Leucine-rich Glioma-inactivated 1 Antibodies Research Articles

Risk of Seizure Recurrence Due to Autoimmune Encephalitis With NMDAR, LGI1, CASPR2, and GABABR Antibodies: Implications for Return to Driving.

Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

Patient-derived antibodies reveal the subcellular distribution and heterogeneous interactome of LGI1.

Autoantibodies against leucine-rich glioma-inactivated 1 (LGI1) occur in patients with encephalitis who present with frequent focal seizures and a pattern of amnesia consistent with focal hippocampal damage. To investigate whether the cellular and subcellular distribution of LGI1 may explain the localization of these features, and hence gain broader insights into LGI1's neurobiology, we analysed the detailed localization of LGI1 and the diversity of its protein interactome, in mouse brains using patient-derived recombinant monoclonal LGI1 antibodies. Combined immunofluorescence and mass spectrometry analyses showed that LGI1 is enriched in excitatory and inhibitory synaptic contact sites, most densely within CA3 regions of the hippocampus. LGI1 is secreted in both neuronal somatodendritic and axonal compartments, and occurs in oligodendrocytic, neuro-oligodendrocytic and astro-microglial protein complexes. Proteomic data support the presence of LGI1-Kv1-MAGUK complexes, but did not reveal LGI1 complexes with postsynaptic glutamate receptors. Our results extend our understanding of regional, cellular and subcellular LGI1 expression profiles and reveal novel LGI1-associated complexes, thus providing insights into the complex biology of LGI1 and its relationship to seizures and memory loss.

Peripheral nerve hyperexcitability syndrome: A clinical, electrophysiological, and immunological study.

Peripheral nerve hyperexcitability syndrome (PNHS) is characterized by muscle fasciculations and spasms. Nerve hyperexcitability and after-discharges can be observed in electrophysiological studies. Autoimmune mechanisms play a major role in the pathophysiology of primary PNHS. We retrospectively conducted a case-control study recruiting patients with clinical and electrophysiological features of PNHS. Control patients were diagnosed with other neuronal or muscular diseases. Contactin-associated protein2 (CASPR2) and leucine-rich glioma-inactivated1 (LGI1) antibodies were examined. A total of 19 primary PNHS patients and 39 control patients were analyzed. The most common symptoms for the case group were fasciculations (11/19) and muscle spasms (13/19). Case group patients were likely to demonstrate electrodiagnostic findings of nerve hyperexcitability (17/19) and after-discharges in the tibial nerve (19/19). We found high prevalence of CASPR2 (9/19) and LGI1 (6/19) antibodies in the case group. Primary PNHS patients were likely to show after-discharges in the tibial nerve. The pathogenesis of PNHS is autoimmune CASPR2 and LGI1 antibodies are possible pathogenic antibodies for primary PNHS.

A rare case of anti-LGI1 limbic encephalitis with concomitant positive NMDAR antibodies

BackgroundN-methyl-D-aspartate receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) antibodies define the most prevalently recognized autoimmune encephalitis syndromes, while the simultaneous occurrence of both conditions has hardly been published before.Case presentationWe report the case of a 67-year-old patient who presented with generalized tonic–clonic seizures (GTCS) followed by behavioral changes, psychosis, sleep disorders, decreased consciousness, and faciobrachial dystonic seizures. Ancillary findings included serum hyponatremia and imaging evidence of high-intensity lesions within bilateral medial temporal lobes on T2-weighted fluid attenuation inversion recovery. Both LGI1 and NMDAR antibodies were positive in serum and cerebral spinal fluid using transfected cell based assays. Despite prominent clinical features of anti-LGI1 limbic encephalitis (LGI1-LE), the patient also exhibited overlapping symptoms of anti-NMDAR encephalitis, like early-onset GTCS, which might be related to the concomitant positive NMDAR antibodies.ConclusionsWe report a rare case of LGI1-LE with overlapping symptoms and simultaneous positive NMDAR antibodies. It is necessary to evaluate the presence of NMDAR antibodies in certain LGI1-LE patients with unusual symptoms. However, caution should be exercised in interpreting the observation, given the fact of a single-case study.

