Angela Vincent

University of Oxford, Oxford, England, United Kingdom

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Publications (300)1634.71 Total impact

  • James Varley, Angela Vincent, Sarosh R Irani
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    ABSTRACT: The field of neuronal surface-directed antibody-mediated diseases of the central nervous system has dramatically expanded in the last few years and now forms an important cluster of treatable neurological conditions. In this review, we focus on three areas. First, we review the demographics, clinical features and treatment responses of these conditions. Second, we consider their pathophysiology and compare autoantibody mechanisms and their effects to genetic or pharmacological disruptions of the target antigens. Third, we discuss areas of controversy within the field, propose possible resolutions, and explore new directions for neuronal surface antibody-mediated diseases.
    Journal of neurology. 12/2014;
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    ABSTRACT: In 2007, serum IgG autoantibodies to the NMDAR (NMDAR-Ab) were identified in subjects with an autoimmune encephalopathy responsive to immunotherapy; two thirds of whom present with psychiatric symptoms (Dalmau et al., 2007, Irani et al., 2010 and Titulaer et al., 2013). There is increasing evidence for NMDAR-hypofunction and neuroinflammation in the pathophysiology of first episode schizophrenia (Kahn and Sommer, 2014). Whilst many patients with NMDAR-ab develop a widespread encephalopathy, restricted phenotypes, including isolated psychosis, epilepsy, or movement disorders have also been described (Irani et al., 2010, Zandi et al., 2011, Brenner et al., 2013, Titulaer et al., 2013 and Hacohen et al., 2014). We reported in 2010 for the first time IgG NMDAR, and voltage gated potassium channel-complex (VGKC), antibodies in 3 of 46 (6.5%) patients with a first episode psychosis without other neurological symptoms (Zandi et al., 2011). Pollak and colleagues, found IgG NMDAR-ab in 1.46% (95% CI 0.94–2.23) cases of psychosis and schizophrenia from 7 studies, compared to (5/1598) 0.3% controls, but a variety of assays including fixed assays were compared (Pollak et al., 2013). In their analysis, rates of IgA and IgM antibodies were higher in both cases (7.1%) and controls (10.2%), though IgA and IgM antibodies are of unlikely pathogenic relevance. Dalmau and colleagues found isolated psychotic episodes in 23/571 (4%) patients with NMDAR-Ab encephalitis either in presentation (5) or at relapse (18) (Kayser et al., 2013). One test of clinical relevance of autoantibodies is the immunotherapy response. Here we describe 18 cases of acute psychosis with NMDAR-ab measured by live cell based assay without clear clinical ‘neurological’ involvement, 9 of whom we treated with immunotherapy.
    Schizophrenia Research 11/2014; · 4.59 Impact Factor
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    ABSTRACT: The pathogenesis of Guillain-Barré syndrome (GBS) is considered to be, at least in part, mediated by autoantibodies directed against neuronal antigens. Antibodies to contactin-associated protein-like 2 (CASPR2), part of the voltage-gated potassium channel complex (VGKC-complex), are associated with neurological disease predominantly affecting the peripheral nervous system but are not known to be associated with GBS. We report 2 cases of ganglioside antibody-negative paediatric GBS associated with CASPR2 antibodies. Both patients made a full clinical recovery. The tissue distribution and function of CASPR2 make it a biologically plausible autoimmune target in GBS and its clincial relevance in GBS should be determined in further studies.
    Journal of the Peripheral Nervous System 11/2014; · 2.57 Impact Factor
  • Journal of Neuroimmunology. 10/2014; 275(1).
  • Journal of Neuroimmunology. 10/2014; 275(1).
