Voltage-gated Potassium Channel Complex Research Articles

Molecular dissection of an immunodominant epitope in Kv1.2-exclusive autoimmunity.

Subgroups of autoantibodies directed against voltage-gated potassium channel (Kv) complex components have been associated with immunotherapy-responsive clinical syndromes. The high prevalence and the role of autoantibodies directly binding Kv remain, however, controversial. Our objective was to determine Kv autoantibody binding requirements and to clarify their contribution to the observed immune response. Binding epitopes were studied in sera (n = 36) and cerebrospinal fluid (CSF) (n = 12) from a patient cohort positive for Kv1.2 but negative for 32 common neurological autoantigens and controls (sera n = 18 and CSF n = 5) by phospho and deep mutational scans. Autoantibody specificity and contribution to the observed immune response were resolved on recombinant cells, cerebellum slices, and nerve fibers. 83% of the patients (30/36) within the studied cohort shared one out of the two major binding epitopes with Kv1.2-3 reactivity. Eleven percent (4/36) of the serum samples showed no binding. Fingerprinting resolved close to identical sequence requirements for both shared epitopes. Kv autoantibody response is directed against juxtaparanodal regions in peripheral nerves and the axon initial segment in central nervous system neurons and exclusively mediated by the shared epitopes. Systematic mapping revealed two shared autoimmune responses, with one dominant Kv1.2-3 autoantibody epitope being unexpectedly prevalent. The conservation of the molecular binding requirements among these patients indicates a uniform autoantibody repertoire with monospecific reactivity. The enhanced sensitivity of the epitope-based (10/12) compared with that of the cell-based detection (7/12) highlights its use for detection. The determined immunodominant epitope is also the primary immune response visible in tissue, suggesting a diagnostic significance and a specific value for routine screening.

Dual allosteric modulation of voltage and calcium sensitivities of the Slo1-LRRC channel complex

Modulation of large conductance intracellular ligand-activated potassium (BK) channel family (Slo1-3) by auxiliary subunits allows diverse physiological functions in excitable and non-excitable cells. Cryoelectron microscopy (cryo-EM) structures of voltage-gated potassium (Kv) channel complexes have provided insights into how voltage sensitivity is modulated by auxiliary subunits. However, the modulation mechanisms of BK channels, particularly as ligand-activated ion channels, remain unknown. Slo1 is a Ca2+-activated and voltage-gated BK channel and is expressed in neurons, muscle cells, and epithelial cells. Using cryo-EM and electrophysiology, we show that the LRRC26-γ1 subunit modulates not only voltage but also Ca2+ sensitivity of Homo sapiens Slo1. LRRC26 stabilizes the active conformation of voltage-senor domains of Slo1 by an extracellularly S4-locking mechanism. Furthermore, it also stabilizes the active conformation of Ca2+-sensor domains of Slo1 intracellularly, which is functionally equivalent to intracellular Ca2+ in the activation of Slo1. Such a dual allosteric modulatory mechanism may be general in regulating the intracellular ligand-activated BK channel complexes.

Anti-Kv1.4 Antibody-positive Nivolumab-induced Myasthenia Gravis and Myositis Presenting with Bilateral Ptosis and Demonstrating Different Pathophysiologies.

Nivolumab blocks inhibitors of T-cell activation and restores antitumor immunity but promotes T-cell activity in host tissues by blocking inhibition of the T-cell function, resulting in immune-related adverse effects. We herein report an 80-year-old man presenting with nivolumab-related myasthenia gravis with anti-muscular voltage-gated potassium channel-complex (Kv1.4) antibodies. On day 29 after nivolumab administration, he simultaneously developed rapidly progressing right ptosis and left facial paralysis. Nivolumab administration was discontinued. He subsequently presented with bulbar paralysis, dyspnea, and muscle weakness and received intravenous immunoglobulin, methylprednisolone, and plasma exchange. The severity of nivolumab-related myasthenia gravis with anti-Kv1.4 antibodies presented with diverse clinical findings.

