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102. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

Author

Symonds, Joseph D, primary, Zuberi, Sameer M, additional, Stewart, Kirsty, additional, McLellan, Ailsa, additional, O‘Regan, Mary, additional, MacLeod, Stewart, additional, Jollands, Alice, additional, Joss, Shelagh, additional, Kirkpatrick, Martin, additional, Brunklaus, Andreas, additional, Pilz, Daniela T, additional, Shetty, Jay, additional, Dorris, Liam, additional, Abu-Arafeh, Ishaq, additional, Andrew, Jamie, additional, Brink, Philip, additional, Callaghan, Mary, additional, Cruden, Jamie, additional, Diver, Louise A, additional, Findlay, Christine, additional, Gardiner, Sarah, additional, Grattan, Rosemary, additional, Lang, Bethan, additional, MacDonnell, Jane, additional, McKnight, Jean, additional, Morrison, Calum A, additional, Nairn, Lesley, additional, Slean, Meghan M, additional, Stephen, Elma, additional, Webb, Alan, additional, Vincent, Angela, additional, and Wilson, Margaret, additional

Published
2019
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106. The Role of Autoantibodies in Lambert-Eaton Myasthenic Syndromeaa

Author

LANG, BETHAN, WATERMAN, SALLY, PINTO, ASHWIN, JONES, DOMINIC, MOSS, FRASER, BOOT, JOHN, BRUST, PAUL, WILLIAMS, MARK, STAUDERMAN, KENNETH, HARPOLD, MICHAEL, MOTOMURA, MASAKATSU, WIBE MOLL, J., VINCENT, ANGELA, and NEWSOM-DAVIS, JOHN

Published
1998

108. Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.

Author

McGinty, Ronan N., Handel, Adam, Moloney, Teresa, Ramesh, Archana, Fower, Andrew, Torzillo, Emma, Kramer, Holger, Howell, Stephen, Waters, Patrick, Adcock, Jane, Sen, Arjune, Lang, Bethan, and Irani, Sarosh R.

Subjects
PARTIAL epilepsy, ANTI-NMDA receptor encephalitis, AUTOANTIBODIES, LIMBIC system, IMMUNOTHERAPY, ENCEPHALITIS
Abstract

Objective: To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this clinical setting.Methods: Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy.Results: 10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. 9/23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (p<0.0001). Multivariate analysis identified six features which predicted autoantibody positivity (area under the curve=0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, MRI limbic system changes and the absence of conventional epilepsy risk factors. 11/14 (79%) patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score=0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (p<0.05).Conclusions: Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggests immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis. [ABSTRACT FROM AUTHOR]

Published
2021
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110. Association of Leucine-Rich Glioma Inactivated Protein 1, Contactin-Associated Protein 2, and Contactin 2 Antibodies With Clinical Features and Patient-Reported Pain in Acquired Neuromyotonia

Author

Vincent, Angela, primary, Pettingill, Philippa, additional, Pettingill, Rosie, additional, Lang, Bethan, additional, Birch, Ron, additional, Waters, Patrick, additional, Irani, Sarosh R., additional, Buckley, Camilla, additional, Watanabe, Osamu, additional, Arimura, Kimiyoshi, additional, and Kiernan, Matthew C., additional

Published
2018
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111. Correction: Myasthenia gravis seronegative for acetylcholine receptor antibodies in South Korea: Autoantibody profiles and clinical features

Author

Park, Kee Hong, primary, Waters, Patrick, additional, Woodhall, Mark, additional, Lang, Bethan, additional, Smith, Thomas, additional, Sung, Jung-Joon, additional, Kim, Kwang-Kuk, additional, Lim, Young-Min, additional, Kim, Jee-Eun, additional, Kim, Byung-Jo, additional, Park, Jin-Sung, additional, Lim, Jeong-Geon, additional, Kim, Dae-Seong, additional, Kwon, Ohyun, additional, Sohn, Eun Hee, additional, Bae, Jong Seok, additional, Yoon, Byung-Nam, additional, Kim, Nam-Hee, additional, Ahn, Suk-Won, additional, Oh, Jeeyoung, additional, Park, Hyung Jun, additional, Shin, Kyong Jin, additional, and Hong, Yoon-Ho, additional

