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Angela Vincent - One of the best experts on this subject based on the ideXlab platform.
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1645 vgkc is dead long live lgi1 and caspr2 antibodies intracellular and non neuronal targets of voltage gated Potassium Channel complex antibodies
Journal of Neurology Neurosurgery and Psychiatry, 2017Co-Authors: Bethan Lang, Angela Vincent, Camilla Buckley, Paul Maddison, Inga M Dettmann, Jane E Adcock, Isabel Leite, Lars Komorowski, Patrick Waters, Sarosh R IraniAbstract:Introduction 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 commoner 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 125I-aDTX-labelled VGKC-complexes, 125I-aDTX and 125I-aDTX-labelled Kv1-subunits, live hippocampal neuron reactivity, and by cell-based assays using Kv1-subunits, LGI1 and CASPR2. Results VGKC-complex-antibodies were found in 162 of 1131 (14%) sera. Ninety of these (56%) had antibodies targeting the extracellular domains of LGI1 or CASPR2. Of the remaining 72 double-negative sera, ten (14%) immunoprecipitated 125I-aDTX itself, and 27 (38%) bound to solubilized 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 Kv1-precipitating samples only bound to permeabilised Kv1-expressing HEK 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 aDTX. These are not neuronal-surface antibodies. They consequently lack pathogenic potential, and do not in themselves support use of immunotherapies. VGKC-complex radioimmunoassay testing should cease; antibodies against LGI1 and CASPR2 provide greater specificity and sensitivity.
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clinical relevance of positive voltage gated Potassium Channel vgkc complex antibodies experience from a tertiary referral centre
Journal of Neurology Neurosurgery and Psychiatry, 2014Co-Authors: Ross W Paterson, Angela Vincent, Michael S Zandi, Richard N Armstrong, Jonathan M SchottAbstract:Background Voltage-Gated Potassium Channel (VGKC)-complex antibodies can be associated with a range of immunotherapy-responsive clinical presentations including limbic encephalitis, Morvan9s syndrome and acquired neuromyotonia. However, there are patients with positive levels in whom the significance is uncertain. Objective To evaluate the clinical significance associated with positive (>100 pM) VGKC-complex antibodies. Methods Over a 4-year period, 1053 samples were sent for testing of which 55 were positive. The clinical presentations, final diagnoses and responses to immunotherapies, when given, were assessed retrospectively and the likelihood of autoimmunity was categorised as definite, possible, unlikely or undetermined (modified from Zuliani et al 2012). Results Only 4 of the 32 patients with low-positive (100–400 pM) levels were considered definitely autoimmune, 3 with peripheral nerve hyperexcitability and 1 with a thymoma; 3 were given immunotherapies. Of the remaining 28 with low-positive levels, 13 (3 of whom had tumours) were considered possibly autoimmune, and 15 were unlikely or undetermined; 1 was given immunotherapy unsuccessfully. Of the 23 patients with high-positive (>400 pM) levels, 12 were given immunotherapies, 11 of whom showed a good response. 11 were considered definitely autoimmune, 10 with limbic encephalitis (antibody specificity: 5 LGI1, 1 contactin2, 2 negative, 2 untested) and 1 with a tumour. In the remaining 12, autoimmunity was considered possible (n=9; most had not received immunotherapies), or unlikely (n=3). Conclusions As antibody testing becomes more widely available, and many samples are referred from patients with less clear-cut diagnoses, it is important to assess the utility of the results. VGKC-complex antibodies in the range of 100–400 pM (0.1–0.4 nM) were considered clinically relevant in rare conditions with peripheral nerve hyperexcitability and appeared to associate with tumours (12.5%). By contrast high-positive (>400 pM; >0.4 nM) levels were considered definitely (38%) or possibly (49%) clinically relevant, but not all patients had a ‘classical’ limbic encephalitis and some did not receive immunotherapies.
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persistent anterograde amnesia following limbic encephalitis associated with antibodies to the voltage gated Potassium Channel complex
Journal of Neurology Neurosurgery and Psychiatry, 2014Co-Authors: Christopher Collett Butler, Thomas D Miller, Angela Vincent, Manveer S Kaur, Ian Baker, Georgie D Boothroyd, Nathan A Illman, Clive R Rosenthal, Camilla BuckleyAbstract:Objective Limbic encephalitis (LE) associated with antibodies to the Voltage-Gated Potassium Channel complex (VGKC) is a potentially reversible cause of cognitive impairment. Despite the prominence of cognitive dysfunction in this syndrome, little is known about patients’ neuropsychological profile at presentation or their long-term cognitive outcome. Methods We used a comprehensive neuropsychological test battery to evaluate cognitive function longitudinally in 19 patients with VGKC-LE. Results Before immunotherapy, the group had significant impairment of memory, processing speed and executive function, whereas language and perceptual organisation were intact. At follow-up, cognitive impairment was restricted to the memory domain, with processing speed and executive function having returned to the normal range. Residual memory function was predicted by the antibody titre at presentation. Conclusions The results show that, despite broad cognitive dysfunction in the acute phase, patients with VGKC-LE often make a substantial recovery with immunotherapy but may be left with permanent anterograde amnesia.