Autoimmune encephalitis, a diagnostic and therapeutic challenge in the intensive care unit

Autoimmune encephalitis is a progressive inflammation of the brain, from acute to subacute, associated with antibodies against neuronal cell surface and synaptic protein, most commonly encephalitis against the N-methyl-D-aspartate (NMDA) receptor. New significant findings on etiology show that autoimmune encephalitis is triggered by several etiologies, for example neoplastic processes (breast, lung, kidney, thyroid cancer, ovarian teratoma, and B-cell lymphoma) but also by infections of the nervous system, such as herpes encephalitis. Antibodies against neuronal surface structures are usually direct pathogens and develop their effect through internalization of target proteins, through receptor blockade or complement activation. The type and titer of the antibody e.g. against NMDA receptors, Gamma Amino Butyric (GABA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or voltage-gated potassium channel complexes. An associated tumor, biomarkers, imaging studies, and cerebrospinal fluid are decisive for the prognosis. We present the clinical case of a male patient in the fourth decade of life who is diagnosed with autoimmune encephalitis, we will address the diagnosis and treatment.

Seronegative Isaac Syndrome Presenting as Focal Limb Stiffness Responsive to Plasma Exchange Therapy (P8-8.015)

<h3>Objective:</h3> N/A <h3>Background:</h3> Isaac syndrome is an autoimmune disorder of peripheral nerve hyperexcitability characterized by neuromyotonia, myokymia, muscles stiffness, pseudomyotonia, and pseudotetany frequently accompanied by dysautonomia and neuropathic pain. Approximately 50% of cases are associated with antibodies against contactin-associated protein-like 2 (CASPR2) or less commonly leucine-rich glioma inactivated protein 1 (LGI1), both components of the voltage-gated potassium channel (VGKC) complex. Paraneoplastic, genetic, and toxic etiologies must be considered. Management includes membrane-stabilizing drugs as well as immunotherapy in more severe cases. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 50-year-old woman presented with one year of left neck, shoulder, and upper extremity pain and stiffness that began one month after an upper respiratory illness. Her exam was notable for anterocollis, left shoulder elevation, impaired left shoulder abduction beyond 35–40 degrees, tonically contracted left biceps, and marked tenderness to palpation of the affected muscles. Symptomatic management with diazepam, lorazepam, baclofen, mexiletine, and trihexyphenidyl was ineffective. EMG demonstrated widespread neuromyotonic discharges throughout the proximal greater than distal left upper extremity, cervical and thoracic paraspinals, and right deltoid. Laboratory studies including CASPR2, LGI1, VGKC, GAD-65, and amphiphysin antibodies were unremarkable. Comprehensive screening for occult malignancy was unrevealing. She received partial benefit from carbamazepine, levetiracetam, cyclobenzaprine, and onabotulinumtoxinA injections, but symptoms remained debilitating. She was treated with IVIg 1g/kg Q2 weeks for three months with symptom progression to the jaw and lower extremities. She was started on plasmapheresis QOD for ten days every four weeks with rapid improvement in symptoms. <h3>Conclusions:</h3> We report a case of seronegative Isaac syndrome initially presenting with focal limb stiffness and dystonic posturing that was exquisitely responsive to plasmapheresis. This case highlights the need to consider peripheral nerve hyperexcitability syndromes in patients presenting with focal limb stiffness or painful dystonia and provides additional support for plasmapheresis as an effective treatment option for patients with debilitating symptoms. <b>Disclosure:</b> Dr. Khalil has received personal compensation in the range of $0-$499 for serving as a Resident and Fellow Council Member with American Association of Neuromuscular &amp; Electrodiagnostic Medicine. Dr. Khalil has received personal compensation in the range of $0-$499 for serving as a MS Mentorship Forum Participant with Foundation of the Consortium of Multiple Sclerosis Centers. Dr. Bradshaw has nothing to disclose.

Autoimmune Encephalitis, a Diagnostic and Therapeutic Challenge in the Intensive Care Unit.

