Validation of the 2023 international diagnostic criteria for MOGAD in a pediatric cohort.

OBJECTIVE: To validate the recently published diagnostic criteria for Myelin Oligodendrocyte Glycoprotein-antibody associated disease (MOGAD) in real-world cohort of children with acquired demyelinating syndromes. METHODS: Patients <18yrs presenting with demyelinating disease to Pediatric neuroimmunology clinics at two Israeli tertiary centers who had MOG antibodies (MOG-Abs) tested between 01/07/2017 and 15/08/2023 were included. Diagnostic criteria for MOGAD were applied and sensitivity and specificities were calculated. RESULTS: MOG-Abs were detected in 28/63 (44 %). Median age at onset for all patients was 11.4 yrs (range 1.1-17.6 yrs) and 41 (65 %) were female. Of the patients testing negative, ADEM was the most common diagnosis (n = 11) followed by MS (n = 8). No patients without MOG-Abs were diagnosed with MOGAD. All patients with a clinical diagnosis of MOGAD had positive MOG-Abs and fulfilled the 2023 international diagnostic criteria for MOGAD. Sensitivity, specificity, positive predictive value, and negative predictive value were 100 %. We found no difference between younger (<10yrs old) and older (>10 yrs old) children in the number of supportive criteria fulfilled at onset (median 2 vs. 2.5, p = 0.4) The number of supporting features was higher in patients with relapsing (n = 5) vs. monophasic (n = 23) disease course at onset (median 3 vs. 2, p = 0.03) and at final follow-up (median 5 vs. 2, p = 0.004). CONCLUSION: Recent MOGAD diagnostic criteria had excellent performance in this pediatric cohort but did not add to the diagnostic accuracy of the antibody test alone.

Electrolyte Imbalance in Anti-LGI1 Encephalitis: It Is Not All in Your Head.

BACKGROUND AND OBJECTIVES: Antileucine-rich glioma-inactivated 1 (anti-LGI1) autoimmune encephalitis was first described in 2010 and is today the most common type of limbic encephalitis. During the course of the disease, 60%-88% of the patients develop hyponatremia. The etiology of the sodium disorder is unclear, often presumed to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Other electrolyte abnormalities have not been reported in association with anti-LGI1 antibody encephalitis. Due to the presence of hypomagnesemia and hypophosphatemia in our patients, we set out to try to find the expression of LGI1 protein in the kidney as an explanation for these abnormalities. METHODS: We reviewed the medical files of all patients diagnosed with anti-LGI1 antibody encephalitis, at the Department of Neurology in the Tel Aviv Medical Center between January 2011 and December 2020, exploring for electrolyte abnormalities. Using tissue staining, Western blot, mass spectrometry, and RNA expression techniques, we tried to demonstrate the expression of LGI1 protein in the human kidney. RESULTS: We identified 15 patients diagnosed with anti-LGI1 antibody encephalitis. Their average age was 65 years (44-80), and 9 were male individuals. Thirteen of the 15 patients (87%) developed varying degrees of hyponatremia. Laboratory studies demonstrated low serum osmolality, low serum blood urea nitrogen, and low uric acid, with a high urinary sodium and inappropriately high urine osmolality, supporting the presumable diagnosis of SIADH. One patient with hyponatremia that was tested, had high levels of copeptin, supporting the diagnosis of SIADH. In addition to hyponatremia, 7 patients (47%) exhibited other electrolyte abnormalities; 5 patients (33%) had overt hypophosphatemia, 4 patients (27%) had overt hypomagnesemia, and 2 other patients (13%) had borderline low magnesium levels. Western blot analysis of human kidney lysate, mass spectrometry, and qRT-PCR failed to demonstrate the expression of LGI1 protein in the kidney. DISCUSSION: Hyponatremia in patients with anti-LGI1 antibody encephalitis is due to SIADH as previously assumed. Other electrolyte abnormalities such as hypomagnesemia and hypophosphatemia occur in at least 40% of patients and may be another clue for the diagnosis of anti-LGI1 antibody encephalitis. Because we failed to demonstrate LGI1 expression in the kidney, the results of our study suggest that renal losses lead to these disturbances, most probably due to SIADH.

Sleep disturbances associated with DPPX autoantibodies: a case series.