Published
2018
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113. The Importance of Early Immunotherapy in patients with Faciobrachial Dystonic Seizures (P1.290)

Author

Thompson, Julia, primary, Bi, Mian, additional, Makuch, Mateusz, additional, Murchison, Andrew, additional, Bien, Christian, additional, Chu, Kon, additional, Farooque, Pue, additional, Gelfand, Jeffrey, additional, Geschwind, Michael, additional, Somerville, Ernest, additional, Lang, Bethan, additional, Vincent, Angela, additional, Leite, M Isabel, additional, Waters, Patrick, additional, and Irani, Sarosh, additional

Published
2018
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114. Myasthenia gravis seronegative for acetylcholine receptor antibodies in South Korea: Autoantibody profiles and clinical features

Author

Park, Kee Hong, primary, Waters, Patrick, additional, Woodhall, Mark, additional, Lang, Bethan, additional, Smith, Thomas, additional, Sung, Jung-Joon, additional, Kim, Kwang-Kuk, additional, Lim, Young-Min, additional, Kim, Jee-Eun, additional, Kim, Byung-Jo, additional, Park, Jin-Sung, additional, Lim, Jeong-Geon, additional, Kim, Dae-Seong, additional, Kwon, Ohyun, additional, Sohn, Eun Hee, additional, Bae, Jong Seok, additional, Yoon, Byung-Nam, additional, Kim, Nam-Hee, additional, Ahn, Suk-Won, additional, Oh, Jeeyoung, additional, Park, Hyung Jun, additional, Shin, Kyong Jin, additional, and Hong, Yoon-Ho, additional

Published
2018
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116. Autoantibodies to neuronal surface antigens in thyroid antibody-positive and -negative limbic encephalitis

Author

Tuzun, Erdem, Erdag, Ece, Durmus, Hacer, Brenner, Tanja, Turkoglu, Recai, Kurtuncu, Murat, Lang, Bethan, Akman-Demir, Gulsen, Eraksoy, Mefkure, and Vincent, Angela

Subjects
Potassium channels -- Physiological aspects -- Genetic aspects -- Research, Encephalitis -- Diagnosis -- Risk factors -- Genetic aspects -- Care and treatment -- Research, Autoantibodies -- Health aspects, Health
Abstract

Byline: Erdem. Tuzun, Ece. Erdag, Hacer. Durmus, Tanja. Brenner, Recai. Turkoglu, Murat. Kurtuncu, Bethan. Lang, Gulsen. Akman-Demir, Mefkure. Eraksoy, Angela. Vincent Background : Thyroid antibodies (Thy-Abs) are frequently detected in [...]

Published
2011

117. Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study

Author

Lennox, Belinda R., Palmer-Cooper, Emma C., Pollak, Thomas, Hainsworth, Jane, Marks, Jacqui, Jacobson, Leslie, Lang, Bethan, Fox, Hannah, Ferry, Berne, Linda Scoriels, Crowley, Hannah, Jones, Peter B., Harrison, Paul J., Vincent, Angela, Jones, Peter [0000-0002-0387-880X], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Neurons, Young Adult, Adolescent, Psychotic Disorders, Case-Control Studies, Antigens, Surface, Prevalence, Antibodies, Monoclonal, Humans, Female
Abstract

$\textbf{Background}$ Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies—especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)—more commonly than do healthy controls. $\textbf{Methods}$ We recruited patients aged 14–35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABAA receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. $\textbf{Findings}$ Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8–7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. $\textbf{Interpretation}$ Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation.

Published
2017
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118. Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca2+ channels

Author

Spillane, Jennifer, Ermolyuk, Yaroslav, Cano-Jaimez, Marife, Lang, Bethan, Vincent, Angela, Volynski, Kirill E., and Kullmann, Dimitri M.