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suspected limbic encephalitis and seizure in cats associated with voltage gated Potassium Channel vgkc complex antibody
Journal of Veterinary Internal Medicine, 2013Co-Authors: Akos Pakozdy, Peter Halasz, Michael Leschnik, Bethan Lang, Andrea Klang, Jan Bauer, Alexander Tichy, Johann G Thalhammer, Angela VincentAbstract:Background Treatment-resistant complex partial seizures (CPS) with orofacial involvement recently were reported in cats in association with hippocampal pathology. The features had some similarity to those described in humans with limbic encephalitis and Voltage-Gated Potassium Channel (VGKC) complex antibody. Hypothesis/Objectives The purpose of this pilot study was to evaluate cats with CPS and orofacial involvement for the presence of VGKC-complex antibody. Animals Client-owned cats with acute orofacial CPS and control cats were investigated. Methods Prospective study. Serum was collected from 14 cats in the acute stage of the disease and compared with 19 controls. VGKC-complex antibodies were determined by routine immunoprecipitation and by binding to leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), the 2 main targets of VGKC-complex antibodies in humans. Results Five of the 14 affected cats, but none of the 19 controls, had VGKC-complex antibody concentrations above the cut-off concentration (>100 pmol/L) based on control samples and similar to those found in humans. Antibodies in 4 cats were directed against LGI1, and none were directed against CASPR2. Follow-up sera were available for 5 cats in remission and all antibody concentrations were within the reference range. Conclusion and Clinical Importance Our study suggests that an autoimmune limbic encephalitis exists in cats and that VGKC-complex/LGI1 antibodies may play a role in this disorder, as they are thought to in humans.
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immunotherapy responsive chorea as the presenting feature of lgi1 antibody encephalitis
Neurology, 2012Co-Authors: George K Tofaris, Sarosh R Irani, Ian Baker, Binith Cheeran, Zameel M Cader, Angela VincentAbstract:We describe 2 patients who presented with subacute chorea as the initial feature of autoimmune encephalitis associated with antibodies against leucine-rich glioma inactivated 1 (LGI1), a component of the Voltage-Gated Potassium Channel (VGKC) complex.
Sarosh R Irani - One of the best experts on this subject based on the ideXlab platform.
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1645 vgkc is dead long live lgi1 and caspr2 antibodies intracellular and non neuronal targets of voltage gated Potassium Channel complex antibodies
Journal of Neurology Neurosurgery and Psychiatry, 2017Co-Authors: Bethan Lang, Angela Vincent, Camilla Buckley, Paul Maddison, Inga M Dettmann, Jane E Adcock, Isabel Leite, Lars Komorowski, Patrick Waters, Sarosh R IraniAbstract:Introduction 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 commoner 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 125I-aDTX-labelled VGKC-complexes, 125I-aDTX and 125I-aDTX-labelled Kv1-subunits, live hippocampal neuron reactivity, and by cell-based assays using Kv1-subunits, LGI1 and CASPR2. Results VGKC-complex-antibodies were found in 162 of 1131 (14%) sera. Ninety of these (56%) had antibodies targeting the extracellular domains of LGI1 or CASPR2. Of the remaining 72 double-negative sera, ten (14%) immunoprecipitated 125I-aDTX itself, and 27 (38%) bound to solubilized 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 Kv1-precipitating samples only bound to permeabilised Kv1-expressing HEK 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 aDTX. These are not neuronal-surface antibodies. They consequently lack pathogenic potential, and do not in themselves support use of immunotherapies. VGKC-complex radioimmunoassay testing should cease; antibodies against LGI1 and CASPR2 provide greater specificity and sensitivity.
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episodic bradycardia as neurocardiac prodrome to voltage gated Potassium Channel complex leucine rich glioma inactivated 1 antibody encephalitis
JAMA Neurology, 2014Co-Authors: Georges Naasan, Michael D. Geschwind, Bm Bettcher, Sarosh R Irani, Jeffrey M GelfandAbstract:Importance Voltage-Gated Potassium Channel complex antibody (VGKCc-Ab) encephalitis is an immunotherapy-responsive syndrome usually associated with causative antibodies that target the leucine-rich, glioma inactivated 1 (LGI1) protein. Although it is expressed throughout the brain, LGI1 is not known to be expressed in cardiac tissue. We describe a novel neurocardiac prodrome of VGKCc-Ab/LGI1-encephalitis. Observations Among 14 patients with VGKCc/LGI1-Ab encephalitis evaluated in the University of California, San Francisco Autoimmune Encephalitis Clinic and Rapid Dementia Research Program, 3 patients (2 men and 1 woman; aged 53, 55, and 64 years) exhibited episodic bradycardia that preceded the onset of encephalopathy by approximately 2 months and was severe enough to lead to pacemaker implantation. Serum LGI1-Ab results were positive when tested at the time of the subsequent encephalopathy. All 3 patients developed hyponatremia; none had faciobrachial dystonic seizures or malignancy. Brain magnetic resonance imaging was abnormal in 2 cases. None of the patients experienced further symptomatic bradyarrythmias after 1.7 to 7 years of follow-up. Conclusions and Relevance Episodic bradycardia is a distinctive neurocardiac prodrome of VGKCc/LGI1-Ab encephalitis. The neuroanatomical localization most likely relates to insular and temporal lobe involvement, cortical regions that modulate cardiac autonomic function. Further study is needed to determine if recognition of this neurocardiac prodrome and earlier institution of immunosuppression can prevent the development of encephalopathy.