STUDY OBJECTIVES: To describe a case series of patients with prominent sleep disturbances and their polysomnography findings in six patients with dipeptidyl-peptidase-like protein-6 (DPPX) autoimmunity syndrome. METHODS: Of 13 patients with DPPX autoimmunity evaluated at Mayo Clinic, 6 were seen by Sleep Medicine with polysomnography and were assessed with blood and cerebrospinal fluid, neuroimaging, neuropsychological testing, and evaluation tailored to clinical presentation. RESULTS: Median age of our six DPPX autoimmunity patients was 57 (range 27-70) years, with one woman. All patients had prominent gastrointestinal disturbances, most with prominent and early weight loss, and a spectrum of neuropsychiatric disturbances including cognitive impairment, myoclonus, exaggerated startle, and dysautonomia. Sleep disturbances included insomnia and obstructive sleep apnea in six patients, periodic leg movements of sleep in four, and REM sleep behavior disorder in two. Polysomnography demonstrated REM sleep-atonia loss in four patients, and ambiguous sleep with status dissociatus (mixed features of wakefulness, non-rapid eye movement [NREM], and REM sleep) appeared in one patient. Five of six patients showed neurological improvement with immunotherapy, including three with at least partial improvement in sleep disturbances. CONCLUSION: Our patients with DPPX autoimmunity syndrome had prominent sleep disturbances including sleep-disordered breathing, REM sleep behavior disorder, and abnormal NREM sleep architecture with highly variable clinical presentations. DPPX autoimmunity should be considered in cases with a triad of sleep disturbance, neurological features of hyperexcitability, and systemic symptoms of gastrointestinal disturbance and weight loss. Future prospective studies of DPPX autoimmunity syndrome including detailed sleep evaluation and follow-up are necessary.

New Insights on DR and DQ Human Leukocyte Antigens in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: To explore the clinical characteristics and HLA associations of patients with anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel. Anti-LGI1E is the most commonly diagnosed antibody-associated encephalitic syndrome in adults. Recent studies of various populations reveal significant associations with specific HLA genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients. METHODS: Seventeen consecutive patients with anti-LGI1E diagnosed at Tel Aviv Medical Center between the years 2011 and 2018 were included. HLA typing was performed using next-generation sequencing at the tissue typing laboratory of Sheba Medical Center and compared with data from the Ezer Mizion Bone Marrow Donor Registry, containing over 1,000,000 samples. RESULTS: Our cohort displayed a male predominance and median age at onset in the 7th decade, as previously reported. The most common presenting symptom was seizures. Notably, paroxysmal dizziness spells were significantly more common than previously reported (35%), whereas faciobrachial dystonic seizures were found only in 23%. HLA analysis revealed overrepresentation of DRB1*07:01 (OR: 3.18, CI: 20.9 p < 1.e-5) and DRB1*04:02 (OR: 3.8, CI: 20.1 p < 1.e-5), as well as of the DQ allele DQB1*02:02 (OR: 2.8, CI: 14.2 p < 0.0001) as previously reported. A novel overrepresentation observed among our patients was of the DQB1*03:02 allele (OR: 2.3, CI: 6.9 p < 0.008). In addition, we found DR-DQ associations, among patients with anti-LGI1E, that showed complete or near-complete linkage disequilibrium (LD). By applying LD analysis to an unprecedentedly large control cohort, we were able to show that although in the general population, DQB*03:02 is not fully associated with DRB1*04:02, in the patient population, both alleles are always coupled, suggesting the DRB1*04:02 association to be primary to disease predisposition. In silico predictions performed for the overrepresented DQ alleles reveal them to be strong binders of LGI1-derived peptides, similarly to overrepresented DR alleles. These predictions suggest a possible correlation between peptide binding sites of paired DR-DQ alleles. DISCUSSION: Our cohort presents distinct immune characteristics with substantially higher overrepresentation of DRB1*04:02 and slightly lower overrepresentation of DQB1*07:01 compared with previous reports implying differences between different populations. DQ-DR interactions found in our cohort may shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying a possible relevance of certain DQ alleles and DR-DQ interactions.

Bilateral hearing loss preceding rhomboencephalitis - a hint for Kelch-like 11 syndrome.