Autoimmune encephalitis is a progressive inflammation of the brain, from acute to subacute, associated with antibodies against neuronal cell surface and synaptic protein, most commonly encephalitis against the N-methyl-D-aspartate (NMDA) receptor. New significant findings on etiology show that autoimmune encephalitis is triggered by several etiologies, for example neoplastic processes (breast, lung, kidney, thyroid cancer, ovarian teratoma, and B-cell lymphoma) but also by infections of the nervous system, such as herpes encephalitis. Antibodies against neuronal surface structures are usually direct pathogens and develop their effect through internalization of target proteins, through receptor blockade or complement activation. The type and titer of the antibody e.g. against NMDA receptors, Gamma Amino Butyric (GABA), αAmino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or voltage-gated potassium channel complexes. An associated tumor, biomarkers, imaging studies, and cerebrospinal fluid are decisive for the prognosis. We present the clinical case of a male patient in the fourth decade of life who is diagnosed with autoimmune encephalitis, we will address the diagnosis and treatment

Sleep disorders and polysomnography findings in patients with autoimmune encephalitis.

Sleep disorders in patients with autoimmune encephalitis (AE) are increasingly reported. Early recognition and treatment have significant importance regarding the potential of sleep disorders' effect on morbidity and even mortality. There are a limited number of studies related to polysomnography (PSG) in these patients. Here, we report the clinical and PSG data of patients with AE and sleep disorders, with a particular interest in sleep-related breathing disorders (SRBD). Seventeen patients with diagnosed AE and acute or subacute onset sleep complaints who underwent video-electroencephalography-PSG recordings in our tertiary center were investigated. The mean age was 50, with eight females and nine males. The detected antibodies were against leucine-rich glioma-inactivated 1(LGI-1) in 6, anti-contactin-associated protein-2(CASPR2) in 3, voltage-gated potassium channel complex antigens(VGKC) in 1, anti-glycine in 1, dipeptidyl-peptidase-like protein-6(DPPX) in 1, anti-Hu in 1, and anti-amphiphysin in 1. All commercially available and known autoimmune encephalitis-related antibodies were negative in 3 of the patients. Final diagnosis after PSG was circadian rhythm sleep disorder (n = 3), periodic limb movement disorder (n = 3), insomnia (n = 5), central apnea with or without Cheyne-Stokes breathing (CSB) (n = 4), obstructive sleep apnea (OSA) (n = 4), non-rapid eye movement (NREM) and REM parasomnia (n = 8), faciobrachial dystonic seizures (n = 2), and subclinical seizures (n = 1). Sleep microstructure was disrupted in 9, REM periods without atonia occurred in 4, and brief sleep fragments consisting of theta activity interspersed with faster rhythms existed in 7 patients. Nearly half of our patients (47%) had SRBD, and the mean apnea-hypopnea index (AHI) was 14. Sleep disorders are frequent and essential components of AEs. Systematic clinical questionnaires and routine PSG assessments would significantly impact the correct diagnosis and proper treatment of SRBD and the overall prognosis of AE.

Autoimmune Encephalitis Misdiagnosis in Adults

Autoimmune encephalitis misdiagnosis can lead to harm. To determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis. This retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), University of Washington in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded. Data were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions. A total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficits from comorbidities (11 [10%]), cerebral neoplasm (10 [9.5%]), and other (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 [46%] vs 7 of 91 [8%]) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-d-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]). When evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.