A case of anti-LGI-1 encephalitis presented as acute psychosis

Anti-leucine-rich glioma inactivated protein-1 (LGI-1) encephalitis is a rare autoimmune disease with a varied neuropsychiatric clinical manifestation and have potential for reversal with immunotherapy. Early identification and treatment are therefore of paramount importance. We present the case of a 43-year-old man admitted for acute psychosis with facio-brachial dystonic seizures not responding to anti-epileptic drugs (AEDs). His symptoms started approximately 5 months prior admission to the hospital and associated with progressive cognitive impairment (particularly verbal and visio-spatial domains) followed by altered behavior, irrelevant talk, and disturbance in daily activities of living and facio-brachial dystonic seizures. There was history of allergic reaction to valproate, carbamazepine and levetiracetam, and serum sample tested strongly positive for LGI-1 (leucine rich glioma inactivated-1) antibodies. He was treated with injection methylprednisolone (1 gm intravenous) brief pulse therapy for 7 days and then underwent four sessions of plasma exchange followed by oral steroids and immunosuppressant therapy. Treatment was successful and patient returned to his previous baseline functioning but patient develops steroid induced hypomania and diabetes mellitus in the due course of time. Patient was discharged after successful resolution of symptoms. Patient did not come up for follow-up. He was contacted telephonically and we get to know that he relapsed after 2 weeks and consulted at higher center where he died while on treatment. Prognosis of anti-LGI-1 encephalitis is usually good but our patient died.

Intrathecal B-cell activation in LGI1 antibody encephalitis.

ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability.

Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418.

Acquired neuromyotonia in thymoma-associated myasthenia gravis: a clinical and serological study.

Background and purposeAcquired neuromyotonia can occur in patients with thymoma, alone or in association with myasthenia gravis (MG), but the clinical prognostic significance of such comorbidity is largely unknown. The clinico‐pathological features were investigated along with the occurrence of neuromyotonia as predictors of tumour recurrence in patients with thymoma‐associated myasthenia.MethodsA total number of 268 patients with thymomatous MG were studied retrospectively. Patients with symptoms of spontaneous muscle overactivity were selected for autoantibody testing using immunohistology for neuronal cell‐surface proteins and cell‐based assays for contactin‐associated protein 2 (CASPR2), leucine‐rich glioma inactivated 1 (LGI1), glycine receptor and Netrin‐1 receptor antibodies. Neuromyotonia was diagnosed according to the presence of typical electromyography abnormalities and/or autoantibodies against LGI1/CASPR2.ResultsOverall, 33/268 (12%) MG patients had a thymoma recurrence. Five/268 (2%) had neuromyotonia, four with typical autoantibodies, including LGI1 (n = 1), CASPR2 (n = 1) or both (n = 2). Three patients had Netrin‐1 receptor antibodies, two with neuromyotonia and concomitant CASPR2+LGI1 antibodies and one with spontaneous muscle overactivity without electromyography evidence of neuromyotonia. Thymoma recurrence was more frequent in those with (4/5, 80%) than in those without (28/263, 10%, P < 0.001) neuromyotonia. Neuromyotonia preceded the recurrence in 4/5 patients. In univariate analysis, predictors of thymoma recurrence were age at thymectomy [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.93–0.97], Masaoka stage ≥IIb (OR 10.73, 95% CI 2.38–48.36) and neuromyotonia (OR 41.78, 95% CI 4.71–370.58).Conclusions De novo occurrence of neuromyotonia in MG patients with previous thymomas is a rare event and may herald tumour recurrence. Neuronal autoantibodies can be helpful to assess the diagnosis. These observations provide pragmatic risk stratification for tumour vigilance in patients with thymomatous MG.

LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory.