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more than memory impairment in voltage gated Potassium Channel complex encephalopathy
European Journal of Neurology, 2014Co-Authors: Bm Bettcher, Sarosh R Irani, Jeffrey M Gelfand, John Neuhaus, Sven Forner, Christopher P Hess, Michael D. GeschwindAbstract:Author(s): Bettcher, BM; Gelfand, JM; Irani, SR; Neuhaus, J; Forner, S; Hess, CP; Geschwind, MD | Abstract: Autoimmune encephalopathies (AEs) are a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly endorsed, few reports of AEs inclusively assess all cognitive domains in detail. Our aim was to perform an unbiased cognitive evaluation of AE patients with Voltage-Gated Potassium Channel complex antibodies (VGKCC -Abs) in order to delineate cognitive strengths and weaknesses.Serial VGKCC -Ab AE subjects (n = 12) were assessed with a comprehensive evaluation of memory, executive functions, visuospatial skills and language. Clinical magnetic resonance imaging (MRI) (n = 10/12) was evaluated. Five subjects had serial cognitive testing available, permitting descriptive analysis of change.Subjects demonstrated mild to moderate impairment in memory (mean Z = -1.9) and executive functions (mean Z = -1.5), with variable impairments in language and sparing of visuospatial skills. MRI findings showed T2 hyperintensities in medial temporal lobe (10/10) and basal ganglia (2/10). Serial cognitive examination revealed heterogeneity in cognitive function; whereas most patients improved in one or more domains, residual impairments were observed in some patients.This study augments previous neuropsychological analyses in VGKCC -Ab AE by identifying not only memory and executive function deficits but also language impairments, with preservation of visuospatial functioning. The study further highlights the importance of domain-specific testing to parse out the complex cognitive phenotypes of VGKCC -Ab AE.
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neuropsychological profiles of voltage gated Potassium Channel complex and other autoimmune encephalopathies more than memory impairment s18 005
Neurology, 2014Co-Authors: Michael D. Geschwind, Sarosh R Irani, Jeffrey M Gelfand, John Neuhaus, Sven Forner, Bm BettcherAbstract:Objective: To evaluate cognitive function and imaging findings in patients with Voltage-Gated Potassium Channel complex antibody (VGKCC-Abs) associated encephalopathy . We compared indices of memory, visuospatial, language, and executive functions to deficits in patients with other antibody-associated autoimmune encephalopathies (AEs). Background: AEs represent a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly reported, few reports of AE assess all cognitive domains in detail. Methods: We assessed subjects (n=12) with AE who tested positive for VGKCC-Abs with a comprehensive neuropsychological protocol and compared their profiles to subjects with antibodies against intracellular (GAD, n=2) or another cell-surface protein (AMPAR, n=3), relative to a normative sample. Clinical MRI data were available for 10/12 VGKCC-Abs patients and evaluated descriptively. Four VGKCC-Abs subjects had serial cognitive testing available, permitting description of longitudinal change. Results: Patients with VGKCC-Abs demonstrated particular impairment in memory (mean Z=-1.9) and executive functions (mean Z=-1.5), with isolated difficulties in language (mean Z=-1.4) and sparing of visuospatial skills. By contrast, AMPAR-antibody positive subjects displayed striking executive dysfunction, whereas GAD-antibody positive subjects displayed less severe impairments across all domains. Longitudinal testing of four VGKCC-Abs AE subjects revealed heterogeneity in cognitive change over time; whereas most subjects improved in one domain, residual impairments or cognitive plateaus were observed. MRI findings in the VGKCc-Ab patients nearest to time of cognitive testing showed atrophy (5 of 10), and subtle or obvious hyperintensities in medial temporal lobe (MTL) structures (9 of 10). Conclusions: This study offers one of the first comprehensive evaluations of cognitive functioning in VGKCC associated AE and other antibody-mediated AE’s, and highlights the importance of domain-specific tests of cognition to parse out their complex clinical phenotypes. Delineating the relative strengths and weaknesses for AE subtypes remains critical for differential diagnosis, and has implications for development of focused cognitive therapies. Study supported by NIH/NIA R01 AG31189/K23021989, and the Michael J. Homer Family Fund Disclosure: Dr. Geschwind has received personal compensation for activities with Lundbeck, Inc., MedaCorp, The Council of Advisors, and Neurophage. Dr. Geschwind has received research support from NIH/NIA, the Tau Consortium and CurePSP. Dr. Gelfand has received personal compensation for activities with the National Multiple Sclerosis Society. Dr. Gelfand has received personal compensation in an editorial capacity for Watch Neurology. Dr. Irani has nothing to disclose. Dr. Neuhaus has nothing to disclose. Dr. Forner has nothing to disclose. Dr. Bettcher has nothing to disclose.