CNSC-28. IDENTIFICATION OF EAG2-KVß2 POTASSIUM CHANNEL COMPLEX IN NEURON-GBM COMMUNICATIONS REVEALS GBM VULNERABILITY TO DESIGNER INTERFERENCE PEPTIDE

Abstract Glioblastomas (GBMs) are the most aggressive brain tumors. GBM cells form extensive tumoral networks to communicate with each other and with surrounding neurons. Neuronal activity promotes GBM cell proliferation by secreting protumorigenic factors and triggering neuronal-activity-dependent Ca2+ transients, which are persisted and transmitted via tumor networks to promote overall tumor growth and therapy resistance. While how these processes are regulated is largely unknown. Here we show the GBM networks and Ca2+ transients are regulated by a voltage-gated potassium channel complex comprised of EAG2 and Kvβ2. GBM cells selectively overexpress Kvβ2 isoform 4 to facilitate tumor-specific Kvβ2-EAG2 interaction, which regulates neuron-GBM contact-dependent localization of EAG2. Rationally designed interfering peptide K90-114TAT blocks EAG2-Kvβ2 interaction, leading to reduced tumor cell proliferation, increased apoptosis, and prolonged survival of patient-derived xenograft mouse models with no evidence of toxicity to normal tissue. Single-cell RNA sequencing revealed a subgroup of GBM cells is highly sensitive to K90-114TAT treatment. These cells exhibit neuronal signatures and are highly associated with TMZ resistance and worse prognosis. In accordance with the notion, we found neurons promote TMZ resistance of GBM cells, which is regulated by the EAG2-Kvβ2 complex. Treating TMZ-resistant GBM xenograft mice with K90-114TAT yielded significant tumor burden reduction and prolonged survival. Together, our findings revealed the EAG2-Kvβ2 channel complex as a key regulator of neuron promoted GBM progression and designed an interfering peptide with anti-GBM efficacy and low general toxicity, which may have significant clinical impact.

Abstract 10026: Augmentation of Slow Repolarizing Potassium Channel (I Ks ) Links Truncated Titin Mutations to Atrial Fibrillation

Introduction: Rare titin-truncating variants ( TTN tv) are associated with early-onset atrial fibrillation (AF) but the pathogenic mechanisms and therapeutic implications remain unclear. To determine the function of a highly conserved immunoglobulin-like domain of the A-band of TTN , a region enriched in AF-associated variants, we employed CRISPR-Cas9-mediated deletion of 9 amino acids (Δ9) in human induced pluripotent stem cells and then derived atrial cardiomyocytes (hiPSC-aCMs) for electrophysiological (EP) analysis. Hypothesis: We hypothesized that the TTN -Δ9 mutation results in augmentation of the slow delayed rectifier potassium current (I Ks ) resulting in shortened action potential duration (APD). Methods: TTN -WT hiPSC-aCMs (healthy control) and TTN -Δ9 hiPSC-aCMs (isogenic mutant) were matured with metabolic conditioning, electrical stimulation, co-culture with atrial fibroblasts, and micropatterning. We used transmission electron microscopy (TEM) to assess sarcomeric defects, RNA-sequencing and RT-qPCR to assess molecular ion channel remodeling, and high throughput automated patch clamp and optical voltage mapping to assess the EP properties of TTN -Δ9 hiPSC-aCMs. We also performed targeted pharmacological inhibition of I Ks . Results: We showed that TTN -Δ9 hiPSC-aCMs displayed disrupted organization and myofibril assembly ( Fig. 1A-B ), upregulated voltage-gated potassium channel complexes and increased KCNQ1 expression ( Fig 1C-D ), and shortened APD ( Fig. 1E-F ). I Ks was significantly augmented in TTN -Δ9 hiPSC-aCMs ( Fig. 1G-H ). Infusion of the I Ks -specific blocker HMR-1556, and not I Kr blocker dofetilide, fully restored the shortened APD 90 and partially recovered defects in contractility in TTN -Δ9 hiPSC-aCMs compared to TTN -WT hiPSC-aCMs ( Fig. 1I-J ). Conclusion: Our findings suggest that augmentation of I Ks contributes to the pathogenic mechanism of TTN -mediated AF, pointing to I Ks as a potential therapeutic target.