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    ABSTRACT: Our aim was to determine the presence and possible role of autoantibodies in epileptic patients with an undetermined etiology. Eighty epilepsy patients, who were referred to the Pediatric Neurology Department at Ankara University between November 2011 and April 2012, were enrolled in the study. Antinuclear antibodies (ANA), anticardiolipin IgG, antiphospholipid, antithyroid peroxidase, paraneoplastic, glutamic acid decarboxylase (GAD), and N-methyl-d-aspartate (NMDA) receptor antibodies were studied in our university laboratory. In addition, NMDA receptor (NMDAR), voltage-gated potassium channel (VGKC)-complex, leucine-rich, glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2) antibodies were studied at the Oxford University Immunology Laboratory. The study included 35 girls (44%) and 45 boys (56%) with a mean symptom age of 8.6 ± 4.53 years. ANA was detected in 15 (18.8%), antiphospholipid Ab in 3 (3.75%), anticardiolipin Ab in 1 (1.25%), and antithyroid peroxidase in 3 (3.75%) epileptic patients. In addition, anti-GAD Ab was detected in 7 (8.75%), anti-Yo Ab in 3 (3.75%), and anti-Ma2 in 3 (3.75%) epileptic patients. Anti-VGKC was positive in 13 (16.25%) epileptic patients. We performed a pioneer study to investigate the association between autoimmunity and pediatric epilepsy and we conclude that autoimmunity should be considered in epileptic patients with an undetermined etiology.
    Neuropediatrics 10/2014; · 1.19 Impact Factor
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    ABSTRACT: Abstract Objective There are now a large number of requests for N-methyl-d-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as ‘Low Positive’. Methods The clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as ‘Definite’, ‘Possible’ or ‘Unlikely’. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated. Results Twenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin's lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases. Interpretation Using live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level.
    Journal of Neurology Neurosurgery & Psychiatry 09/2014; · 4.92 Impact Factor
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    ABSTRACT: Complex Regional Pain Syndrome (CRPS) is a limb-confined post-traumatic pain syndrome with sympathetic features. The cause is unknown, but the results of a randomized crossover trial on low-dose IVIG treatment point to a possible autoimmune mechanism. We tested purified serum immunoglobulin G (IgG) from patients with longstanding CRPS for evidence of antibodies interacting with autonomic receptors on adult primary cardiomyocytes, comparing with control IgG from healthy and disease controls, and related the results to the clinical response to treatment with low-dose intravenous immunoglobulins (IvIG). We simultaneously recorded both single cell contractions and intracellular calcium handling in an electrical field. Ten of 18 CRPS preparations and only 1/57 control preparations (p<0.0001) increased the sensitivity of the myocytes to the electric field and this effect was abrogated by pre-incubation with alpha1a receptor blockers. By contrast, effects on baseline calcium were blocked by pre-incubation with atropine. Interestingly, serum-IgG preparations from all four CRPS patients who had responded to low-dose IVIG with meaningful pain relief were effective in these assays, although 4/8 of the non-responders were also active. To see if there were antibodies to the alpha1a receptor, CRPS-IgG was applied to alpha 1a receptor transfected rat1-fibroblast cells. The CRPS serum IgG induced calcium flux, and FACS showed that there was serum IgG binding to the cells. The results suggest that patients with longstanding CRPS have serum antibodies to alpha 1a receptors, and that measurement of these antibodies may be useful in the diagnosis and management of the patients.
    Pain 09/2014; · 5.64 Impact Factor
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    ABSTRACT: Patients with autoimmune disorders often have low levels of 25-hydroxyvitamin D [25(OH)D3], which correlates with disability or disease activity. Vitamin D may play a role in neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD), as an important factor involved in immunological pathways. We investigated the relationship between vitamin D levels and disease related disability and clinical activity in patients with NMOSD. Blood samples from 51 patients with NMOSD who were positive for anti-aquaporin4-antibody (AQP4-ab) and 204 healthy controls were collected for 25(OH)D3 measurement. Clinical parameters, including expanded disability status scale (EDSS) score, annualized relapse rate (ARR) and time of blood sampling relative to attack, were determined in patients with NMOSD. We found that 25(OH)D3 levels were significantly lower in patients with NMOSD compared to healthy controls. There was no difference between 25(OH)D3 levels in blood samples taken at relapse or remission, and no association between 25(OH)D3 levels and ARR, but there was an inverse correlation between 25(OH)D3 levels and EDSS scores in patients with NMOSD. It remains to be determined whether low vitamin D levels predispose to NMO and/or modify disease severity, or are secondary to neurological disability. In either case the results could also be of relevance to other neurological diseases such as multiple sclerosis as well as NMO.
