Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis.

OBJECTIVES: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). METHODS: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. RESULTS: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. INTERPRETATION: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21-33.

Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

OBJECTIVE: The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. METHODS: We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. RESULTS: The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). INTERPRETATION: CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024;96:34-45.

Cerebral Cortical Encephalitis in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N-Methyl-D-aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high-dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2023;93:297-302.

Neurological autoimmunity in patients with non-pulmonary neuroendocrine neoplasms: clinical manifestations and neural autoantibody profiles.

BACKGROUND AND PURPOSE: Paraneoplastic neurological autoimmunity is well described with small-cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs). METHODS: Adult patients with histopathologically confirmed non-pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116). RESULTS: Thirty-four patients were identified (median age 68 years, range 31-87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non-ICI-treated patients. The most frequent neurological phenotypes (non-ICI-treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q-type voltage-gated calcium channel [seven], muscle-type acetylcholine receptor [three], anti-neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non-ICI-treated) and neural autoantibody positivity was associated with poor neurological outcome. DISCUSSION: Neurological autoimmunity associated with non-pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment.

Seizure characteristics and outcomes in patients with neurological conditions related to high-risk paraneoplastic antibodies.

OBJECTIVE: Seizures are a common manifestation of paraneoplastic neurologic syndromes. The objective of this study was to describe the seizure characteristics and outcomes in patients with high-risk paraneoplastic autoantibodies (>70% cancer association) and to determine factors associated with ongoing seizures. METHODS: Patients from 2000 to 2020 with seizures and high-risk paraneoplastic autoantibodies were retrospectively identified. Factors associated with ongoing seizures at last follow-up were evaluated. RESULTS: Sixty patients were identified (34 males, median age at presentation = 52 years). ANNA1-IgG (Hu; n = 24, 39%), Ma2-IgG (n = 14, 23%), and CRMP5-IgG (CV2; n = 11, 18%) were the most common underlying antibodies. Seizures were the initial presenting symptom in 26 (43%), and malignancy was present in 38 (63%). Seizures persisted for >1 month in 83%, and 60% had ongoing seizures, with almost all patients (55/60, 92%) still being on antiseizure medications at last follow-up a median of 25 months after seizure onset. Ongoing seizures at last follow-up were associated with Ma2-IgG or ANNA1-IgG compared to other antibodies (p = .04), highest seizure frequency being at least daily (p = .0002), seizures on electroencephalogram (EEG; p = .03), and imaging evidence of limbic encephalitis (LE; p = .03). Death occurred in 48% throughout the course of follow-up, with a higher mortality in patients with LE than in those without LE (p = .04). Of 31 surviving patients at last follow-up, 55% continued to have intermittent seizures. SIGNIFICANCE: Seizures in the setting of high-risk paraneoplastic antibodies are frequently resistant to treatment. Ongoing seizures are associated with ANNA1-IgG and Ma2-IgG, high seizure frequency, and EEG and imaging abnormalities. Although a subset of patients may respond to immunotherapy and achieve seizure freedom, poor outcomes are frequently encountered. Death was more common among patients with LE.

Immune checkpoint inhibitor-associated central nervous system autoimmunity.

BACKGROUND AND PURPOSE: Outcome and rechallenge data on central nervous system (CNS) autoimmunity triggered by immune checkpoint inhibitors (ICIs) are limited. We aim to describe a large series of patients with ICI-triggered CNS autoimmunity, and to compare these patients with spontaneous paraneoplastic syndromes (PNS). METHODS: We retrospectively reviewed Mayo Clinic patients with ICI-triggered CNS autoimmunity (February 2015-June 2021). Clinical characteristics were compared to spontaneous PNS patients (with antineuronal nuclear antibody [ANNA]-1 or anti-Hu neurological autoimmunity, and/or neuroendocrine tumors [NET]) evaluated within the same period. RESULTS: Thirty-one patients were included (55% female, median age = 63 years, range = 39-76). Median time from ICI initiation was 3.65 months (range = 0.8-44.5). The most common associated malignancies were melanoma and small cell lung cancer. CNS manifestations included encephalitis (n = 16), meningoencephalitis (n = 8), cerebellar ataxia (n = 4), demyelinating syndrome (n = 2), and myelopathy (n = 1). Magnetic resonance imaging was abnormal in 62%. Cerebrospinal fluid was inflammatory in 70%. Neural autoantibodies were identified in 47%, more frequently in patients with NET (p = 0.046). ICI was discontinued in 97%; 90% received immunosuppressive treatment. After median 6.8 months follow-up (range = 0.7-46), 39% had unfavorable outcomes (grade ≥ 3). This was associated with higher severity degree at onset, shorter period from ICI to neurological symptom onset, and encephalitis. Four patients were rechallenged with ICI, and one relapsed. Patients with NET and with ANNA-1 ICI-triggered CNS autoimmunity had associated peripheral nervous system manifestations more frequently than their spontaneous counterparts (p = 0.007 and p = 0.028, respectively). CONCLUSIONS: One third of ICI-related CNS autoimmunity patients have unfavorable outcomes. Relapses may occur after ICI rechallenge. Neural autoantibodies are often present, more commonly in patients with NET.