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immunotherapy responsive chorea as the presenting feature of lgi1 antibody encephalitis
Neurology, 2012Co-Authors: George K Tofaris, Sarosh R Irani, Ian Baker, Binith Cheeran, Zameel M Cader, Angela VincentAbstract:We describe 2 patients who presented with subacute chorea as the initial feature of autoimmune encephalitis associated with antibodies against leucine-rich glioma inactivated 1 (LGI1), a component of the Voltage-Gated Potassium Channel (VGKC) complex.
Michael D. Geschwind - One of the best experts on this subject based on the ideXlab platform.
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episodic bradycardia as neurocardiac prodrome to voltage gated Potassium Channel complex leucine rich glioma inactivated 1 antibody encephalitis
JAMA Neurology, 2014Co-Authors: Georges Naasan, Michael D. Geschwind, Bm Bettcher, Sarosh R Irani, Jeffrey M GelfandAbstract:Importance Voltage-Gated Potassium Channel complex antibody (VGKCc-Ab) encephalitis is an immunotherapy-responsive syndrome usually associated with causative antibodies that target the leucine-rich, glioma inactivated 1 (LGI1) protein. Although it is expressed throughout the brain, LGI1 is not known to be expressed in cardiac tissue. We describe a novel neurocardiac prodrome of VGKCc-Ab/LGI1-encephalitis. Observations Among 14 patients with VGKCc/LGI1-Ab encephalitis evaluated in the University of California, San Francisco Autoimmune Encephalitis Clinic and Rapid Dementia Research Program, 3 patients (2 men and 1 woman; aged 53, 55, and 64 years) exhibited episodic bradycardia that preceded the onset of encephalopathy by approximately 2 months and was severe enough to lead to pacemaker implantation. Serum LGI1-Ab results were positive when tested at the time of the subsequent encephalopathy. All 3 patients developed hyponatremia; none had faciobrachial dystonic seizures or malignancy. Brain magnetic resonance imaging was abnormal in 2 cases. None of the patients experienced further symptomatic bradyarrythmias after 1.7 to 7 years of follow-up. Conclusions and Relevance Episodic bradycardia is a distinctive neurocardiac prodrome of VGKCc/LGI1-Ab encephalitis. The neuroanatomical localization most likely relates to insular and temporal lobe involvement, cortical regions that modulate cardiac autonomic function. Further study is needed to determine if recognition of this neurocardiac prodrome and earlier institution of immunosuppression can prevent the development of encephalopathy.
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more than memory impairment in voltage gated Potassium Channel complex encephalopathy
European Journal of Neurology, 2014Co-Authors: Bm Bettcher, Sarosh R Irani, Jeffrey M Gelfand, John Neuhaus, Sven Forner, Christopher P Hess, Michael D. GeschwindAbstract:Author(s): Bettcher, BM; Gelfand, JM; Irani, SR; Neuhaus, J; Forner, S; Hess, CP; Geschwind, MD | Abstract: Autoimmune encephalopathies (AEs) are a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly endorsed, few reports of AEs inclusively assess all cognitive domains in detail. Our aim was to perform an unbiased cognitive evaluation of AE patients with Voltage-Gated Potassium Channel complex antibodies (VGKCC -Abs) in order to delineate cognitive strengths and weaknesses.Serial VGKCC -Ab AE subjects (n = 12) were assessed with a comprehensive evaluation of memory, executive functions, visuospatial skills and language. Clinical magnetic resonance imaging (MRI) (n = 10/12) was evaluated. Five subjects had serial cognitive testing available, permitting descriptive analysis of change.Subjects demonstrated mild to moderate impairment in memory (mean Z = -1.9) and executive functions (mean Z = -1.5), with variable impairments in language and sparing of visuospatial skills. MRI findings showed T2 hyperintensities in medial temporal lobe (10/10) and basal ganglia (2/10). Serial cognitive examination revealed heterogeneity in cognitive function; whereas most patients improved in one or more domains, residual impairments were observed in some patients.This study augments previous neuropsychological analyses in VGKCC -Ab AE by identifying not only memory and executive function deficits but also language impairments, with preservation of visuospatial functioning. The study further highlights the importance of domain-specific testing to parse out the complex cognitive phenotypes of VGKCC -Ab AE.