Orofacial dyskinesia in a patient with autoimmune encephalitis and voltagegated potassium channel complex antibodies

Orofacial dyskinesia in a patient with autoimmune encephalitis and voltagegated potassium channel complex antibodies

Persistent hiccup as one of the initial symptoms of leucine-rich glioma-inactivated-1 encephalitis: a case report

BackgroundAnti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, an autoimmune disorder, is characterized by faciobrachial dystonic seizures, epilepsy, memory deficits and altered mental status while hiccup is not commonly found in patients.Case presentationA 62-year-old male was presented with slurred speech, abnormal gait, faciobrachial dystonic seizures and impaired cognition. Besides, the hiccup was one of the initial symptoms. His brain magnetic resonance images (MRI) revealed multiple lesions with left caudate nucleus, putamen, insula and left hippocampus involvement. Because a diagnosis of antibody-related limbic encephalitis was suspected, studies including an autoimmune profile were done by cell-based assays. After anti-LGI1 antibodies were detected in both cerebrospinal fluid and serology, pulse methylprednisolone and intravenous immunoglobulin were started and hence hiccups disappeared along with other symptoms.ConclusionsClinicians should be aware that persistent hiccups might be one of the initial manifestations of LGI1 subtype of voltage-gated potassium channel complex antibody associated autoimmune encephalitis.

Clinical features and outcomes of leucine-rich glioma-inactivated protein 1 and contactin protein-like 2 antibody-associated autoimmune encephalitis in a Chinese cohort

The present study aimed to investigate the clinical manifestations, epidemiological characteristics, and outcomes of Chinese patients with voltage-gated potassium channel complex (VGKC) antibody–associated encephalitis. Patients diagnosed with VGKC antibody-associated encephalitis at our institution between January 2016 and December 2020 were included in this study. We retrospectively evaluated their clinical features, auxiliary examination results, treatments details, long-term outcomes, and risk factors for poor outcome. Of the 91 included patients, 61 (67.78%) were men and 30 (32.97%) were women. The most common clinical symptoms were seizures (n = 63, 69.23%), memory deficits (n = 62, 68.13%), mental behavioral disorders (n = 29, 31.87%), and hyponatremia (n = 57, 62.64%). Although patients with anti- leucine-rich glioma-inactivated 1 (LGI1) (n = 76) and anti- contactin-associated protein-like 2 (CASPR2) encephalitis (n = 15) had similar clinical manifestations, the former were more diverse. In total, 86 (94.51%) patients were treated with immunotherapy. Over a median follow-up period of 25 months, there were no mortalities and 14 (15.38%) patients experienced a relapse. Univariate analysis indicated differences in sex, modified Rankin Scale scores at onset, movement disorders, central hypoventilation, and intensive care unit occupancy between the good- and poor- outcome groups. Patients with anti-LGI1 and anti-CASPR2 encephalitis showed similar clinical manifestations while presenting delineating characteristics. Those with VGKC antibody-associated diseases generally responded well to immunotherapy and demonstrated favorable clinical outcomes. Several factors affected the prognosis, and a long-term follow-up examination is necessary.

Immunoglobulin use in childhood epilepsy

Background: Epilepsy's aetiology is well-known to include an immune component. Several clinical and laboratory research have discovered abnormalities in epileptic patients' immune system branches when compared to the general population. Such anomalies include immunoglobulin deficiencies (mainly immunoglobulin A and immunoglobulin G2), an increased prevalence of specific human leukocyte antigen types, and alterations in cytokine and interleukin profiles. In people with epilepsy, autoantibodies were discovered against glutamic acid decarboxylase, components of the voltage-gated potassium channel complex, and the N-methyl-D-aspartate, gamma-aminobutyric acid, a-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid, and glutamate receptor three receptors. Immune modulating drugs like corticosteroids and corticotrophin have also been demonstrated to help with seizures. In view of these findings, immunosuppressive medicine has potential as an add-on therapy for refractory epilepsy. Aim: We aimed to evaluate the efficacy of immunoglobulin in childhood epilepsy. Conclusion: Despite the fact that new medications are constantly being developed to treat intractable infantile epilepsy, the refractory rate remains high. Despite several investigations on the subject, predictive variables for a good intravenous immunoglobulin response have yet to be identified. In some epileptic disorders, such as idiopathic West syndrome and electrical status epilepticus during sleep, intravenous immunoglobulin appears to be beneficial.