    PLoS ONE 09/2014; 9(9):e107274. · 3.53 Impact Factor
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    ABSTRACT: Background Identification of auto antibodies has defined distinct clinico-immuno-pathological subtypes of myasthenia gravis (MG) such as AChR-antibody-positive-MG and MuSK-antibody-positive-MG. The use of more sensitive assays such as the cell-based assay (CBA) is expected to reduce the proportion of seronegative-MG. We studied the seroprevalence of AChR and MuSK antibodies using both radioimmunoprecipitation (RIA) and CBA amongst MG patients in Sri Lanka and related their antibody status to their clinical subtypes and severity. Methods 113 patients with MG attending Neurology units in the district of Colombo were studied. Clinical data were obtained using an interviewer-administered questionnaire and medical records. The severity of MG was assessed according to MGFA clinical grading. RIA and CBA were used to detect serum AChR and MuSK antibodies. Patients with other neurological diseases were recruited as controls. Results We detected either AChRAb (85%) or MuSKAb (6.2%) in 91.2% of MG patients. Complementing the RIA with the CBA improved the diagnostic power of detecting AChRAbs by 21% and MuSKAbs by 77%. The clinical characteristics and the occurrence of thymic pathology were similar to other populations except for a male preponderance (1.5:1). The AChRAb titer appeared to parallel the clinical severity. Seven of 11 (63.6%) patients with AChRAb-negative generalized MG had MuSK–MG. Conclusions Clinical characteristics of MG in Sri Lanka are similar to other populations. Complementing the RIA with CBA increases the diagnostic power of detecting pathogenic autoantibodies.
    Journal of the Neurological Sciences 08/2014; 342(1):82-83. · 2.24 Impact Factor
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    ABSTRACT: Neuromyelitis Optica (NMO) is a severe and rare inflammatory condition, where relapses are predictive of disability.
    Journal of neurology, neurosurgery, and psychiatry. 08/2014;
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    ABSTRACT: There is increasing evidence to support the relevance of immune system in the pathogenesis of Alzheimer Disease (AD) and also there is growing evidence for importance of specific antibodies in some neurological disorders. Antibodies against Voltage Gated Potassium Channels (VGKC) and Glutamic Decarboxylase (GAD) are of interest for AD. The presence of these antibodies is thought to be related to cognitive impairment and memory problems. In our study we attempted to find a relationship between these antibodies in individuals with AD compared with healthy controls.
    Journal of neurology, neurosurgery, and psychiatry. 08/2014; 85(8):e3.
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    08/2014; 1(2):e16.
  • JAMA Neurology 07/2014; 71(7):924. · 7.58 Impact Factor
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    ABSTRACT: The clinical associations of glycine receptor antibodies have not yet been described fully. We identified prospectively 52 antibody-positive patients and collated their clinical features, investigations and immunotherapy responses. Serum glycine receptor antibody endpoint titres ranged from 1:20 to 1:60 000. In 11 paired samples, serum levels were higher than (n = 10) or equal to (n = 1) cerebrospinal fluid levels; there was intrathecal synthesis of glycine receptor antibodies in each of the six pairs available for detailed study. Four patients also had high glutamic acid decarboxylase antibodies (>1000 U/ml), and one had high voltage-gated potassium channel-complex antibody (2442 pM). Seven patients with very low titres (<1:50) and unknown or alternative diagnoses were excluded from further study. Three of the remaining 45 patients had newly-identified thymomas and one had a lymphoma. Thirty-three patients were classified as progressive encephalomyelitis with rigidity and myoclonus, and two as stiff person syndrome; five had a limbic encephalitis or epileptic encephalopathy, two had brainstem features mainly, two had demyelinating optic neuropathies and one had an unclear diagnosis. Four patients (9%) died during the acute disease, but most showed marked improvement with immunotherapies. At most recent follow-up, (2-7 years, median 3 years, since first antibody detection), the median modified Rankin scale scores (excluding the four deaths) decreased from 5 at maximal severity to 1 (P < 0.0001), but relapses have occurred in five patients and a proportion are on reducing steroids or other maintenance immunotherapies as well as symptomatic treatments. The glycine receptor antibodies activated complement on glycine receptor-transfected human embryonic kidney cells at room temperature, and caused internalization and lysosomal degradation of the glycine receptors at 37°C. Immunoglobulin G antibodies bound to rodent spinal cord and brainstem co-localizing with monoclonal antibodies to glycine receptor-α1. Ten glycine receptor antibody positive samples were also identified in a retrospective cohort of 56 patients with stiff person syndrome and related syndromes. Glycine receptor antibodies are strongly associated with spinal and brainstem disorders, and the majority of patients have progressive encephalomyelitis with rigidity and myoclonus. The antibodies demonstrate in vitro evidence of pathogenicity and the patients respond well to immunotherapies, contrasting with earlier studies of this syndrome, which indicated a poor prognosis. The presence of glycine receptor antibodies should help to identify a disease that responds to immunotherapies, but these treatments may need to be sustained, relapses can occur and maintenance immunosuppression may be required.