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neuropsychological profiles of voltage gated Potassium Channel complex and other autoimmune encephalopathies more than memory impairment s18 005
Neurology, 2014Co-Authors: Michael D. Geschwind, Sarosh R Irani, Jeffrey M Gelfand, John Neuhaus, Sven Forner, Bm BettcherAbstract:Objective: To evaluate cognitive function and imaging findings in patients with Voltage-Gated Potassium Channel complex antibody (VGKCC-Abs) associated encephalopathy . We compared indices of memory, visuospatial, language, and executive functions to deficits in patients with other antibody-associated autoimmune encephalopathies (AEs). Background: AEs represent a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly reported, few reports of AE assess all cognitive domains in detail. Methods: We assessed subjects (n=12) with AE who tested positive for VGKCC-Abs with a comprehensive neuropsychological protocol and compared their profiles to subjects with antibodies against intracellular (GAD, n=2) or another cell-surface protein (AMPAR, n=3), relative to a normative sample. Clinical MRI data were available for 10/12 VGKCC-Abs patients and evaluated descriptively. Four VGKCC-Abs subjects had serial cognitive testing available, permitting description of longitudinal change. Results: Patients with VGKCC-Abs demonstrated particular impairment in memory (mean Z=-1.9) and executive functions (mean Z=-1.5), with isolated difficulties in language (mean Z=-1.4) and sparing of visuospatial skills. By contrast, AMPAR-antibody positive subjects displayed striking executive dysfunction, whereas GAD-antibody positive subjects displayed less severe impairments across all domains. Longitudinal testing of four VGKCC-Abs AE subjects revealed heterogeneity in cognitive change over time; whereas most subjects improved in one domain, residual impairments or cognitive plateaus were observed. MRI findings in the VGKCc-Ab patients nearest to time of cognitive testing showed atrophy (5 of 10), and subtle or obvious hyperintensities in medial temporal lobe (MTL) structures (9 of 10). Conclusions: This study offers one of the first comprehensive evaluations of cognitive functioning in VGKCC associated AE and other antibody-mediated AE’s, and highlights the importance of domain-specific tests of cognition to parse out their complex clinical phenotypes. Delineating the relative strengths and weaknesses for AE subtypes remains critical for differential diagnosis, and has implications for development of focused cognitive therapies. Study supported by NIH/NIA R01 AG31189/K23021989, and the Michael J. Homer Family Fund Disclosure: Dr. Geschwind has received personal compensation for activities with Lundbeck, Inc., MedaCorp, The Council of Advisors, and Neurophage. Dr. Geschwind has received research support from NIH/NIA, the Tau Consortium and CurePSP. Dr. Gelfand has received personal compensation for activities with the National Multiple Sclerosis Society. Dr. Gelfand has received personal compensation in an editorial capacity for Watch Neurology. Dr. Irani has nothing to disclose. Dr. Neuhaus has nothing to disclose. Dr. Forner has nothing to disclose. Dr. Bettcher has nothing to disclose.
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Adult-onset drug-refractory seizure disorder associated with anti-Voltage-Gated Potassium-Channel antibody.
Epilepsia, 2010Co-Authors: Ramon F. Barajas, D. Eric Collins, Soonmee Cha, Michael D. GeschwindAbstract:Voltage gated Potassium Channels are widely expressed throughout the entire nervous system. These Channels play a critical role in establishing the resting membrane potential and generation of neuronal action potentials. There is mounting evidence that auto-antibodies reactive to neuronal cell surface antigens, such as Voltage-Gated Potassium Channels, play a pathogenic role in a wide spectrum of central and peripheral nervous system disorders. We report a case of new onset drug refractory seizure disorder associated with the presence of high levels of serum anti Voltage-Gated Potassium Channel antibodies that responded only to immunotherapy. As demonstrated by this case report, anti Voltage-Gated Potassium Channel antibody associated drug refractory seizure disorder, while rare, should be considered in patients with unexplained adult-onset seizure activity. Once the diagnosis has been established the initiation of immunotherapy should be undertaken without delay.
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voltage gated Potassium Channel autoimmunity mimicking creutzfeldt jakob disease
JAMA Neurology, 2008Co-Authors: Michael D. Geschwind, Ramon F. Barajas, Vanda A Lennon, Christopher J Klein, Meng K Tan, Aissa Haman, Andrew S Josephson, Sean J PittockAbstract:Background Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal Voltage-Gated Potassium Channel (VGKC) autoantibody–associated encephalopathy. Objective To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity. Design Observational, prospective case series. Setting Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco. Patients A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review. Main Outcome Measures Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy. Results All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients' conditions (92%) improved after immunomodulatory therapy. Conclusions Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody–associated encephalopathy may be confused with those of CJD. Serologic evaluation for markers of neurologic autoimmunity, including VGKC autoantibodies, may be warranted in suspected CJD cases.
Bm Bettcher - One of the best experts on this subject based on the ideXlab platform.
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Episodic bradycardia as neurocardiac prodrome to Voltage-Gated Potassium Channel complex/leucine-rich, glioma inactivated 1 antibody encephalitis.
