213 research outputs found
Brainstem involvement - frequency, presentation and outcome
Background Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are
present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic
neuritis (ON) and/or myelitis. Little is known so far about brainstem
involvement in MOG-IgG-positive patients. Objective To investigate the
frequency, clinical and paraclinical features, course, outcome, and prognostic
implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis.
Methods Retrospective case study. Results Among 50 patients with MOG-IgG-
positive ON and/or myelitis, 15 (30 %) with a history of brainstem
encephalitis were identified. All were negative for AQP4-IgG. Symptoms
included respiratory insufficiency, intractable nausea and vomiting (INV),
dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and
diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis,
trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance
difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic
in three cases. Brainstem inflammation was already present at or very shortly
after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks
were accompanied by acute myelitis and/or ON. Lesions were located in the pons
(11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14),
and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in
2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or
cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier
damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in
11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells),
and oligoclonal bands in 4/14. Attacks were preceded by acute infection or
vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The
disease followed a relapsing course in 13/15 (87 %); the brainstem was
involved more than once in 6. Immunosuppression was not always effective in
preventing relapses. Interferon-beta was followed by new attacks in two
patients. While one patient died from central hypoventilation, partial or
complete recovery was achieved in the remainder following treatment with high-
dose steroids and/or plasma exchange. Brainstem involvement was associated
with a more aggressive general disease course (higher relapse rate, more
myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at
last follow-up). Conclusions Brainstem involvement is present in around one
third of MOG-IgG-positive patients with ON and/or myelitis. Clinical
manifestations are diverse and may include symptoms typically seen in AQP4
-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency,
or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem
encephalitis may take a serious or even fatal course, particular attention
should be paid to signs or symptoms of additional brainstem involvement in
patients presenting with MOG-IgG-positive ON and/or myelitis
HLAâDRB1*15:01 is a coâreceptor for EpsteinâBarr virus, linking genetic and environmental risk factors for multiple sclerosis
Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin
Background Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have
been suggested to play a role in a subset of patients with neuromyelitis
optica and related disorders. Objective To assess (i) the frequency of MOG-IgG
in a large and predominantly Caucasian cohort of patients with optic neuritis
(ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive
patients and vice versa; (iii) the origin and frequency of MOG-IgG in the
cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and
(v) the influence of disease activity and treatment status on MOG-IgG titers.
Methods 614 serum samples from patients with ON and/or myelitis and from
controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples
were tested for MOG-IgG using a live cell-based assay (CBA) employing full-
length human MOG-transfected HEK293A cells. Results MOG-IgG was detected in 95
sera from 50 patients with ON and/or myelitis, including 22/54 (40.7%)
patients with a history of both ON and myelitis, 22/103 (21.4%) with a history
of ON but no myelitis and 6/45 (13.3%) with a history of longitudinally
extensive transverse myelitis but no ON, and in 1 control patient with
encephalitis and a connective tissue disorder, all of whom were negative for
AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients
with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with
multiple sclerosis (MS). MOG-IgG was found in 12/18 (67%) CSF samples from
MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was
negative in all cases, indicating a predominantly peripheral origin of CSF
MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1
subclass. MOG-IgG was present already at disease onset. The antibodies
remained detectable in 40/45 (89%) follow-up samples obtained over a median
period of 16.5 months (range 0â123). Serum titers were higher during attacks