Leucine-rich glioma-inactivated 1 (LGI1) is a secreted neuronal protein that forms a trans-synaptic complex that includes the presynaptic disintegrin and metalloproteinase domain-containing protein 23 (ADAM23), which interacts with voltage-gated potassium channels Kv1.1, and the postsynaptic ADAM22, which interacts with AMPA receptors. Human autoantibodies against LGI1 associate with a form of autoimmune limbic encephalitis characterized by severe but treatable memory impairment and frequent faciobrachial dystonic seizures. Although there is evidence that this disease is immune-mediated, the underlying LGI1 antibody-mediated mechanisms are unknown. Here, we used patient-derived immunoglobulin G (IgG) antibodies to determine the main epitope regions of LGI1 and whether the antibodies disrupt the interaction of LGI1 with ADAM23 and ADAM22. In addition, we assessed the effects of patient-derived antibodies on Kv1.1, AMPA receptors, and memory in a mouse model based on cerebroventricular transfer of patient-derived IgG. We found that IgG from all patients (n = 25), but not from healthy participants (n = 20), prevented the binding of LGI1 to ADAM23 and ADAM22. Using full-length LGI1, LGI3, and LGI1 constructs containing the LRR1 domain (EPTP1-deleted) or EPTP1 domain (LRR3-EPTP1), IgG from all patients reacted with epitope regions contained in the LRR1 and EPTP1 domains. Confocal analysis of hippocampal slices of mice infused with pooled IgG from eight patients, but not pooled IgG from controls, showed a decrease of total and synaptic levels of Kv1.1 and AMPA receptors. The effects on Kv1.1 preceded those involving the AMPA receptors. In acute slice preparations of hippocampus, patch-clamp analysis from dentate gyrus granule cells and CA1 pyramidal neurons showed neuronal hyperexcitability with increased glutamatergic transmission, higher presynaptic release probability, and reduced synaptic failure rate upon minimal stimulation, all likely caused by the decreased expression of Kv1.1. Analysis of synaptic plasticity by recording field potentials in the CA1 region of the hippocampus showed a severe impairment of long-term potentiation. This defect in synaptic plasticity was independent from Kv1 blockade and was possibly mediated by ineffective recruitment of postsynaptic AMPA receptors. In parallel with these findings, mice infused with patient-derived IgG showed severe memory deficits in the novel object recognition test that progressively improved after stopping the infusion of patient-derived IgG. Different from genetic models of LGI1 deficiency, we did not observe aberrant dendritic sprouting or defective synaptic pruning as potential cause of the symptoms. Overall, these findings demonstrate that patient-derived IgG disrupt presynaptic and postsynaptic LGI1 signalling, causing neuronal hyperexcitability, decreased plasticity, and reversible memory deficits.

Clinical characteristics and short-term prognosis of LGI1 antibody encephalitis: a retrospective case study

BackgroundRecently, most reports of Leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis are from Europe and the US, while the short term outcome and clinical characteristics of Chinese patients are rarely reported,we study the clinical manifestations, laboratory results and brain magnetic resonance images (MRI) of eight patients who were recently diagnosed with LGI1 antibody encephalitis in our hospital to improve the awareness and knowledge of this disease.MethodsEight patients (five males and three females; mean age, 63.4) with LGI1 antibody encephalitis who were diagnosed and treated in the Department of Neurology of Shengjing Hospital of China Medical University from September 2016 to June 2017 were recruited for the current study. Their general information, clinical manifestations, treatment regimens, and short-term prognoses were retrospectively analyzed, as were the results from MRI and laboratory findings.ResultsOverall, patient symptoms included cognitive impairment, which manifested primarily as memory deficits (8/8), seizures (including faciobrachial dystonic seizure, (FBDS)) (8/8), psychiatric and behavioral disorders (7/8), sleep disorders (4/8), and autonomic abnormalities (3/8). Five patients also had abnormal findings on brain MRI, mainly involving the hippocampus, basal ganglia and insula. Hyponatremia occurred in six cases. All patients tested positive for LGI1 antibodies in their serum/cerebrospinal fluid (CSF)and patients were negative for tumors. Symptoms rapidly improved after treatment with immunoglobulin and/or steroid therapy. The patients were followed up for 4–13 months after discharge, and two patients relapsed.ConclusionPrimary symptoms of LGI1 antibody encephalitis include memory impairments, seizures, FBDS, and mental and behavioral abnormalities. Increased titers of LGI1 antibodies are also present in the serum/CSF of patients. Patients often have hyponatremia, and MRIs show abnormalities in various brain regions. Finally, immunotherapy shows good efficacy and positive benefits, although patients may relapse in the short-term.

Distinct HLA associations of LGI1 and CASPR2-antibody diseases.