    Brain : a journal of neurology. 06/2014;
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    ABSTRACT: The recent discovery of several potentially pathogenic autoantibodies has helped identify patients with clinically-distinctive central nervous system diseases that appear to benefit from immunotherapy. The associated autoantibodies are directed against the extracellular domains of cell-surface expressed neuronal or glial proteins such as LGI1, the NMDA-receptor and aquaporin-4. The original descriptions of the associated clinical syndromes were phenotypically well-circumscribed. However, as availability of antibody testing has increased, the range of associated patient phenotypes and demographics has expanded. This, in turn, has led to the recognition of more immunotherapy-responsive syndromes in patients presenting with cognitive and behavioural problems, seizures, movement disorders, psychiatric features, and demyelinating disease. While antibody detection remains diagnostically important, clinical recognition of these distinctive syndromes should ensure early and appropriate immunotherapy administration. We review the emerging paradigm of cell-surface directed antibody-mediated neurological diseases, describe how the associated disease spectrums have broadened since the original descriptions, discuss some of the issues regarding antibody detection and syndrome definitions, and emphasize considerations surrounding immunotherapy administration. As these disorders continue to reach mainstream neurology, and even psychiatry, more cell-surface directed antibodies will be discovered and their possible relevance to other commoner disease presentations should become more clearly defined. ANN NEUROL 2014. © 2014 American Neurological Association.
    Annals of Neurology 06/2014; · 11.19 Impact Factor
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    ABSTRACT: To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders.
    06/2014; 1(1):e2.
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    ABSTRACT: Postictal psychosis (PIP) is a serious psychiatric complication of epilepsy that occurs in approximately 6% of patients following multiple complex partial or generalized seizures. The psychosis is classically described as having a pleomorphic phenomenology, including paranoid, grandiose, and religious delusions as well as multimodal hallucinations with prominent affective changes and agitation. Little is understood about the pathophysiology of the condition. There has been a recent increase in interest in the relevance of autoimmunity to the pathogenesis of both epilepsy and psychosis. Studies have demonstrated the presence of antibodies directed against synaptic autoantigens (such as the N-methyl-d-aspartate receptor or the voltage-gated potassium channel complex) in approximately 10% of cases of sporadic epilepsy. These same autoantibodies are known to cause encephalopathy syndromes which feature psychiatric symptoms, usually psychosis, as a prominent part of the phenotype as well as other neurological features such as seizures, movement disorders, and autonomic dysfunction. It is beginning to be asked if these antibodies can be associated with a purely psychiatric phenotype. Here, we hypothesize that PIP may be an autoimmune phenomenon mediated by autoantibodies against synaptic antigens. More specifically, we outline a potential mechanism whereby long or repeated seizures cause short-lived blood-brain barrier (BBB) dysfunction during which the brain becomes exposed to pathogenic autoantibodies. In essence, we propose that PIP is a time-limited, seizure-dependent, autoantibody-mediated encephalopathy syndrome. We highlight a number of features of PIP that may be explained by this mechanism, such as the lucid interval between seizures and onset of psychosis and the progression in some cases to a chronic, interictal psychosis.
