not appear to be a substantial risk factor. Rather, it is reasonable to assume that the therapies could be protective, either directly, by mitigating the cytokine storm, or indirectly, by reducing the disease activity of MS.
Multiple sclerosis is a chronic immune mediated demyelinating disease leading to neurological disabilities that need to be diagnosed and treated early. Guidelines on multiple sclerosis diagnosis and ...monitoring experienced comprehensive changes over the last decades. The first McDonald criteria published in 2001 emphasized the importance of MR imaging but also recognized the role of cerebrospinal fluid diagnostics. The demonstration of an intrathecal immunoglobulin G synthesis is a well-established additional component and has a long tradition in the diagnosis of relapsing-remitting multiple sclerosis. However, the role of cerebrospinal fluid for diagnostic purposes was rather diminished in each revision of the McDonald criteria. In the latest revision of the McDonald criteria of 2017, the detection of an intrathecal immunoglobulin G synthesis as oligoclonal bands experienced a revival. Patients with the first clinical event suggesting multiple sclerosis who fulfill the criteria for dissemination in space can be diagnosed with relapsing-remitting multiple sclerosis when oligoclonal bands in cerebrospinal fluid are detected. The diagnostic sensitivity of these novel criteria with a focus on dissemination in time and oligoclonal bands as a substitute for dissemination in time was published in different cohorts in the last year and is of special interest in this review. Recently published data show that by applying the 2017 McDonald criteria, multiple sclerosis can be diagnosed more frequently at the time of first clinical event as compared to the 2010 McDonald criteria. The main effect was due to the implementation of oligoclonal bands as a substitute for dissemination in time. However, careful differential diagnosis is essential in patients with atypical clinical manifestations to avoid misdiagnoses.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic keeps the world in suspense. In addition to the fundamental challenges for the health care system, the individual departments ...must decide how to deal with patients at risk. Neurologists are confronted with the question, how they should advise their patients regarding immunosuppressive treatment. In particular, the large number of different disease-modifying therapies (DMTs) in the treatment of neuroimmunological diseases such as multiple sclerosis poses a challenge. To a limited extent, it might be useful to transfer knowledge from previous SARS- and Middle East respiratory syndrome (MERS) coronavirus outbreaks in 2002/2003 and 2012 to the current situation. Overall, immunosuppressive therapy does neither seem to have a major impact on infection with SARS- and MERS-CoV nor does it seem to lead to a severe disease course in many cases. Considering the immunological responses against infections with novel coronaviruses in humans, interferons, glatiramer acetate, and teriflunomide appear to be safe. As lymphopenia seems to be associated with a more severe disease course, all DMTs causing lymphopenia, such as cladribine, alemtuzumab, and dimethyl fumarate, need to be reviewed more thoroughly. As they are, in general, associated with a higher risk of infection, depleting anti-CD20 antibodies may be problematic drugs. However, it has to be differentiated between the depletion phase and the phase of immune reconstitution. In summary, previous coronavirus outbreaks have not shown an increased risk for immunocompromised patients. Patients with severe neuroimmunological diseases should be kept from hasty discontinuation of immunotherapy.
Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral disease of the brain—caused by human polyomavirus 2. It affects patients whose immune system is compromised by a ...corresponding underlying disease or by drugs. Patients with an underlying lymphoproliferative disease have the worst prognosis with a mortality rate of up to 90%. Several therapeutic strategies have been proposed but failed to show any benefit so far. Therefore, the primary therapeutic strategy aims to reconstitute the impaired immune system to generate an effective endogenous antiviral response. Recently, anti-PD-1 antibodies and application of allogeneic virus-specific T cells demonstrated promising effects on the outcome in individual PML patients. This article aims to provide a detailed overview of the literature with a focus on these two treatment approaches.
Optic neuritis is often an initial symptom in multiple sclerosis (MS) or clinically isolated syndrome (CIS), yet comprehensive studies using the 2017 McDonald criteria for MS are scarce. Patient ...records from our academic centre (2010-2018) were reviewed. Using the 2017 McDonald criteria, three groups were formed: MS optic neuritis (optic neuritis with confirmed MS), CIS optic neuritis (optic neuritis without confirmed MS) and suspected optic neuritis (sON). We compared clinical and paraclinical findings among the groups to identify predictors for CIS- or MS-optic neuritis. The study included 129 MS, 108 CIS, and 44 sON cases. The combination of visual impairment, dyschromatopsia, and retrobulbar pain was observed in 47% of MS patients, 42% of CIS patients, and 30% of sON patients. Dyschromatopsia was the strongest indicator of MS or CIS diagnosis in the backward regression model. 56% of MS patients had relative afferent pupillary defect, 61% optic nerve anomalies within magnetic resonance imaging, and 81% abnormal visual evoked potentials. Our results emphasize the challenges in diagnosing optic neuritis, as not all patients with objectively diagnosed MS exhibit the triad of typical symptoms. To address potentially missing clinical features, incorporating additional paraclinical findings is proposed.
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