'American Medical Association (AMA)', 2014Co-Authors: Naasan G, Bm Bettcher, Jm GelfandAbstract:IMPORTANCE: Voltage-Gated Potassium Channel complex antibody (VGKCc-Ab) encephalitis is an immunotherapy-responsive syndrome usually associated with causative antibodies that target the leucine-rich, glioma inactivated 1 (LGI1) protein. Although it is expressed throughout the brain, LGI1 is not known to be expressed in cardiac tissue. We describe a novel neurocardiac prodrome of VGKCc-Ab/LGI1-encephalitis. OBSERVATIONS: Among 14 patients with VGKCc/LGI1-Ab encephalitis evaluated in the University of California, San Francisco Autoimmune Encephalitis Clinic and Rapid Dementia Research Program, 3 patients (2 men and 1 woman; aged 53, 55, and 64 years) exhibited episodic bradycardia that preceded the onset of encephalopathy by approximately 2 months and was severe enough to lead to pacemaker implantation. Serum LGI1-Ab results were positive when tested at the time of the subsequent encephalopathy. All 3 patients developed hyponatremia; none had faciobrachial dystonic seizures or malignancy. Brain magnetic resonance imaging was abnormal in 2 cases. None of the patients experienced further symptomatic bradyarrythmias after 1.7 to 7 years of follow-up. CONCLUSIONS AND RELEVANCE: Episodic bradycardia is a distinctive neurocardiac prodrome of VGKCc/LGI1-Ab encephalitis. The neuroanatomical localization most likely relates to insular and temporal lobe involvement, cortical regions that modulate cardiac autonomic function. Further study is needed to determine if recognition of this neurocardiac prodrome and earlier institution of immunosuppression can prevent the development of encephalopathy
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episodic bradycardia as neurocardiac prodrome to voltage gated Potassium Channel complex leucine rich glioma inactivated 1 antibody encephalitis
JAMA Neurology, 2014Co-Authors: Georges Naasan, Michael D. Geschwind, Bm Bettcher, Sarosh R Irani, Jeffrey M GelfandAbstract:Importance Voltage-Gated Potassium Channel complex antibody (VGKCc-Ab) encephalitis is an immunotherapy-responsive syndrome usually associated with causative antibodies that target the leucine-rich, glioma inactivated 1 (LGI1) protein. Although it is expressed throughout the brain, LGI1 is not known to be expressed in cardiac tissue. We describe a novel neurocardiac prodrome of VGKCc-Ab/LGI1-encephalitis. Observations Among 14 patients with VGKCc/LGI1-Ab encephalitis evaluated in the University of California, San Francisco Autoimmune Encephalitis Clinic and Rapid Dementia Research Program, 3 patients (2 men and 1 woman; aged 53, 55, and 64 years) exhibited episodic bradycardia that preceded the onset of encephalopathy by approximately 2 months and was severe enough to lead to pacemaker implantation. Serum LGI1-Ab results were positive when tested at the time of the subsequent encephalopathy. All 3 patients developed hyponatremia; none had faciobrachial dystonic seizures or malignancy. Brain magnetic resonance imaging was abnormal in 2 cases. None of the patients experienced further symptomatic bradyarrythmias after 1.7 to 7 years of follow-up. Conclusions and Relevance Episodic bradycardia is a distinctive neurocardiac prodrome of VGKCc/LGI1-Ab encephalitis. The neuroanatomical localization most likely relates to insular and temporal lobe involvement, cortical regions that modulate cardiac autonomic function. Further study is needed to determine if recognition of this neurocardiac prodrome and earlier institution of immunosuppression can prevent the development of encephalopathy.
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more than memory impairment in voltage gated Potassium Channel complex encephalopathy
European Journal of Neurology, 2014Co-Authors: Bm Bettcher, Sarosh R Irani, Jeffrey M Gelfand, John Neuhaus, Sven Forner, Christopher P Hess, Michael D. GeschwindAbstract:Author(s): Bettcher, BM; Gelfand, JM; Irani, SR; Neuhaus, J; Forner, S; Hess, CP; Geschwind, MD | Abstract: Autoimmune encephalopathies (AEs) are a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly endorsed, few reports of AEs inclusively assess all cognitive domains in detail. Our aim was to perform an unbiased cognitive evaluation of AE patients with Voltage-Gated Potassium Channel complex antibodies (VGKCC -Abs) in order to delineate cognitive strengths and weaknesses.Serial VGKCC -Ab AE subjects (n = 12) were assessed with a comprehensive evaluation of memory, executive functions, visuospatial skills and language. Clinical magnetic resonance imaging (MRI) (n = 10/12) was evaluated. Five subjects had serial cognitive testing available, permitting descriptive analysis of change.Subjects demonstrated mild to moderate impairment in memory (mean Z = -1.9) and executive functions (mean Z = -1.5), with variable impairments in language and sparing of visuospatial skills. MRI findings showed T2 hyperintensities in medial temporal lobe (10/10) and basal ganglia (2/10). Serial cognitive examination revealed heterogeneity in cognitive function; whereas most patients improved in one or more domains, residual impairments were observed in some patients.This study augments previous neuropsychological analyses in VGKCC -Ab AE by identifying not only memory and executive function deficits but also language impairments, with preservation of visuospatial functioning. The study further highlights the importance of domain-specific testing to parse out the complex cognitive phenotypes of VGKCC -Ab AE.