Subjects
Adult, Male, Mice, Knockout, Neurons, Action Potentials, Middle Aged, Calcium Channel Blockers, Synaptic Transmission, Article, Exocytosis, Lambert-Eaton Myasthenic Syndrome, Mice, Calcium Channels, N-Type, Immunoglobulin G, Animals, Humans, Female, Calcium Channels, Aged, Autoantibodies, Fluorescent Dyes
Abstract

Objective: To determine whether immunoglobulin G (IgG) from patients with Lambert-Eaton myasthenic syndrome (LEMS) decreases action potential–evoked synaptic vesicle exocytosis, and whether the effect is mediated by P/Q-type voltage-gated calcium channels (VGCCs). Methods: IgG was obtained from 4 patients with LEMS (3 males, 1 female), including 2 patients with lung malignancy. Antibodies against P/Q-type VGCCs were detected in all 4 patients, and against N-type VGCCs in 2. We incubated neuronal cultures with LEMS IgG and determined the size of the total recycling pool of synaptic vesicles and the rate of action potential–evoked exocytosis using fluorescence imaging of the amphiphilic dye SynaptoRed C1. Pooled IgG from healthy volunteers was used as a control. We repeated the experiments on synapses lacking P/Q-type calcium channels from a Cacna1a knockout mouse to determine whether these channels account for the pathogenic effect of LEMS IgG. Results: LEMS IgG had no effect on the total recycling pool size but significantly reduced the rate of action potential–evoked synaptic exocytosis in wild-type neurons when compared with neurons treated with control IgG. In contrast, LEMS IgG had no effect on the rate of synaptic vesicle exocytosis in neurons lacking P/Q-type channels. Conclusions: These data provide direct evidence that LEMS IgG inhibits neurotransmitter release by acting on P/Q-type VGCCs.

Published
2016
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119. Neuronal antibodies in pediatric epilepsy:Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy

Author

Wright, Sukhvir, Geerts, Ada T., Jol-Van Der Zijde, Cornelia Maria, Jacobson, Leslie, Lang, Bethan, Waters, Patrick, Van Tol, Maarten J.D., Stroink, Hans, Neuteboom, Rinze F., Brouwer, Oebele F., and Vincent, Angela

Abstract

Objective In autoimmune encephalitis the etiologic role of neuronal cell-surface antibodies is clear; patients diagnosed and treated early have better outcomes. Neuronal antibodies have also been described in patients with pediatric epilepsy without encephalitis. The aim was to assess whether antibody presence had any effect on long-term outcomes in these patients. Methods Patients (n = 178) were recruited between 1988 and 1992 as part of the prospective Dutch Study of Epilepsy in Childhood; none received immunotherapy. Healthy age-matched bone-marrow donors served as controls (n = 112). All sera were tested for serum N-methyl-d-aspartate receptor (NMDAR), alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, leucine rich glioma inactivated 1, contactin associated protein like 2 (CASPR2), contactin-2, glutamic acid decarboxylase, and voltage gated potassium channel (VGKC)-complex antibodies by standard techniques. No cerebrospinal fluid (CSF) samples were available. Results were correlated with clinical data collected over 15 years. Results Seventeen patients (9.5%) were positive for VGKC complex (n = 3), NMDAR (n = 7), CASPR2 (n = 4), and contactin-2 (n = 3), compared to three (3/112; 2.6%) healthy controls (VGKC complex [n = 1], NMDAR [n = 2]; p = 0.03; Fisher's exact test). Titers were relatively low (≤1:100 for cell-surface antibodies), but 8 (47%) of the 17 positive samples bound to the surface of live hippocampal neurons consistent with a potential pathogenic antibody. Preexisting cognitive impairment was more frequent in antibody-positive patients (9/17 vs. 33/161; p = 0.01). Fourteen antibody-positive patients were treated with standard antiepileptic drugs (AEDs); three (17%) became intractable but this was not different from the 16 (10%) of 161 antibody-negative patients. In 96 patients with available follow-up samples at 6 and/or 12 months, 6 of 7 positive antibodies had disappeared and, conversely, antibodies had appeared for the first time in a further 7 patients. Significance Neuronal antibodies were found at low levels in 9.5% of patients with new-onset pediatric epilepsy but did not necessarily persist over time, and the development of antibodies de novo in later samples suggests they could be due to a secondary response to neuronal damage or inflammation. Moreover, as the response to standard AEDs and the long-term outcome did not differ from those of antibody-negative pediatric patients, these findings suggest that routine neuronal antibody testing is unlikely to be helpful in pediatric epilepsy. However, the higher incidence of preexisting cognitive problems in the antibody-positive group, the CASPR2 and contactin-2 antibodies in 7 of 17 patients, and the binding of 8 of 17 of serum samples to live hippocampal neurons suggest that neuronal antibodies, even if secondary, could contribute to the comorbidities of pediatric epilepsy.