    Epilepsy & Behavior 05/2014; 36C:33-38. · 2.06 Impact Factor
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    ABSTRACT: A wide range of clinical presentations including neuromuscular disorders and autoimmune encephalopathies is being recognized to be associated with various autoantibodies. Glycine receptor (GlyR) antibodies have so far been found mainly in adult patients with phenotypes comprising progressive encephalomyelitis with rigidity and myoclonus or stiff-person syndrome. We report a four-year-old boy who presented with a two-year-history of drug-resistant focal epilepsy with unusual seizure semiology, temper tantrums, headache, clumsiness, and intermittently impaired speech. While MRI and CSF were normal, screening for autoimmune antibodies revealed GlyR antibodies in serum. Immunomodulatory treatment with steroids resulted in rapid and complete resolution of symptoms. Our observation widens the spectrum of clinical presentations associated with GlyR antibodies and emphasizes the potential relevance of neuronal autoantibodies in epilepsies of unknown cause in children as well as in adults.
    Neuropediatrics 05/2014; · 1.19 Impact Factor

Publication Stats

6k Citations
1,634.71 Total Impact Points


  • 1997–2014
    • University of Oxford
      • • Nuffield Department of Clinical Neurosciences
      • • Neurosciences Research Group
      Oxford, England, United Kingdom
  • 1993–2014
    • Oxford University Hospitals NHS Trust
      • Department of Clinical Neurology
      Oxford, England, United Kingdom
  • 2013
    • Children's Hospital at Westmead
      • Institute of Neuroscience and Muscle Research
      Sydney, New South Wales, Australia
  • 2012–2013
    • Universität Heidelberg
      • Institute of Papyrology
      Heidelberg, Baden-Wuerttemberg, Germany
    • Guy's and St Thomas' NHS Foundation Trust
      Londinium, England, United Kingdom
    • University of Veterinary Medicine in Vienna
      Wien, Vienna, Austria
    • Christian-Albrechts-Universität zu Kiel
      Kiel, Schleswig-Holstein, Germany
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Kitasato University
      • Medical Department
      Edo, Tōkyō, Japan
  • 2011–2013
    • University of London
      Londinium, England, United Kingdom
  • 2010–2013
    • Istanbul University
      • Department of Family Medicine (Istanbul Medical Faculty)
      İstanbul, Istanbul, Turkey
    • University of Liverpool
      Liverpool, England, United Kingdom
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
    • The University of Hong Kong
      • Department of Paediatrics and Adolescent Medicine
      Hong Kong, Hong Kong
  • 2009–2013
    • University of Colombo
      • Department of Clinical Medicine
      Columbo, Western, Sri Lanka
    • University of Sydney
      • Discipline of Paediatrics and Child Health
      Sydney, New South Wales, Australia
    • University of Padova
      • Department of Neurosciences
      Padova, Veneto, Italy
  • 2010–2011
    • St George's, University of London
      Londinium, England, United Kingdom
  • 2009–2010
    • University of Bonn
      • Department of Neurobiology
      Bonn, North Rhine-Westphalia, Germany
  • 2008
    • Osaka City University
      Ōsaka, Ōsaka, Japan
  • 2007
    • Tongji Hospital
      Wu-han-shih, Hubei, China
  • 2006–2007
    • Khon Kaen University
      • Department of Medicine
      Khon Kaen, Changwat Khon Kaen, Thailand
    • Kempenhaeghe
      Heeze, North Brabant, Netherlands
    • Seoul National University Hospital
      • Department of Neurology
      Seoul, Seoul, South Korea
  • 2002–2007
    • University of Wuerzburg
      • Institute for Pathology
      Würzburg, Bavaria, Germany
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1999–2006
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
  • 2003
    • Kanazawa Medical University
      • Department of Neurology
      Kanazawa-shi, Ishikawa-ken, Japan