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neuropsychological profiles of voltage gated Potassium Channel complex and other autoimmune encephalopathies more than memory impairment s18 005
Neurology, 2014Co-Authors: Michael D. Geschwind, Sarosh R Irani, Jeffrey M Gelfand, John Neuhaus, Sven Forner, Bm BettcherAbstract:Objective: To evaluate cognitive function and imaging findings in patients with Voltage-Gated Potassium Channel complex antibody (VGKCC-Abs) associated encephalopathy . We compared indices of memory, visuospatial, language, and executive functions to deficits in patients with other antibody-associated autoimmune encephalopathies (AEs). Background: AEs represent a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly reported, few reports of AE assess all cognitive domains in detail. Methods: We assessed subjects (n=12) with AE who tested positive for VGKCC-Abs with a comprehensive neuropsychological protocol and compared their profiles to subjects with antibodies against intracellular (GAD, n=2) or another cell-surface protein (AMPAR, n=3), relative to a normative sample. Clinical MRI data were available for 10/12 VGKCC-Abs patients and evaluated descriptively. Four VGKCC-Abs subjects had serial cognitive testing available, permitting description of longitudinal change. Results: Patients with VGKCC-Abs demonstrated particular impairment in memory (mean Z=-1.9) and executive functions (mean Z=-1.5), with isolated difficulties in language (mean Z=-1.4) and sparing of visuospatial skills. By contrast, AMPAR-antibody positive subjects displayed striking executive dysfunction, whereas GAD-antibody positive subjects displayed less severe impairments across all domains. Longitudinal testing of four VGKCC-Abs AE subjects revealed heterogeneity in cognitive change over time; whereas most subjects improved in one domain, residual impairments or cognitive plateaus were observed. MRI findings in the VGKCc-Ab patients nearest to time of cognitive testing showed atrophy (5 of 10), and subtle or obvious hyperintensities in medial temporal lobe (MTL) structures (9 of 10). Conclusions: This study offers one of the first comprehensive evaluations of cognitive functioning in VGKCC associated AE and other antibody-mediated AE’s, and highlights the importance of domain-specific tests of cognition to parse out their complex clinical phenotypes. Delineating the relative strengths and weaknesses for AE subtypes remains critical for differential diagnosis, and has implications for development of focused cognitive therapies. Study supported by NIH/NIA R01 AG31189/K23021989, and the Michael J. Homer Family Fund Disclosure: Dr. Geschwind has received personal compensation for activities with Lundbeck, Inc., MedaCorp, The Council of Advisors, and Neurophage. Dr. Geschwind has received research support from NIH/NIA, the Tau Consortium and CurePSP. Dr. Gelfand has received personal compensation for activities with the National Multiple Sclerosis Society. Dr. Gelfand has received personal compensation in an editorial capacity for Watch Neurology. Dr. Irani has nothing to disclose. Dr. Neuhaus has nothing to disclose. Dr. Forner has nothing to disclose. Dr. Bettcher has nothing to disclose.
Jeffrey M Gelfand - One of the best experts on this subject based on the ideXlab platform.
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episodic bradycardia as neurocardiac prodrome to voltage gated Potassium Channel complex leucine rich glioma inactivated 1 antibody encephalitis
JAMA Neurology, 2014Co-Authors: Georges Naasan, Michael D. Geschwind, Bm Bettcher, Sarosh R Irani, Jeffrey M GelfandAbstract:Importance Voltage-Gated Potassium Channel complex antibody (VGKCc-Ab) encephalitis is an immunotherapy-responsive syndrome usually associated with causative antibodies that target the leucine-rich, glioma inactivated 1 (LGI1) protein. Although it is expressed throughout the brain, LGI1 is not known to be expressed in cardiac tissue. We describe a novel neurocardiac prodrome of VGKCc-Ab/LGI1-encephalitis. Observations Among 14 patients with VGKCc/LGI1-Ab encephalitis evaluated in the University of California, San Francisco Autoimmune Encephalitis Clinic and Rapid Dementia Research Program, 3 patients (2 men and 1 woman; aged 53, 55, and 64 years) exhibited episodic bradycardia that preceded the onset of encephalopathy by approximately 2 months and was severe enough to lead to pacemaker implantation. Serum LGI1-Ab results were positive when tested at the time of the subsequent encephalopathy. All 3 patients developed hyponatremia; none had faciobrachial dystonic seizures or malignancy. Brain magnetic resonance imaging was abnormal in 2 cases. None of the patients experienced further symptomatic bradyarrythmias after 1.7 to 7 years of follow-up. Conclusions and Relevance Episodic bradycardia is a distinctive neurocardiac prodrome of VGKCc/LGI1-Ab encephalitis. The neuroanatomical localization most likely relates to insular and temporal lobe involvement, cortical regions that modulate cardiac autonomic function. Further study is needed to determine if recognition of this neurocardiac prodrome and earlier institution of immunosuppression can prevent the development of encephalopathy.