Published
2016

120. 293 Autoimmune autonomic ganglionopathy: the NHNN experience

Author

Watson Laura, Lang Bethan, Bremner Fion, Lunn Michael, Hagen Ellen Merete, Iodice Valeria, Ingle Gordon, Koay Shiwen, Vincent Angela, and Mathias Christopher

Subjects
medicine.medical_specialty, Neurology, business.industry, Autonomic ganglion, Autoimmune autonomic ganglionopathy, medicine.disease, Gastroenterology, Sudomotor, Psychiatry and Mental health, Orthostatic vital signs, Autonomic nervous system, medicine.anatomical_structure, Internal medicine, Medicine, Surgery, Rituximab, Neurology (clinical), business, Pure autonomic failure, medicine.drug
Abstract

BackgroundAutoimmune Autonomic Ganglionopathy (AAG) is a rare, immune-mediated condition characterised by subacute pandysautonomia. 50% have auto-antibodies to the ganglionic nicotinic acetylcholine receptor (gAChR), affecting synaptic transmission at autonomic ganglia.MethodsWe describe 13 patients (5 female, median age 47) presenting with widespread autonomic failure, confirmed on cardiovascular, sudomotor and pupillometry testing at the National Hospital for Neurology and Neurosurgery (NHNN), and high gAChR antibody levels (>200 pm) measured by radioimmunoprecipitation assay at Oxford University.ResultsOf the 13 patients, 8 had other autoimmune conditions, 3 had antecedent infection and 3 were paraneoplastic. All had orthostatic hypotension, gastro-intestinal and urinary symptoms, 11 had documented pupillary abnormalities (9 mixed sympathetic and parasympathetic deficits, 2 subclinical sympathetic deficits), 11 had secretomotor dysfunction, 8 had generalised/partial anhidrosis, 8 had sexual dysfunction and 7 had evidence of small fibre dysfunction on neurophysiology.Ten received immunomodulatory treatment; 6 plasma exchange and 4 combination treatment including intravenous immunoglobulin, mycophenolate and rituximab. Earlier treatment was associated with greater clinical response.DiscussionPatients with AAG and high gAChR antibody levels have widespread dysfunction of the autonomic nervous system, which can respond dramatically to immunomodulation. Further research is needed to develop robust clinical biomarkers to guide treatment and monitor response.

Published
2018
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122. Brain-relevant antibodies in first-episode psychosis: a matched case–control study

Author

Gaughran, Fiona, primary, Lally, John, additional, Beck, Katherine, additional, McCormack, Ruaidhri, additional, Gardner-Sood, Poonam, additional, Coutinho, Ester, additional, Jacobson, Leslie, additional, Lang, Bethan, additional, Sainz-Fuertes, Ricardo, additional, Papanastasiou, Evangelos, additional, Di Forti, Marta, additional, Nicholson, Tim, additional, Vincent, Angela, additional, and Murray, Robin M., additional

Published
2017
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126. Maternal CASPR2 antibodies and neurodevelopmental disorders in the offspring: epidemiological findings and an animal model

Author

Coutinho, Ester, primary, Menassa, David, additional, Jacobson, Leslie, additional, West, Steven, additional, Domingos, Joana, additional, Moloney, Teresa, additional, Pedersen, Marianne G, additional, Benros, Michael E, additional, Lang, Bethan, additional, Bennett, David, additional, Harrison, Paul J, additional, Mortensen, Preben B, additional, Nørgaard-Pedersen, Bent, additional, Bannerman, David, additional, and Vincent, Angela, additional

Published
2017
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129. Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies

Author

Lang, Bethan, primary, Makuch, Mateusz, additional, Moloney, Teresa, additional, Dettmann, Inga, additional, Mindorf, Swantje, additional, Probst, Christian, additional, Stoecker, Winfried, additional, Buckley, Camilla, additional, Newton, Charles R, additional, Leite, M Isabel, additional, Maddison, Paul, additional, Komorowski, Lars, additional, Adcock, Jane, additional, Vincent, Angela, additional, Waters, Patrick, additional, and Irani, Sarosh R, additional

Published
2017
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134. Brain-relevant antibodies in first-episode psychosis: a matched case–control study.