BACKGROUND: Paraneoplastic neurological syndromes have diverse clinical presentations and offer an opportunity for early diagnosis of malignancy and treatment. Recently, a new paraneoplastic syndrome associated with seminoma was described, consisting of rhombencephalitis with antibodies targeting the Kelch-like protein 11 (KLHL11). Questions were raised as to the spectrum of clinical symptoms and strength of association to seminoma. METHODS: We present a 45-year-old man with bilateral sensorineural hearing loss, vertigo, and progressive ataxia. An extensive diagnostic workup led to the diagnosis of anti-KLHL11 paraneoplastic syndrome based on an immunofluorescence assay showing a typical pattern and a confirmatory serological assay. As a result, the patient underwent a meticulous search for an underlying seminoma. RESULTS: Although initially, all images were interpreted as negative, a revision of the positron emission tomography-CT (PET-CT) examination identified a small mediastinal suspicious mass. The mass was resected, and pathological examination confirmed it to be an extra-testicular seminoma. CONCLUSIONS: Patients presenting with progressive sensorineural hearing loss, vertigo, and ataxia should be evaluated for KLHL11 paraneoplastic syndrome. Furthermore, we support a strong association between anti-KLH11 rhombencephalitis and an underlying seminoma and recommend a thorough search for an undiagnosed germ cell tumor in these patients.

The importance of tissue-based assay in the diagnosis of autoimmune encephalitis.

BACKGROUND: The evaluation of autoimmune encephalitis (AIE) usually includes antibody testing with commercial kits capable of detecting only preselected antibodies. A non-antigen-specific assay may help detect other antibodies. In this study, we evaluate the utility and clinical relevance of an immunofluorescence assay (IFA) in the evaluation of AIE. METHODS: Immunofluorescence assay was performed on 1949 patients' serum/CSF between 2017 and 2020 and clinical relevance was designated to each case based on clinical course, suggested criteria and ancillary testing. RESULTS: Sixty-one patients (3.1%) had positive serum IFA, positive CSF, or both. Twenty-eight out of 42 patients who were positive only on IFA were designated as clinically relevant (67%), 8 inconclusive (19%), and 6 non-relevant (14%). Pleocytosis was significantly higher in the clinically relevant cases (74% vs. 20% for non-clinically relevant cases). Encephalopathy was the most common presentation (36%), followed by cerebellar syndrome (32%) and seizures (25%). The initial diagnosis changed due to IFA results in 13/28 (46%) cases and IFA result led to the initiation or modification of treatment in all cases (68% and 43%, respectively). Twenty-five patients were treated with 1st line immunotherapy and 12 with 2nd line immunotherapy, with 92% responding to treatment. Twenty-six clinically relevant patients underwent cancer workup: seven (25%) had confirmed malignancy and three had high suspicion of malignancy (total of 37%). CONCLUSION: Non-antigen-specific assays, such as IFA, can identify antibodies not detected in commercially available kits and therefore are recommended in the evaluation of autoimmune encephalitis.

PD-1-inhibitor-induced PCA-2 (MAP1B) Autoimmunity in a Patient with Renal Cell Carcinoma.

Immune check point inhibitors (ICIs) are a group of anti-cancer pharmacological agents which modify T cell activity in order to potentiate an effective immune response against tumor cells. While these drugs prove extremely potent against several types of malignancies, they may be associated with significant autoimmune adverse events. We report a patient who developed a subacute cerebellar syndrome shortly after starting treatment with nivolumab, a PD-1 inhibitor, for renal clear cell carcinoma, with detectable paraneoplastic PCA-2 antibodies. The tumor specimen stained positively for MAP1B, the antigen of PCA-2. The patient responded well to treatment with glucocorticosteroids. This is the first case to our knowledge of PCA-2 paraneoplastic cerebellar degeneration associated with ICI use, which presents in a patient with a malignancy not typically associated with neurological paraneoplastic phenomena. Treatment with immune checkpoint inhibitors (ICIs) is extremely effective in potentiating an immune response against tumor cells, but bears a substantial risk for the development of autoimmune phenomena, including paraneoplastic neurological syndromes. Increasing use of ICIs is leading to increasing numbers of patients with new-onset neurological symptoms. Awareness of these novel entities will aid in early diagnosis and proper treatment.

LGI1 antibody encephalitis: acute treatment comparisons and outcome.

OBJECTIVE: To compare acute treatment responses and long-term outcome in leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. METHODS: Retrospective case series of 118 patients with LGI1 antibody encephalitis evaluated at Mayo Clinic across all US sites from 1 May 2008 to 31 March 2019. Patient clinical data were identified and analysed through the neuroimmunology laboratory and electronic medical record. LGI1 antibody detection was by cell-based indirect immunofluorescence assay of serum, cerebrospinal fluid or both. Clinical outcomes were faciobrachial dystonic seizure (FBDS) resolution, modified Rankin Scale (mRS) score, Kokmen Short Test of Mental Status (STMS) score (0-38 point scale) and neuropsychometric testing results. RESULTS: Compared with intravenous immunoglobulin (IVIg) (n=21), patients treated with single-agent acute corticosteroids (intravenous, oral or both) (n=49) were more likely to experience resolution of FBDS (61% vs 7%, p=0.002) and improvements in mRS score (ΔmRS score 2 vs 0, p=0.008) and median Kokmen STMS scores (ΔKokmen STMS score 5 points vs 0 points, p=0.01). In 54 patients with long-term follow-up (≥2 years), the median mRS score was 1 (range 0-6) and the median Kokmen STMS score was 36 (range 24-38) after all combinations of immunotherapy. Neuropsychometric testing in 32 patients with long-term follow-up (≥2 years) demonstrated short-term memory impairments in 37%. CONCLUSIONS: Corticosteroids appeared more effective acutely than IVIg in improving LGI1 antibody encephalitis in this retrospective comparison of immunotherapies. While improvement with immunotherapy is typical and long-term outcome is favourable, short-term memory deficits are noted in approximately a third of the patients.