Hyperventilation-induced focal seizures in adults: think autoimmune encephalitis.

Case reports have described rare patients with autoimmune encephalitis in whom focal seizures could be reliably provoked by hyperventilation. With the hypothesis that this phenomenon may have diagnostic significance, all cases of hyperventilation‐induced focal seizures identified during ~10,000 consecutive routine electroencephalography (EEG) studies were reviewed, and corresponding diagnoses established. Seven EEG recordings, in six patients, contained focal hyperventilation‐induced seizures, each of temporal lobe onset. All patients were diagnosed with autoimmune encephalitis, in two cases after EEG; five had voltage‐gated potassium channel complex autoantibodies. Although rare, a hyperventilation‐induced focal seizure during EEG in an adult should raise concern for autoimmune encephalitis.

Isaacs\u2019 syndrome as the initial presentation of malignant thymoma and associated with double-positive voltage-gated potassium channel complex antibodies, a case report

BackgroundIsaacs’ syndrome is a peripheral nerve hyperexcitability (PNH) syndrome due to peripheral motor nerve instability. Acquired Isaacs’ syndrome is recognized as a paraneoplastic autoimmune disease with possible pathogenic voltage-gated potassium channel (VGKC) complex antibodies. However, the longitudinal correlation between clinical symptoms, VGKC antibodies level, and drug response is still unclear.Case presentationA 45-year-old man had progressive four limbs soreness, muscle twitching, cramps, and pain 4 months before admission. Electromyography (EMG) studies showed myokymic discharges, neuromyotonia, and an incremental response in the high-rate (50 Hz) repetitive nerve stimulation (RNS) test. Isaacs’ syndrome was diagnosed based on clinical presentations and EMG reports. Serum studies showed positive VGKC complex antibodies, including leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. The acetylcholine receptor antibody was negative. Whole-body computed tomography (CT) and positron emission tomography revealed a mediastinal tumor with the great vessels encasement, right pleura, and diaphragm seeding. Biopsy confirmed a World Health Organization type B2 thymoma, with Masaoka stage IVa. His symptoms gradually improved and both LGI1 and CASPR2 antibodies titer became undetectable after concurrent chemoradiotherapy (CCRT) and high dose steroid treatment. However, his Isaacs’ syndrome recurred after the steroid was reduced 5 months later. Follow-up chest CT showed probable thymoma progression. LGI1 antibody turned positive again while CASPR2 antibody remained undetectable.ConclusionsOur patient demonstrates that Isaacs’ syndrome could be the initial and only neuromuscular manifestation of malignant thymoma. His Isaacs’ syndrome is correlated well with the LGI1 antibody level. With an unresectable thymoma, long-term immunosuppressant therapy may be necessary for the management of Isaacs’ syndrome in addition to CCRT for thymoma.

75.1 AUTOIMMUNE ENCEPHALITIS: A CLINICAL PRACTICE OVERVIEW

In this portion of our broader presentation, we will provide a clinical overview of autoantibody-mediated brain diseases in children and adolescents, including autoimmune encephalitis (AE). This clinical overview will include a summarized review of the current literature describing the neurobiology, presentation, and treatment of the most common antibody-mediated autoimmune brain diseases affecting children and adolescents, including anti–N-methyl-D-aspartate receptor (anti-NMDAR) AE, anti–glutamic acid decarboxylase (anti-GAD65) AE, anti–voltage-gated potassium channel complex (anti-VGKC) AE, and anti–myelin oligodendrocyte glycoprotein (MOG)-associated AE. We will review the most common clinical presentations of these disorders with an emphasis on the symptoms of psychosis, delirium, and catatonia seen in children and adolescents with AE. Audience members will gain an understanding of the similarities and differences in the neurobiology, pathogenesis, and presentation of the most commonly diagnosed antibody-mediated autoimmune brain diseases affecting children and adolescents. The antineuronal autoantibodies implicated in AE in the pediatric population vary in their mechanisms of neurobiology, pathogenesis, and clinical presentation. It is essential for child and adolescent psychiatrists to understand the importance of testing for all known autoantibodies when evaluating patients with clinical presentations suspicious for AE and other antibody-mediated autoimmune brain diseases.

