1,070 research outputs found
‘Medusa-head ataxia’: the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: Anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII
Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as ‘Medusa-head antibodies’ due to their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects and provides a summary and outlook
The history of neuromyelitis optica
The discovery of a novel serum autoantibody (termed NMO-IgG or AQP4-Ab) in a subset of patients in 2004 has revived interest in neuromyelitis optica (NMO). While the history of classical multiple sclerosis has been extensively studied, only little is known about the history of NMO. In the present article, we provide a comprehensive review of the early history of this rare but intriguing syndrome. We trace the origins of the concept of NMO in the 19th century medical literature and follow its evolution throughout the 20th and into the 21st century. Finally, we discuss recent proposals to revise the concept of NMO and explain why there is indeed a need for a more systematic and descriptive nomenclature
‘Medusa head ataxia’: the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 2: Anti-PKC-gamma, anti-GluR-delta2, anti-Ca/ARHGAP26 and anti-VGCC
Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as ‘Medusa head antibodies’ due their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects, and provides a summary and outlook
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
Baló’s concentric sclerosis is immunologically distinct from multiple sclerosis: results from retrospective analysis of almost 150 lumbar punctures
Multiple sclerosis: Immunopathology and treatment update
The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumab, ocrelizumab, alemtuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS
Evaluation of a Multiparametric Immunofluorescence Assay for Standardization of Neuromyelitis Optica Serology
Background: Neuromyelitis optica (NMO) is a severely disabling autoimmune disorder of the central nervous system, which predominantly affects the optic nerves and spinal cord. In a majority of cases, NMO is associated with antibodies to aquaporin-4 (AQP4) (termed NMO-IgG). Aims: In this study, we evaluated a new multiparametric indirect immunofluorescence (IIF) assay for NMO serology. Methods: Sera from 20 patients with NMO, 41 patients with multiple sclerosis (MS), 30 healthy subjects, and a commercial anti-AQP4 IgG antibody were tested in a commercial composite immunofluorescence assay ("Neurology Mosaic 17"; Euroimmun, Germany), consisting of five different diagnostic substrates (HEK cells transfected with AQP4, non-transfected HEK cells, primate cerebellum, cerebrum, and optic nerve tissue sections). Results: We identified AQP4 specific and non-specific fluorescence staining patterns and established positivity criteria. Based on these criteria, this kit yielded a high sensitivity (95%) and specificity (100%) for NMO and had a significant positive and negative likelihood ratio (LR+ = ∞, LR- = 0.05). Moreover, a 100% inter- and intra-laboratory reproducibility was found. Conclusions: The biochip mosaic assay tested in this study is a powerful tool for NMO serology, fast to perform, highly sensitive and specific for NMO, reproducible, and suitable for inter-laboratory standardization as required for multi-centre clinical trials
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 0–123). Serum titers were higher during attacks
than during remission (p < 0.0001), 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
A new Purkinje cell antibody (anti-Ca) associated with subacute cerebellar ataxia: immunological characterization
We report on a newly discovered serum and cerebrospinal fluid (CSF) reactivity to Purkinje cells (PCs) associated with subacute inflammatory cerebellar ataxia. The patient, a previously healthy 33-year-old lady, presented with severe limb and gait ataxia, dysarthria, and diplopia two weeks after she had recovered from a common cold. Immunohistochemical studies on mouse, rat, and monkey brain sections revealed binding of a high-titer (up to 1:10,000) IgG antibody to the cerebellar molecular layer, Purkinje cell (PC) layer, and white matter. The antibody is highly specific for PCs and binds to the cytoplasm as well as to the inner side of the membrane of PC somata, dendrites and axons. It is produced by B cell clones within the CNS, belongs to the IgG1 subclass, and activates complement in vitro. Western blotting of primate cerebellum extract revealed binding of CSF and serum IgG to an 80-97 kDa protein. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic antibodies known to be associated with cerebellar ataxia. Screening of >9000 human full length proteins by means of a protein array and additional confirmatory experiments revealed Rho GTPase activating protein 26 (ARHGAP26, GRAF, oligophrenin-1-like protein) as the target antigen. Preadsorption of the patient's serum with human ARHGAP26 but not preadsorption with other proteins resulted in complete loss of PC staining. Our findings suggest a role of autoimmunity against ARHGAP26 in the pathogenesis of subacute inflammatory cerebellar ataxia, and extend the panel of diagnostic markers for this devastating disease
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 (P < 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 60–80% of MS patients, but was absent in all pattern II or III MS patients tested (P < 0.00001 vs. previous cohorts). In contrast, the albumin CSF/serum ratio (QAlb), a marker of blood–CSF barrier function, was more frequently elevated in samples from pattern II and III MS patients (P < 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 (P < 0.005, P < 0.009 and P < 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 blood–CSF barrier function. Our findings strongly corroborate the notion that pattern II and pattern III MS are entities distinct from pattern I MS
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