Growing Spectrum of Autoimmune Nodopathies.

PURPOSE OF REVIEW: Recognition of node of Ranvier as the site of injury in inflammatory neuropathies contributed to discovery of antibodies against the nodal/paranodal structures. These antibodies mediate a unique type of inflammatory neuropathies that are different from typical chronic inflammatory demyelinating polyneuropathy. This review discusses the advancements made in the field of autoimmune neuropathies secondary to antibodies to nodal and paranodal proteins. RECENT FINDINGS: Neuropathies caused by antibodies to nodal-paranodal antigens including neurofascin 186, neurofascin 155, contactin1, and contactin-associated protein1 were termed as autoimmune nodopathies (AN) in 2021. Since the initial description almost a decade ago, newer cohorts have expanded the clinical spectrum of AN. In addition to IgG4, other subclasses of IgG such as IgG1/IgG3 have been identified, particularly in relation to acute presentations and anti-pan neurofascin antibody disease. In vitro and in vivo studies have also supported antibody-mediated pathogenicity of many of these biomarkers. Antibodies to nodal-paranodal antigens have emerged as a biomarker for a novel type of immune-mediated neuropathies. These antibodies have distinct pathogenic mechanisms and produce a unique set of clinicopathologic features. Their clinical profile and treatment may also vary depending on the antibody isotype. B cell depleting therapies are effective in managing some of these patients.

Kelch-like Protein 11 Antibodies in Seminoma-Associated Paraneoplastic Encephalitis.

A 37-year-old man with a history of seminoma presented with vertigo, ataxia, and diplopia. An autoantibody specific for kelch-like protein 11 (KLHL11) was identified with the use of programmable phage display. Immunoassays were used to identify KLHL11 IgG in 12 other men with similar neurologic features and testicular disease. Immunostaining of the patient's IgG on mouse brain tissue showed sparse but distinctive points of staining in multiple brain regions, with enrichment in perivascular and perimeningeal tissues. The onset of the neurologic syndrome preceded the diagnosis of seminoma in 9 of the 13 patients. An age-adjusted estimate of the prevalence of autoimmune KLHL11 encephalitis in Olmsted County, Minnesota, was 2.79 cases per 100,000 men. (Funded by the Rochester Epidemiology Project and others.).

Cancer and immune-mediated necrotizing myopathy: a longitudinal referral case-controlled outcomes evaluation.

OBJECTIVES: To investigate immune-mediated necrotizing myopathy (IMNM) association with cancer and its clinical implications. METHODS: IMNM cases were identified 1 January 2000 to 31 December 2020 matching sex and age controls (4:1). RESULTS: A total of 152 patients with IMNM were identified and among serologically tested, 60% (83/140) were HMGCR-IgG+, 14% (20/140) were SRP-IgG+ and 26% (37/140) were seronegative. Cancer rates were not significantly different between serological subgroups; 18.1% (15/83) HMGCR-IgG+, 25% (5/20) SRP-IgG+ and 30% (11/37) seronegative (P = 0.34). Cancer screening was performed within 12 months from IMNM diagnosis in 88% (134/152) (whole-body CT plus FDG-PET CT in 53, CT alone in 72 and FDG-PET alone in 9). FDG-PET/CT was positive in 73% (25/34) of cancers. Increasing age was the only risk associated with cancer (P = 0.02). The odds of developing cancer at ±3 or ±5 years from IMNM diagnosis was not higher than controls (OR = 0.49; CI: 0.325-0.76). Lifetime IMNM diagnosis of cancer was less compared with controls (OR = 0.5 CI: 0.33-0.78, P = 0.002). Most patients responded to treatment (137/147, P < 0.001). Death and treatment response did not significantly differ between cancer [23% (8/34); 88% (29/33)] and non-cancer patients [19% (23/118); 92% (108/118)]. In total, 13% (20/152) of patients died during follow-up compared with 14% (41/290) of medicine and 16% (46/290) of neurology controls (P = 0.8). Seropositives had greater life expectancy than seronegatives (P = 0.01). CONCLUSIONS: Greater cancer risk is not observed in IMNM vs controls. Cancer screening in IMNM should be individualized based on age-personal and family history, including consideration of FDG-PET/CT. Immune-treatment response did not differ with cancer.