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more than memory impairment in voltage gated Potassium Channel complex encephalopathy
European Journal of Neurology, 2014Co-Authors: Bm Bettcher, Sarosh R Irani, Jeffrey M Gelfand, John Neuhaus, Sven Forner, Christopher P Hess, Michael D. GeschwindAbstract:Author(s): Bettcher, BM; Gelfand, JM; Irani, SR; Neuhaus, J; Forner, S; Hess, CP; Geschwind, MD | Abstract: Autoimmune encephalopathies (AEs) are a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly endorsed, few reports of AEs inclusively assess all cognitive domains in detail. Our aim was to perform an unbiased cognitive evaluation of AE patients with Voltage-Gated Potassium Channel complex antibodies (VGKCC -Abs) in order to delineate cognitive strengths and weaknesses.Serial VGKCC -Ab AE subjects (n = 12) were assessed with a comprehensive evaluation of memory, executive functions, visuospatial skills and language. Clinical magnetic resonance imaging (MRI) (n = 10/12) was evaluated. Five subjects had serial cognitive testing available, permitting descriptive analysis of change.Subjects demonstrated mild to moderate impairment in memory (mean Z = -1.9) and executive functions (mean Z = -1.5), with variable impairments in language and sparing of visuospatial skills. MRI findings showed T2 hyperintensities in medial temporal lobe (10/10) and basal ganglia (2/10). Serial cognitive examination revealed heterogeneity in cognitive function; whereas most patients improved in one or more domains, residual impairments were observed in some patients.This study augments previous neuropsychological analyses in VGKCC -Ab AE by identifying not only memory and executive function deficits but also language impairments, with preservation of visuospatial functioning. The study further highlights the importance of domain-specific testing to parse out the complex cognitive phenotypes of VGKCC -Ab AE.
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neuropsychological profiles of voltage gated Potassium Channel complex and other autoimmune encephalopathies more than memory impairment s18 005
Neurology, 2014Co-Authors: Michael D. Geschwind, Sarosh R Irani, Jeffrey M Gelfand, John Neuhaus, Sven Forner, Bm BettcherAbstract:Objective: To evaluate cognitive function and imaging findings in patients with Voltage-Gated Potassium Channel complex antibody (VGKCC-Abs) associated encephalopathy . We compared indices of memory, visuospatial, language, and executive functions to deficits in patients with other antibody-associated autoimmune encephalopathies (AEs). Background: AEs represent a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly reported, few reports of AE assess all cognitive domains in detail. Methods: We assessed subjects (n=12) with AE who tested positive for VGKCC-Abs with a comprehensive neuropsychological protocol and compared their profiles to subjects with antibodies against intracellular (GAD, n=2) or another cell-surface protein (AMPAR, n=3), relative to a normative sample. Clinical MRI data were available for 10/12 VGKCC-Abs patients and evaluated descriptively. Four VGKCC-Abs subjects had serial cognitive testing available, permitting description of longitudinal change. Results: Patients with VGKCC-Abs demonstrated particular impairment in memory (mean Z=-1.9) and executive functions (mean Z=-1.5), with isolated difficulties in language (mean Z=-1.4) and sparing of visuospatial skills. By contrast, AMPAR-antibody positive subjects displayed striking executive dysfunction, whereas GAD-antibody positive subjects displayed less severe impairments across all domains. Longitudinal testing of four VGKCC-Abs AE subjects revealed heterogeneity in cognitive change over time; whereas most subjects improved in one domain, residual impairments or cognitive plateaus were observed. MRI findings in the VGKCc-Ab patients nearest to time of cognitive testing showed atrophy (5 of 10), and subtle or obvious hyperintensities in medial temporal lobe (MTL) structures (9 of 10). Conclusions: This study offers one of the first comprehensive evaluations of cognitive functioning in VGKCC associated AE and other antibody-mediated AE’s, and highlights the importance of domain-specific tests of cognition to parse out their complex clinical phenotypes. Delineating the relative strengths and weaknesses for AE subtypes remains critical for differential diagnosis, and has implications for development of focused cognitive therapies. Study supported by NIH/NIA R01 AG31189/K23021989, and the Michael J. Homer Family Fund Disclosure: Dr. Geschwind has received personal compensation for activities with Lundbeck, Inc., MedaCorp, The Council of Advisors, and Neurophage. Dr. Geschwind has received research support from NIH/NIA, the Tau Consortium and CurePSP. Dr. Gelfand has received personal compensation for activities with the National Multiple Sclerosis Society. Dr. Gelfand has received personal compensation in an editorial capacity for Watch Neurology. Dr. Irani has nothing to disclose. Dr. Neuhaus has nothing to disclose. Dr. Forner has nothing to disclose. Dr. Bettcher has nothing to disclose.