A paraneoplastic syndrome misdiagnosed as ALS: What are the red flags? A case report and review of the literature.

Background Paraneoplastic motor neuron disease (PMND) is a rare, non-classical form of paraneoplastic neurological syndrome (PNS). Anti-Hu and anti-CV2/CRMP5 PNS are mostly associated with small-cell lung cancer (SCLC) and consist of highly variable clinical syndromes, including sensory neuronopathy, cerebellar ataxia and/or limbic encephalitis. However, substantial motor impairment is uncommon, particularly when no sensory dysfunction co-exists. Case A 72-year-old man with a recent diagnosis of amyotrophic lateral sclerosis (ALS) was referred to our department of neurology for evaluation. The patient sub-acutely developed progressive neurological dysfunction including erectile dysfunction, behavioral changes, limb weakness, dysphagia, anorexia, as well as worsening stridor that necessitated tracheostomy due to bilateral vocal cord paralysis (BVCP). Neurological examination revealed motor weakness of upper and lower motor neuron origin with autonomic and cognitive dysfunction. Cerebrospinal fluid (CSF) analysis demonstrated pleocytosis, elevated protein, presence of oligoclonal bands (OCB), and neuronal antibody testing was positive for anti-Hu and anti-CV2/CRMP5. Based on these findings a diagnosis of a PNS was made. Evaluation for malignancy was negative, and immunosuppressive/immunomodulatory treatment was initiated but had little effect during fifteen months of follow-up. Conclusions Although PMND is very rare, in an atypical presentation, especially with features that are not usually present in ALS such as autonomic dysfunction, sensory disturbance or cognitive decline, this etiology should be in the differential diagnosis.

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Clinical spectrum of high-titre GAD65 antibodies.

OBJECTIVE: To determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity. METHODS: We identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of 380 514 submitted anti-GAD65 samples (2003-2018). Patients classified as having GAD65 neurological autoimmunity after chart review were analysed to determine disease manifestations, immunotherapy responsiveness and predictors of poor outcome (modified Rankin score >2). RESULTS: On review, 108 patients were classified as not having GAD65 neurological autoimmunity and 3 patients had no more likely alternative diagnoses but atypical presentations (hyperkinetic movement disorders). Of remaining 212 patients with GAD65 neurological autoimmunity, median age at symptom onset was 46 years (range: 5-83 years); 163/212 (77%) were female. Stiff-person spectrum disorders (SPSD) (N=71), cerebellar ataxia (N=55), epilepsy (N=35) and limbic encephalitis (N=7) could occur either in isolation or as part of an overlap syndrome (N=44), and were designated core manifestations. Cognitive impairment (N=38), myelopathy (N=23) and brainstem dysfunction (N=22) were only reported as co-occurring phenomena, and were designated secondary manifestations. Sustained response to immunotherapy ranged from 5/20 (25%) in epilepsy to 32/44 (73%) in SPSD (p=0.002). Complete immunotherapy response occurred in 2/142 (1%). Cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L predicted poor outcome. INTERPRETATION: High-titre GAD65 antibodies were suggestive of, but not pathognomonic for GAD65 neurological autoimmunity, which has discrete core and secondary manifestations. SPSD was most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. Complete immunotherapy response was rare. Serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia predicted poor outcome.

Case report: Isolated muscle neuromyotonia, as presenting feature of Isaacs' syndrome.

An autoimmune form of Isaacs' syndrome is commonly associated with VGKC complex antibodies and characterized by continuous muscle activity of extremity muscles. Here, we describe a CASPR2 and LGI1 positive patient with neuromyotonia clinically and electrophysiologically isolated to gastrocnemius muscles only. IVIG course and plasma exchange were ineffective, but symptoms significantly improved after a course of high-dose steroids. This case demonstrates that focal hyperexcitability should raise suspicion for autoimmunity. LGI1 antibody can be positive in patients with only peripheral nerve system involvement and if one treatment fails, other should be tried.