Leucine Zipper 4 Autoantibody: A Novel Germ Cell Tumor and Paraneoplastic Biomarker.

OBJECTIVE: This study was undertaken to describe a novel biomarker of germ cell tumor and associated paraneoplastic neurological syndrome (PNS). METHODS: Archival sera from patients with germ cell tumor-associated PNS were evaluated. We identified a common autoantigen in a human testicular cancer cell line (TCam-2) by Western blot and mass spectrometry. Its identity was confirmed by recombinant-protein Western blot, enzyme-linked immunosorbent assay (ELISA), and cell-based assay. Autoantibody specificity was confirmed by analyzing assorted control sera/cerebrospinal fluid. RESULTS: Leucine zipper 4 (LUZP4)-immunoglobulin G (IgG) was detected in 28 patients' sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years (range = 28-84). Median titer (ELISA) was 1:300 (1:50 to >1:6,400, normal value < 1:50). Coexistent kelchlike protein 11-IgG was identified in 18 cases (64%). The most common presenting phenotype was rhombencephalitis (17/28, 61%). Other presentations included limbic encephalitis (n = 5, 18%), seizures and/or encephalitis (n = 2, 7%), and motor neuronopathy/polyradiculopathy (n = 4, 14%). The most common malignancy among cancer-evaluated PNS patients was seminoma (21/27, 78%). Nine of the 21 seminomas detected by whole-body fluorodeoxyglucose positron emission tomography scan (43%) were extratesticular. Both female patients had ovarian teratoma. Regressed testicular germ cell tumors were found in 4 patients. Exposure of T-cell-dendritic-cell cocultures from chronic immunosuppression-naïve LUZP4-IgG-seropositive patients to recombinant LUZP4 protein evoked a marked increase in CD69 expression on both CD4+ and CD8+ T cells when compared to vehicle-exposed and healthy control cultures. INTERPRETATION: LUZP4-IgG represents a novel serological biomarker of PNS and has high predictive value for germ cell tumors. The demonstrated antigen-specific T-cell responses support a CD8+ T-cell-mediated cytotoxic paraneoplastic and antitumor potential. ANN NEUROL 2021;89:1001-1010.

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.

Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome.

OBJECTIVES: To report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients. METHODS: Archived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen. RESULTS: IgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25-87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments: encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer: neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration. CONCLUSIONS: This study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.

CASPR2-IgG-associated autoimmune seizures.