Author

Gaughran, Fiona, Murray, Robin M., Di Forti, Marta, Nicholson, Tim, Vincent, Angela, Beck, Katherine, Gardner-Sood, Poonam, Lally, John, McCormack, Ruaidhri, Coutinho, Ester, Jacobson, Leslie, Lang, Bethan, Sainz-Fuertes, Ricardo, and Papanastasiou, Evangelos

Subjects
DIAGNOSIS of neurological disorders, PSYCHOSES, PSYCHIATRIC hospitals, AGE distribution, BRAIN, CELL receptors, DIAGNOSTIC errors, GLYCOPROTEINS, IMMUNOGLOBULINS, LEUCINE, POTASSIUM, SEX distribution, DISEASE prevalence, CASE-control method, BLOOD, DIAGNOSIS
Abstract

Background: There has been much recent excitement about the possibility that some cases of psychosis may be wholly due to brain-reactive antibodies, with antibodies to N-methyl-D-aspartate receptor (NMDAR) and the voltage-gated potassium channel (VGKC)-complex reported in a few patients with first-episode psychosis (FEP). Methods: Participants were recruited from psychiatric services in South London, UK, from 2009 to 2011 as part of the Genetics and Psychosis study. We conducted a case–control study to examine NMDAR and VGKC-complex antibody levels and rates of antibody positivity in 96 patients presenting with FEP and 98 controls matched for age and sex. Leucine-rich glioma inactiviated-1 (LGI1) and contactin-associated protein (CASPR) antibodies were also measured. Notably, patients with suspicion of organic disease were excluded. Results: VGKC-complex antibodies were found in both cases (n = 3) and controls (n = 2). NMDAR antibody positivity was seen in one case and one control. Either LGI1-Abs or CASPR2-Abs were found in three cases and three controls. Neuronal antibody staining, consistent with the above results or indicating potential novel antigens, was overall positive in four patients but also in six controls. Overall, antibody positivity was at low levels only and not higher in cases than in controls. Conclusions: This case–control study of the prevalence of antibodies in FEP does not provide evidence to support the hypothesis that FEP is associated with an immune-mediated process in a subgroup of patients. Nevertheless, as other bio-clinical factors may influence the effect of such antibodies in a given individual, and patients with organic neurological disease may be misdiagnosed as FEP, the field requires more research to put these findings in context. [ABSTRACT FROM AUTHOR]

Published
2018
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136. NK Cell-mediated Neuroblastoma Cell Lysis is Enhanced by IgG From Patients With Pediatric Opsoclonus-Myoclonus Syndrome

Author

Zar, Tahira, Tschernatsch, Marlene, Hero, Barbara, Lang, Bethan, Preissner, Klaus T., and Blaes, Franz

Abstract

Supplemental Digital Content is available in the text.Pediatric opsoclonus-myoclonussyndrome (OMS) is a rare autoimmune disorder of which 50% are associated with neuroblastoma (NB). We investigated whether surface-binding autoantibodies in OMS can enhance natural killer (NK) cell-mediated cytotoxicity in these patients. OMS immunoglobulin G (IgG) bound to NB cell lines and NK cell-mediated cytotoxicity to NB cells was enhanced after preincubation with OMS-IgG, but not IgG from NB without OMS or healthy controls. Activation of NK cells by surface-binding autoantibodies may be an additional mechanism of antitumor immunity in children with NB and OMS.