The recent biochemical distinction between antibodies against leucine-rich, glioma-inactivated-1 (LGI1), contactin-associated protein-2 (CASPR2) and intracellular epitopes of voltage-gated potassium-channels (VGKCs) demands aetiological explanations. Given established associations between human leucocyte antigen (HLA) alleles and adverse drug reactions, and our clinical observation of frequent adverse drugs reactions in patients with LGI1 antibodies, we compared HLA alleles between healthy controls (n = 5553) and 111 Caucasian patients with VGKC-complex autoantibodies. In patients with LGI1 antibodies (n = 68), HLA-DRB1*07:01 was strongly represented [odds ratio = 27.6 (95% confidence interval 12.9-72.2), P = 4.1 × 10-26]. In contrast, patients with CASPR2 antibodies (n = 31) showed over-representation of HLA-DRB1*11:01 [odds ratio = 9.4 (95% confidence interval 4.6-19.3), P = 5.7 × 10-6]. Other allelic associations for patients with LGI1 antibodies reflected linkage, and significant haplotypic associations included HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02, by comparison to DRB1*11:01-DQA1*05:01-DQB1*03:01 in CASPR2-antibody patients. Conditional analysis in LGI1-antibody patients resolved further independent class I and II associations. By comparison, patients with both LGI1 and CASPR2 antibodies (n = 3) carried yet another complement of HLA variants, and patients with intracellular VGKC antibodies (n = 9) lacked significant HLA associations. Within LGI1- or CASPR2-antibody patients, HLA associations did not correlate with clinical features. In silico predictions identified unique CASPR2- and LGI1-derived peptides potentially presented by the respective over-represented HLA molecules. These highly significant HLA associations dichotomize the underlying immunology in patients with LGI1 or CASPR2 antibodies, and inform T cell specificities and cellular interactions at disease initiation.10.1093/brain/awy109_video1awy109media15796480660001.

Current Perspective on Voltage-gated Potassium Channel Complex Antibody Associated Diseases

Voltage-gated potassium channel (VGKC) complex auto-antibodies were initially identified in Isaacs' syndrome (IS), which is characterized by muscle cramps and neuromyotonia. These antibodies were subsequently identified in patients with Morvan's syndrome (MoS), which includes IS in conjunction with psychosis, insomnia, and dysautonomia. The antibodies have also been detected in a patient with limbic encephalopathy (LE) presenting with prominent amnesia and frequent seizures. Typical cases of LE have adult-onset, with frequent, brief dystonic seizures that predominantly affect the arms and ipsilateral face, and has recently been termed faciobrachial dystonic seizures. Autoantibodies against the extracellular domains of VGKC complex proteins, leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein-2 (Caspr2), occur in patients with IS, MoS, and LE. However, routine testing has detected VGKC complex antibodies without LGI1 or Caspr2 reactivities (double-negative) in patients with other diseases, such as Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis. Furthermore, double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits. Therefore, these antibodies should no longer be classified as neuronal-surface antibodies and lacking pathogenic potential. Novel information has been generated regarding autoantibody disruption of the physiological functions of target proteins. LGI1 antibodies neutralize the interaction between LGI1 and ADAM22, thereby reducing the synaptic AMPA receptors. It may be that the main action is on inhibitory neurons, explaining why the loss of AMPA receptors causes amnesia, neuronal excitability and seizures.

The importance of early immunotherapy in patients with faciobrachial dystonic seizures.

Faciobrachial dystonic seizures and limbic encephalitis closely associate with antibodies to leucine-rich glioma-inactivated 1 (LGI1). Here, we describe 103 consecutive patients with faciobrachial dystonic seizures and LGI1 antibodies to understand clinical, therapeutic and serological differences between those with and without cognitive impairment, and to determine whether cessation of faciobrachial dystonic seizures can prevent cognitive impairment. The 22/103 patients without cognitive impairment typically had normal brain MRI, EEGs and serum sodium levels (P < 0.0001). Overall, cessation of faciobrachial dystonic seizures with antiepileptic drugs alone occurred in only 9/89 (10%) patients. By contrast, 51% showed cessation of faciobrachial dystonic seizures 30 days after addition of immunotherapy (P < 0.0001), with earlier cessation in cognitively normal patients (P = 0.038). Indeed, expedited immunotherapy (P = 0.031) and normal cognition (P = 0.0014) also predicted reduced disability at 24 months. Furthermore, of 80 patients with faciobrachial dystonic seizures as their initial feature, 56% developed cognitive impairment after 90 days of active faciobrachial dystonic seizures. Whereas only one patient developed cognitive impairment after cessation of faciobrachial dystonic seizures (P < 0.0001). All patients had IgG4-LGI1 antibodies, but those with cognitive impairment had higher proportions of complement-fixing IgG1 antibodies (P = 0.03). Both subclasses caused LGI1-ADAM22 complex internalization, a potential non-inflammatory epileptogenic mechanism. In summary, faciobrachial dystonic seizures show striking time-sensitive responses to immunotherapy, and their cessation can prevent the development of cognitive impairment.awx323media15681705685001.