Case Report: Anti-LGI1 Encephalitis Following COVID-19 Vaccination.

Anti-leucine rich glioma inactivated 1 (LGI1) autoimmune encephalitis (AE) is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders, faciobrachial dystonic seizures (FBDS) and refractory hyponatremia. Since December 2020, millions of people worldwide have been vaccinated against COVID-19. Several soft neurological symptoms like pain, headache, dizziness, or muscle spasms are common and self-limited adverse effects after receiving the COVID-19 vaccine. However, several major neurological complications, despite the unproven causality, have been reported since the introduction of the COVID-19 vaccine. Herein, we describe a 48 years old man presenting with rapidly progressive cognitive decline and hyponatremia diagnosed with anti LGI1 AE, occurring shortly after the second dose of mRNA COVID -19 vaccine and possibly representing a severe adverse event related to the vaccination. Response to high dose steroid therapy was favorable. As millions of people worldwide are currently receiving COVID-19 vaccinations, this case should serve to increase the awareness for possible rare autoimmune reactions following this novel vaccination in general, and particularly of anti-LGI1 AE.

An uncommon presentation of paraneoplastic limbic encephalitis.

Paraneoplastic limbic encephalitis (PLE) is a rare disease with established diagnostic criteria. We describe a case of an uncommon presentation of PLE in a female who presented with a one- year duration of short-term memory loss and mild behavioral changes who was eventually diagnosed with PLE associated with breast cancer. Our case demonstrates atypical presentation of PLE, with chronic presentation and an uncharacteristic mild neurological symptoms. This case aims to highlight the importance of a diagnostic work up of autoimmune encephalitis in selected cases that does not present with common diagnostic criteria.

Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: Conceptual definitions.

Seizures are a well-recognized and often prominent manifestation of autoimmune encephalitic syndromes. Progress in detection of pathogenic neural autoantibodies has led to increased awareness of autoimmune causes of seizures. Clinical studies of patients with these autoantibodies have improved our understanding of the seizure characteristics, treatments, and seizure prognosis in these disorders. The International League Against Epilepsy (ILAE) Autoimmunity and Inflammation Taskforce proposes conceptual definitions for two main diagnostic entities: (a) acute symptomatic seizures secondary to autoimmune encephalitis, and (b) autoimmune-associated epilepsy, the latter of which suggests an enduring predisposition to seizures. Such a distinction is relevant when discussing the pathophysiology, treatment, prognosis, and social consequences of these disorders. We discuss the role of biomarkers in the application of these conceptual definitions and illustrate their use in patients cared for by members of the task force.

Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy.

OBJECTIVE: Drug-resistant seizures are common in patients with leucine-rich, glioma-inactivated 1 (LGI1)-IgG associated and contactin-associated protein-like 2 (CASPR2)-IgG associated encephalitis. We performed the first randomized double-blind placebo-controlled trial to evaluate efficacy of intravenous immunoglobulin (IVIG) in reducing seizure frequency. METHODS: Our enrollment goal was 30 LGI1/CASPR2-IgG-seropositive adult patients with ≥2 seizures per week. Patients were randomized to receive IVIG (0.5g/kg day 1, 1g/kg day 2, 0.6g/kg weeks 3 and 5) or volume-matched intravenous normal saline. Following the blinded phase, the nonresponders in the placebo group received IVIG. The primary clinical outcome was 50% reduction in seizure frequency from baseline to 5 weeks. RESULTS: After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated due to slow enrollment. Six of 8 patients in the IVIG group were responders, compared to 2 of 9 in the placebo group (p = 0.044, odds ratio = 10.5, 95% confidence interval = 1.1-98.9). For the LGI1-IgG seropositive subgroup, 6 of 8 patients in the IVIG group were responders, compared to zero of 6 in the placebo group. Two LGI1-IgG-seropositive patients receiving IVIG, but none receiving placebo, were seizure-free at the end of the blinded phase. Four of the 6 patients entering the open-label IVIG arm reported ≥50% reduction in seizure frequency. There were no correlations with LGI1/CASPR2-IgG1-4 subclasses. INTERPRETATION: Superiority of IVIG to placebo reached statistical significance for the primary endpoint for all patients and the subset with LGI1-IgG. These results have to be interpreted with the caveat that the study did not reach its originally selected sample size. ANN NEUROL 2020;87:313-323.