Feline temporal lobe epilepsy: seven cases of hippocampal and piriform lobe necrosis in England and literature review.

Seven cases of feline hippocampal and piriform lobe necrosis (FHN) are described, with particular emphasis on clinical, radiographic and histopathological correlations. FHN is an uncommon acute epileptic condition resembling human autoimmune limbic encephalitis and temporal lobe epilepsy. Seizures are typically focal and feature uni- or bilateral orofacial or head twitching, hypersalivation, lip smacking, mydriasis, vocalisation and motionless staring, with inter-ictal behavioural changes such as unprovoked aggression and rapid running. Emerging evidence supports an autoimmune aetiology, although disruption of hippocampal architecture secondary to brain neoplasia has also been recognised. Most commonly, however, the underlying cause remains unknown. Diagnosis is achieved clinically and with brain MRI; electroencephalography and voltage-gated potassium channel-complex autoantibodies are currently the subject of research. Affected cats are frequently refractory to conventional antiepileptic treatment. Following a review of the literature, including potential complicating factors and comparisons with human medicine, the hippocampus and piriform lobe are proposed as the neuroanatomical localisation for focal seizures with orofacial involvement in cats, regardless of aetiology.

CLINICAL SPECTRUM OF MORVAN SYNDROME: A SINGLE CENTRE STUDY

INTRODUCTION: Morvan syndrome (MoS) is a rare autoimmune disorder characterised by peripheral nerve hyperexcitability, autonomic dysfunction and central nervous system symptoms. It has strong association with autoantibodies to voltage gated potassium channel complex. This was a prospective observationa METHODS: l study. We reported 6 cases of Morvan syndrome. Clinical features, investigations, treatment and outcome were described and review of literature was done. All RESULT: subjects were male. Myokymia and insomnia were present in all patients and no patient had seizure. Voltage gated potassium channel (VGKC) antibody was positive in 66% (n=4) of subjects, all four were positive for CASPER2 and 2 were also weakly positive for LGI1. All patients were treated with immunomodulation and we found good response to therapy. Pain was treated with carbamazepine and phenytoin. CONCLUSION: Morvan syndrome, a VGKC antibody spectrum disorder, is a clinical diagnosis. We found myokymia and insomnia in all patients and no patient had seizure. In our study, response to immunotherapy was good. Awareness about MoS is necessary, as it can be treated successfully.

Neuromuscular hyperexcitability syndromes.

To provide an update on recent developments regarding acquired, antibody-mediated, neuromuscular hyperexcitability syndromes, including Isaac's and Morvan's syndromes, cramp-fasciculation syndrome and rippling muscle disease, and their genetic differential diagnoses. Antibodies in auto-immune peripheral nerve hyperexcitability syndromes (PNHS) are directed against CASPR2 and LGI1, proteins of the voltage-gated potassium channel (VGKC) complex. We discuss the significance of 'double-negative' VGKC antibodies in PNHS and the rationale for ceasing VGKC antibody testing (but testing CASPR2 and LGI1 antibodies instead) in clinical practice. Recent case reports also expand the possible clinical phenotypes related to CASPR2/LGI1 antibodies, but the interpretation of these findings is complicated by the frequent association of antibody-mediated neuromuscular hyperexcitability syndromes with other auto-immune disorders (e.g. myasthenia gravis).Finally, a hereditary origin of neuromuscular hyperexcitability should always be considered, even in non-VGKC-related genes, as evidenced by the recently discovered high frequency of HINT1 mutations in people of Slavic origin. This review provides an update on recent clinical, immunological and genetic developments in neuromuscular hyperexcitability syndromes. We also provide a guide for the clinician for diagnosing and managing these disorders in clinical practice, with a special focus on the main differential diagnoses.