32. Facio-brachial dystonic seizures in LGI1 Limbic Encephalitis: Analysis of video EEG monitoring in a small group of patients

Leucine-rich glioma inactivated 1(LGI1) antibodies are frequently associated with a common form of limbic encephalitis (LE) presenting with cognitive impairment, tonic-clonic and distinctive facio-brachial dystonic seizures (FBDS), not related with a specific EEG pattern. We describe clinical-EEG features of three patients with LGl1-LE with different response to immunotherapy. Three pts, admitted to our Neurology department for LE with positive test for LGI1 antibodies, performed video-EEG monitoring and immunotherapy. Video and still images showed frequently (3–40 episodes/day) paroxysmal brief events characterized by facial grimacing and sometimes dystonic arm posturing, with alternating side, suggestive for FBDS. We observed electrodecremental events (EDEs) or a contralateral slow-wave before “dystonic seizures” but not a clear ictal-EEG pattern. In all of the patients interictal EEG was normal. Furthermore, Video-EEG monitoring revealed multiple daily electrographic temporal seizures. Immunotherapy were associated with control of FBDS in two of three presented patients, with different latency. Video-EEG monitoring of our LGI1-LE patients showed frequent FBDS and bilateral temporal seizures. The lack of a clear ictal-EEG pattern for FBDS and the positive response to immunotherapy, support the hypothesis that dystonic episodes does not have a cortical origin, but are rather related to a possible basal ganglionic dysfunction.

Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies

ObjectivesAutoantibodies 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...

Clinical characterization of autoimmune LGI1 antibody limbic encephalitis.

Autoimmune encephalitis associated with antibodies to leucine-rich glioma inactivated 1 (LGI1) has recently been identified and is characterized by an acute to subacute onset of cognitive impairment and convulsion, faciobrachial dystonic seizures (FBDSs), and psychiatric disturbances. This study analyzed the clinical characteristics and outcomes of 10 patients with LGI1 antibody encephalitis in order to further understand this disease and to improve its therapeutic strategies. Between January 2013 and March 2015, we identified 10 patients with LGI1 antibody encephalitis. We retrospectively analyzed the clinical details, laboratory results, electrophysiological and imaging findings, and the treatment outcomes. All patients tested had LGI1 antibodies. Immunotherapy was effective in all patients. Seizures in patients with FBDS showed a poor response to antiepileptic drugs. Two patients examined by magnetoencephalogram (MEG) during the acute disease phase showed a small quantity of spike-wave dipoles in the temporal lobe close to the lateral fissure and insular lobe. Patients with LGI1 antibody encephalitis responded well to immunotherapy. We speculate that FBDS is likely a form of insular epilepsy.

Chapter 11 - Voltage-gated potassium channel–complex autoimmunity and associated clinical syndromes

Voltage-gated potassium channel (VGKC)-complex antibodies are defined by the radioimmunoprecipitation of Kv1 potassium channel subunits from brain tissue extracts and were initially discovered in patients with peripheral nerve hyperexcitability (PNH). Subsequently, they were found in patients with PNH plus psychosis, insomnia, and dysautonomia, collectively termed Morvan's syndrome (MoS), and in a limbic encephalopathy (LE) with prominent amnesia and frequent seizures. Most recently, they have been described in patients with pure epilepsies, especially in patients with the novel and distinctive semiology termed faciobrachial dystonic seizures (FBDS). In each of these conditions, there is a close correlation between clinical measures and antibody levels. The VGKC-complex is a group of proteins that are strongly associated in situ and after extraction in mild detergent. Two major targets of the autoantibodies are leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2). The patients with PNH or MoS are most likely to have CASPR2 antibodies, whereas LGI1 antibodies are found characteristically in patients with FBDS and LE. Crucially, each of these conditions has a good response to immunotherapies, often corticosteroids and plasma exchange, although optimal regimes require further study. VGKC-complex antibodies have also been described in neuropathic pain syndromes, chronic epilepsies, a polyradiculopathy in porcine abattoir workers, and some children with status epilepticus. Increasingly, however, the antigenic targets in these patients are not defined and in some cases the antibodies may be secondary rather than the primary cause. Future serologic studies should define all the antigenic components of the VGKC-complex, and further inform mechanisms of antibody pathogenicity and related inflammation.

Anti-leucine-rich glioma-inactivated 1 limbic encephalitis: A case report and literature review.