than during remission (pâ<â0.0001), highest during attacks of simultaneous
myelitis and ON, lowest during acute isolated ON, and declined following
treatment. Conclusions To date, this is the largest cohort studied for IgG to
human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a
substantial subset of patients with ON and/or myelitis, but not in classical
MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of
extrathecal origin. Serum MOG-IgG is present already at disease onset and
remains detectable in the long-term course. Serum titers depend on disease
activity and treatment status
Analysis of transcribed human endogenous retrovirus W env loci clarifies the origin of multiple sclerosis-associated retrovirus env sequences
<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis-associated retrovirus (MSRV) RNA sequences have been detected in patients with multiple sclerosis (MS) and are related to the multi-copy human endogenous retrovirus family type W (HERV-W). Only one HERV-W locus (ERVWE1) codes for a complete HERV-W Env protein (Syncytin-1). Syncytin-1 and the putative MSRV Env protein have been involved in the pathogenesis of MS. The origin of MSRV and its precise relation to HERV-W were hitherto unknown.</p> <p>Results</p> <p>By mapping HERV-W <it>env </it>cDNA sequences (n = 332) from peripheral blood mononuclear cells of patients with MS and healthy controls onto individual genomic HERV-W <it>env </it>elements, we identified seven transcribed HERV-W <it>env </it>loci in these cells, including ERVWE1. Transcriptional activity of individual HERV-W <it>env </it>elements did not significantly differ between patients with MS and controls. Remarkably, almost 30% of HERV-W <it>env </it>cDNAs were recombined sequences that most likely arose <it>in vitro </it>between transcripts from different HERV-W <it>env </it>elements. Re-analysis of published MSRV <it>env </it>sequences revealed that all of them can be explained as originating from genomic HERV-W <it>env </it>loci or recombinations among them. In particular, a MSRV <it>env </it>clone previously used for the generation of monoclonal antibody 6A2B2, detecting an antigen in MS brain lesions, appears to be derived from a HERV-W <it>env </it>locus on chromosome Xq22.3. This locus harbors a long open reading frame for an N-terminally truncated HERV-W Env protein.</p> <p>Conclusion</p> <p>Our data clarify the origin of MSRV <it>env </it>sequences, have important implications for the status of MSRV, and open the possibility that a protein encoded by a HERV-W <it>env </it>element on chromosome Xq22.3 may be expressed in MS brain lesions.</p
1,2- 13C 2-Glucose Tracing Approach to Assess Metabolic Alterations of Human Monocytes under Neuroinflammatory Conditions.
1,2-13C2-Glucose Tracing Approach to Assess Metabolic Alterations of Human Monocytes under Neuroinflammatory Conditions
Neuroinflammation is one of the common features in most neurological diseases including multiple sclerosis (MScl) and neurodegenerative diseases such as Alzheimerâs disease (AD). It is associated with local brain inflammation, microglial activation, and infiltration of peripheral immune cells into cerebrospinal fluid (CSF) and the central nervous system (CNS). It has been shown that the diversity of phenotypic changes in monocytes in CSF relates to neuroinflammation. It remains to be investigated whether these phenotypic changes are associated with functional or metabolic alteration, which may give a hint to their function or changes in cell states, e.g., cell activation. In this article, we investigate whether major metabolic pathways of blood monocytes alter after exposure to CSF of healthy individuals or patients with AD or MScl. Our findings show a significant alteration of the metabolism of monocytes treated with CSF from patients and healthy donors, including higher production of citric acid and glutamine, suggesting a more active glycolysis and tricarboxylic acid (TCA) cycle and reduced production of glycine and serine. These alterations suggest metabolic reprogramming of monocytes, possibly related to the change of compartment (from blood to CSF) and/or disease-related. Moreover, the levels of serine differ between AD and MScl, suggesting different phenotypic alterations between diseases
Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis
Background: The diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features. However, histopathological studies have revealed four different patterns of lesion pathology in patients diagnosed with MS, suggesting that MS may be a pathologically heterogeneous syndrome rather than a single disease entity. Objective: The aim of this study was to investigate whether patients with pattern I MS differ from patients with pattern II or III MS with regard to cerebrospinal fluid (CSF) findings, especially with reference to intrathecal IgG synthesis, which is found in most patients with MS but is frequently missing in MS mimics such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-IgG-positive encephalomyelitis. Methods: Findings from 68 lumbar punctures in patients who underwent brain biopsy as part of their diagnostic work-up and who could be unequivocally classified as having pattern I, pattern II or pattern III MS were analysed retrospectively. Results: Oligoclonal bands (OCBs) were present in 88.2% of samples from pattern I MS patients but in only 27% of samples from patients with pattern II or pattern III MS (PÂ <Â 0.00004); moreover, OCBs were present only transiently in some of the latter patients. A polyspecific intrathecal IgG response to measles, rubella and/or varicella zoster virus (so-called MRZ reaction) was previously reported in 60â80% of MS patients, but was absent in all pattern II or III MS patients tested (PÂ <Â 0.00001 vs. previous cohorts). In contrast, the albumin CSF/serum ratio (QAlb), a marker of bloodâCSF barrier function, was more frequently elevated in samples from pattern II and III MS patients (PÂ <Â 0.002). Accordingly, QAlb values and albumin and total protein levels were higher in pattern II and III MS samples than in pattern I MS samples (PÂ <Â 0.005, PÂ <Â 0.009 and PÂ <Â 0.006, respectively). Conclusions: Patients with pattern II or pattern III MS differ significantly from patients with pattern I MS as well as from previous, histologically non-classified MS cohorts with regard to both intrathecal IgG synthesis and bloodâCSF barrier function. Our findings strongly corroborate the notion that pattern II and pattern III MS are entities distinct from pattern I MS
Imaging markers of disability in aquaporin-4 immunoglobulin G seropositive neuromyelitis optica: a graph theory study
Neuromyelitis optica spectrum disorders lack imaging biomarkers associated with disease course and supporting prognosis. This complex and heterogeneous set of disorders affects many regions of the central nervous system, including the spinal cord and visual pathway. Here, we use graph theory-based multimodal network analysis to investigate hypothesis-free mixed networks and associations between clinical disease with neuroimaging markers in 40 aquaporin-4-immunoglobulin G antibody seropositive patients (age = 48.16â±â14.3âyears, female:male = 36:4) and 31 healthy controls (age = 45.92â±â13.3âyears, female:male = 24:7). Magnetic resonance imaging measures included total brain and deep grey matter volumes, cortical thickness and spinal cord atrophy. Optical coherence tomography measures of the retina and clinical measures comprised of clinical attack types and expanded disability status scale were also utilized. For multimodal network analysis, all measures were introduced as nodes and tested for directed connectivity from clinical attack types and disease duration to systematic imaging and clinical disability measures. Analysis of variance, with group interactions, gave weights and significance for each nodal association (hyperedges). Connectivity matrices from 80% and 95% F-distribution networks were analyzed and revealed the number of combined attack types and disease duration as the most connected nodes, directly affecting changes in several regions of the central nervous system. Subsequent multivariable regression models, including interaction effects with clinical parameters, identified associations between decreased nucleus accumbens (ÎČ = â0.85, Pâ=â0.021) and caudate nucleus (ÎČ = â0.61, Pâ=â0.011) volumes with higher combined attack type count and longer disease duration, respectively. We also confirmed previously reported associations between spinal cord atrophy with increased number of clinical myelitis attacks. Age was the most important factor associated with normalized brain volume, pallidum volume, cortical thickness and the expanded disability status scale score. The identified imaging biomarker candidates warrant further investigation in larger-scale studies. Graph theory-based multimodal networks allow for connectivity and interaction analysis, where this method may be applied in other complex heterogeneous disease investigations with different outcome measures
Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination
Background Antibodies to the myelin oligodendrocyte glycoprotein (MOG) are
associated with a subset of inflammatory demyelinating diseases of the central
nervous system such as acute disseminated encephalomyelitis and neuromyelitis
optica spectrum disorders. However, whether human MOG antibodies are
pathogenic or an epiphenomenon is still not completely clear. Although MOG is
highly conserved within mammals, previous findings showed that not all human
MOG antibodies bind to rodent MOG. We therefore hypothesized that human MOG
antibody-mediated pathology in animal models may only be evident using