Published
2024
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144. Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome

Author

Pillai, Sekhar C., primary, Hacohen, Yael, additional, Tantsis, Esther, additional, Prelog, Kristina, additional, Merheb, Vera, additional, Kesson, Alison, additional, Barnes, Elizabeth, additional, Gill, Deepak, additional, Webster, Richard, additional, Menezes, Manoj, additional, Ardern-Holmes, Simone, additional, Gupta, Sachin, additional, Procopis, Peter, additional, Troedson, Christopher, additional, Antony, Jayne, additional, Ouvrier, Robert A., additional, Polfrit, Yann, additional, Davies, Nicholas W. S., additional, Waters, Patrick, additional, Lang, Bethan, additional, Lim, Ming J., additional, Brilot, Fabienne, additional, Vincent, Angela, additional, and Dale, Russell C., additional

Published
2015
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145. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease

Author

Waters, Patrick, primary, Woodhall, Mark, additional, O'Connor, Kevin C., additional, Reindl, Markus, additional, Lang, Bethan, additional, Sato, Douglas K., additional, Juryńczyk, Maciej, additional, Tackley, George, additional, Rocha, Joao, additional, Takahashi, Toshiyuki, additional, Misu, Tatsuro, additional, Nakashima, Ichiro, additional, Palace, Jacqueline, additional, Fujihara, Kazuo, additional, Leite, M. Isabel, additional, and Vincent, Angela, additional

Published
2015
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146. Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero.

Author

Coutinho, Ester, Menassa, David, Jacobson, Leslie, West, Steven, Domingos, Joana, Moloney, Teresa, Lang, Bethan, Harrison, Paul, Bennett, David, Bannerman, David, and Vincent, Angela

Subjects
NEURODEVELOPMENTAL treatment, MICROGLIA, MOVEMENT disorders
Abstract

Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V-VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15-52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target. [ABSTRACT FROM AUTHOR]

Published
2017
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148. Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies.

Author

Bethan Lang, Makuch, Mateusz, Moloney, Teresa, Dettmann, Inga, Mindorf, Swantje, Probst, Christian, Stoecker, Winfried, Buckley, Camilla, Newton, Charles R., Isabel Leite, M., Maddison, Paul, Komorowski, Lars, Adcock, Jane, Vincent, Angela, Waters, Patrick, Irani, Sarosh R., Lang, Bethan, and Leite, M Isabel

Subjects
POTASSIUM channels, IMMUNOGLOBULINS, ENCEPHALITIS, SPASMS, NEUROLOGICAL disorders
Abstract

Objectives: Autoantibodies against the extracellular domains of the voltage-gated potassium channel (VGKC) complex proteins, leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-2 (CASPR2), are found in patients with limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. However, in routine testing, VGKC complex antibodies without LGI1 or CASPR2 reactivities (double-negative) are more common than LGI1 or CASPR2 specificities. Therefore, the target(s) and clinical associations of double-negative antibodies need to be determined.Methods: Sera (n=1131) from several clinically defined cohorts were tested for IgG radioimmunoprecipitation of radioiodinated α-dendrotoxin (125I-αDTX)-labelled VGKC complexes from mammalian brain extracts. Positive samples were systematically tested for live hippocampal neuron reactivity, IgG precipitation of 125I-αDTX and 125I-αDTX-labelled Kv1 subunits, and by cell-based assays which expressed Kv1 subunits, LGI1 and CASPR2.Results: VGKC complex antibodies were found in 162 of 1131 (14%) sera. 90 of these (56%) had antibodies targeting the extracellular domains of LGI1 or CASPR2. Of the remaining 72 double-negative sera, 10 (14%) immunoprecipitated 125I-αDTX itself, and 27 (38%) bound to solubilised co-expressed Kv1.1/1.2/1.6 subunits and/or Kv1.2 subunits alone, at levels proportionate to VGKC complex antibody levels (r=0.57, p=0.0017). The sera with LGI1 and CASPR2 antibodies immunoprecipitated neither preparation. None of the 27 Kv1-precipitating samples bound live hippocampal neurons or Kv1 extracellular domains, but 16 (59%) bound to permeabilised Kv1-expressing human embryonic kidney 293T cells. These intracellular Kv1 antibodies mainly associated with non-immune disease aetiologies, poor longitudinal clinical-serological correlations and a limited immunotherapy response.Conclusions: Double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits and occasionally against non-mammalian αDTX. These antibodies should no longer be classified as neuronal-surface antibodies. They consequently lack pathogenic potential and do not in themselves support the use of immunotherapies. [ABSTRACT FROM AUTHOR]

Published
2017
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