This study describes the case of a 41-year-old woman admitted for anterograde memory loss, right facial grimacing and right arm posturing that had begun 1 month previously. Cranial magnetic resonance-diffusion weighted imaging and -fluid-attenuated inversion recovery imaging revealed a hyperintense signal in the left hippocampus and right basal ganglia, but no contrast enhancement. An electroencephalogram revealed rhythmic sharp and slow waves and rhythmic θ build-ups in the left temporal area. Single-photon emission computed tomography showed increased regional blood flow perfusion in the left cerebral frontal lobe and the right basal ganglia. The cerebrospinal fluid was normal, with the exception of the presence of leucine-rich glioma-inactivated 1 (LGI1) antibodies, and LGI1 antibodies were also found in the blood serum. The presence of the antibodies, the faciobrachial dystonic seizures (FBDSs) and the memory loss indicated limbic encephalitis. After 3 months of immunotherapy, the patient was free from epileptic seizures and had undergone a partial memory restoration. FBDSs alone justify the immediate initiation of immunotherapy, even prior to laboratory confirmation of the disease, as early treatment limits the duration of the illness.

P91. Faciobrachio-crural dystonic seizures in early LGI1 antibody limbic encephalitis – A rare differential diagnosis of falls

Introduction Faciobrachial dystonic seizures (FBDS) are described to be closely associated with LGI1 (leucine-rich, glioma inactivated 1 protein) antibodies and precede a limbic encephalitis ( Irani et al., 2011 ). Studies demonstrated very brief and very frequent dystonic seizure semiology that always affected the arm and commonly also the ipsilateral face ( Irani et al., 2011 ). Little has been reported on the leg involvement, termed faciobrachio-crural dystonic seizures (FBCDS) ( Irani et al., 2011 , Maramattom et al., 2013 ). Case report We present an 83-year-old woman whose main symptoms were sudden falls without loss of consciousness. The falls first appeared two weeks prior to admission to our ward. While standing or walking, the right leg was frequently involved causing buckling at the knee and falls to her right side. She sustained several hematomas on the right arm and knee. Previous medical history included arterial hypertension and type 2 diabetes mellitus. Hence, she was first admitted to cardiology where a cardiac cause could be excluded. Following that she was admitted to our ward for long-term video-EEG (electroencephalography) monitoring. Frequent unilateral but side-alternating (right more than left), very brief dystonic seizures up to five times an hour involving the face, arm, trunk and leg were recorded. They occurred during the day as well as at night during sleep and led to arousal. Ictal electrographic abnormalities were not observed. Interictal EEG showed focal slowing right (fronto-) temporal with periodical enclosed 1–1, 5/s sharp- and sharp-slow-waves for max. 20 s. The patient was tested for antibodies to LGI1 component of the VGKC (voltage-gated potassium channel) complex. Anti-LGI1 antibodies were identified in serum and cerebrospinal fluid (CSF). The routine CSF examination (cell counts, glucose and protein) was unremarkable. Further investigations demonstrated moderate hyponatremia (127 mmol/l in serum). Brain MRI showed unilateral temporomesial T2 signal intensity on the right side. Cognitive impairments were not detected. FBCDS frequency was significantly reduced after immunotherapy with corticosteroids. In contrast, antiepileptic treatment with levetiracetam as first-line therapy was ineffective. Conclusion Based on our case report and other case studies ( Maramattom et al., 2013 ), FBCDS can be a rare differential diagnosis of falls without loss of awareness. The leg ictal dystonia is not to be confused with drop attacks with backward falls ( Irani et al., 2011 ). The timely immunotherapy with corticosteroids can lead to freedom from seizures( Irani et al., 2013 ).

Limbic encephalitis associated with leucine-rich glioma-inactivated 1 antibodies

We describe the case of a patient with confirmed limbic encephalitis associated with leucine-rich glioma-inactivated 1 (LGI1) antibodies. A 59-year-old man presented to the Department of Neurology with bizarre behavior, memory loss, cognitive impairment, visual hallucinations, and myoclonus and faciobrachial dystonic seizures. A brain magnetic resonance imaging (MRI) revealed no hippocampal lesions. Blood tests showed hyponatremia. An electroencephalogram showed disorganization and slowing of background activity. Antiepileptic drugs were ineffective. The patient exhibited considerable improvement following immunotherapy. The diagnosis of limbic encephalitis associated with LGI1 antibodies should be considered in patients with clinical manifestations mimicking psychiatric disorders and in cases of refractory epilepsy especially with faciobrachial dystonic seizures. There is frequently hyponatremia, and cerebral MRI may be normal. Full recovery can be expected with early diagnosis and prompt treatment.