species-specific MOG antibodies. Methods We screened 80 human MOG antibody-
positive samples for their reactivity to mouse and rat MOG using either a live
cell-based assay or immunohistochemistry on murine, rat, and human brain
tissue. Selected samples reactive to either human MOG or rodent MOG were
subsequently tested for their ability to induce complement-mediated damage in
murine organotypic brain slices or enhance demyelination in an experimental
autoimmune encephalitis (EAE) model in Lewis rats. The MOG monoclonal antibody
8-18-C5 was used as a positive control. Results Overall, we found that only a
subset of human MOG antibodies are reactive to mouse (48/80, 60%) or rat
(14/80, 18%) MOG. Purified serum antibodies from 10 human MOG antibody-
positive patients (8/10 reactive to mouse MOG, 6/10 reactive to rat MOG), 3
human MOG-negative patients, and 3 healthy controls were tested on murine
organotypic brain slices. Purified IgG from one patient with high titers of
anti-human, mouse, and rat MOG antibodies and robust binding to myelin tissue
produced significant, complement-mediated myelin loss in organotypic brain
slices, but not in the EAE model. Monoclonal 8-18-C5 MOG antibody caused
complement-mediated demyelination in both the organotypic brain slice model
and in EAE. Conclusion This study shows that a subset of human MOG antibodies
can induce complement-dependent pathogenic effects in a murine ex vivo animal
model. Moreover, a high titer of species-specific MOG antibodies may be
critical for demyelinating effects in mouse and rat animal models. Therefore,
both the reactivity and titer of human MOG antibodies must be considered for
future pathogenicity studies
Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome
Background A subset of patients with neuromyelitis optica spectrum disorders
(NMOSD) has been shown to be seropositive for myelin oligodendrocyte
glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological,
clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological
features of a large cohort of MOG-IgG-positive patients with optic neuritis
(ON) and/or myelitis (nâ=â50) as well as attack and long-term treatment
outcomes. Methods Retrospective multicenter study. Results The sex ratio was
1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease
followed a multiphasic course in 80% (median time-to-first-relapse 5 months;
annualized relapse rate 0.92) and resulted in significant disability in 40%
(mean follow-up 75â±â46.5 months), with severe visual impairment or functional
blindness (36%) and markedly impaired ambulation due to paresis or ataxia
(25%) as the most common long-term sequelae. Functional blindness in one or
both eyes was noted during at least one ON attack in around 70%. Perioptic
enhancement was present in several patients. Besides acute tetra-/paraparesis,
dysesthesia and pain were common in acute myelitis (70%). Longitudinally
extensive spinal cord lesions were frequent, but short lesions occurred at
least once in 44%. Fourty-one percent had a history of simultaneous ON and
myelitis. Clinical or radiological involvement of the brain, brainstem, or
cerebellum was present in 50%; extra-opticospinal symptoms included
intractable nausea and vomiting and respiratory insufficiency (fatal in one).
CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in
only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous
methylprednisolone (IVMP) and long-term immunosuppression were often
effective; however, treatment failure leading to rapid accumulation of
disability was noted in many patients as well as flare-ups after steroid
withdrawal. Full recovery was achieved by plasma exchange in some cases,
including after IVMP failure. Breakthrough attacks under azathioprine were
linked to the drug-specific latency period and a lack of cotreatment with oral
steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was
associated with ongoing or increasing disease activity. Rituximab and
ofatumumab were effective in some patients. However, treatment with rituximab
was followed by early relapses in several cases; end-of-dose relapses occurred
9-12 months after the first infusion. Coexisting autoimmunity was rare (9%).
Wingerchukâs 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald
criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%,
respectively; MS had been suspected in 36%. Disease onset or relapses were
preceded by infection, vaccination, or pregnancy/delivery in several cases.
Conclusion Our findings from a predominantly Caucasian cohort strongly argue
against the concept of MOG-IgG denoting a mild and usually monophasic variant
of NMOSD. The predominantly relapsing and often severe disease course and the
short median time to second attack support the use of prophylactic long-term
treatments in patients with MOG-IgG-positive ON and/or myelitis
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