OBJECTIVE: This study was undertaken to report clinical presentations and outcomes of CASPR2-IgG-associated seizures. METHODS: Mayo Clinic Neuroimmunology database was queried to identify CASPR2-IgG-seropositive (CASPR2-IgG+) patients evaluated at our institution (2009-2019). RESULTS: Of the 53 CASPR2-IgG+ patients (titer ≥ 1:10), 20 had seizures (38%). All seizure patients were male, with median onset age of 68 years. Eighteen (90%) had seizures at initial presentation. One patient was found to have malignancy (colon adenocarcinoma). Two patients had coexisting LGI1-IgG. Twelve patients had archived sera, which on titration had CASPR2-IgG titers ≥ 1:100. Fifteen patients (75%) met criteria for autoimmune encephalitis. Patients most commonly presented with focal onset, nonmotor seizures with impaired awareness (n = 14, 70%). Eleven patients also had focal motor and/or sensory seizures as one of the seizure semiologies. The majority of patients (n = 11, 55%) developed generalized tonic-clonic seizures during their disease course. Seizure clusters occurred in 12 patients. In addition to seizures, patients developed cognitive disturbance (n = 16, 80%), episodic emotional lability (n = 13, 65%), paroxysmal dizziness (n = 9, 45%), episodic ataxia (n = 6, 30%), and chronic ataxia (n = 9, 45%). Only three patients (15%) had coexisting peripheral nervous system involvement. Frontotemporal or temporal ictal and/or interictal electroencephalographic abnormalities were present among nine patients, and three had multifocal epileptiform abnormalities. Eight patients (40%) had medial temporal T2/fluid-attenuated inversion recovery hyperintensity on brain magnetic resonance imaging. Elevated cerebrospinal fluid protein and/or lymphocytic pleocytosis was present in most cases (13/14, 93%). Thirteen patients reached seizure freedom following initiation of antiseizure medication (ASM; n = 4) or a combination of immunotherapy and ASM (n = 9). Median duration of follow-up was 25 months (range = 2-136 months). SIGNIFICANCE: CASPR2-IgG evaluation should be considered among older male patients with new onset focal seizures and impaired awareness often occurring in clusters with/without features of encephalitis. Coexisting neurological manifestations, including episodic emotional lability, ataxia, and paroxysmal dizziness, also aid in the diagnosis.

Acute symptomatic seizures secondary to myelin oligodendrocyte glycoprotein antibody-associated disease.

OBJECTIVE: To report the clinical presentations and outcomes of patients with seizure and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: We retrospectively reviewed the electronic medical records for clinical and paraclinical features among patients with seizures and MOG-IgG (immunoglobulin G) seropositivity. RESULTS: We identified 213 patients with MOG-IgG seropositivity who fulfilled criteria for MOGAD. Seizures attributed to central nervous system (CNS) autoimmunity were observed in 10% of patients (n = 23: 19 children, 4 adults). The majority (n = 19, 83%) had pediatric disease onset. Focal motor seizures were the most common seizure semiology (16/23; 70%). Focal to bilateral tonic-clonic seizures were present in 12 patients (53%), and 3 patients (13%) developed status epilepticus. All patients had features of encephalitis at onset of seizures. Cerebral cortical encephalitis (CCE) was the most common radiological finding (10 unilateral and 5 bilateral cases). Eight of 23 patients (35%) had only CCE, six of 23 patients (26%) had only acute disseminated encephalomyelitis (ADEM), and seven of 23 patients (30%) had features of both. Fifteen patients (65%) had leptomeningeal enhancement. Three patients (13%) had coexistence of N-methyl-d-aspartate receptor (NMDAR) IgG. Only 3 of 23 patients (13%) developed drug- resistant epilepsy. Although the majority had MOGAD relapses (14/23, 60%) had only 5 of 23 patients had recurrence of episodes of encephalitis with associated seizures. Twenty-one of 23 patients (91%) had seizure freedom at last follow-up. SIGNIFICANCE: MOG-IgG evaluation should be considered in patients who present with encephalitis and focal motor and/or focal to bilateral tonic-clonic seizures, especially pediatric patients with magnetic resonance imaging (MRI) brain findings consistent with CCE, ADEM, or other MOGAD presentations. The majority of these seizures are self-limited and do not require maintenance/chronic antiseizure medications. Although seizure recurrence is uncommon, many patients have MOGAD relapses in the form of encephalitis and optic neuritis.

Paraneoplastic neurological syndrome: growing spectrum and relevance.

Paraneoplastic neurological syndromes (PNSs) are group of disorders affecting one or multiple parts of the neuroaxis associated with underlying tumors. An antibody or autoantigen-specific cell-mediated immune response against neural antigen expressed in the tumor is the potential etiology for these rare but refractory disorders. In recent years, wide variety of neurological presentations and autoantibodies has been associated with paraneoplastic autoimmunity, leading to formulation of an updated expert consensus PNS diagnostic criteria. Recognition of these phenotypes and use of serological biomarkers may aid neurologists in early diagnosis of PNS cases encountered in the inpatient or outpatient practice. In this review article, we provide an overview of various clinical, radiological, and immunopathological characteristics of PNS. Furthermore, we discuss the updated PNS criteria and increasing recognition of neurological presentations resembling the PNS among patients receiving immune checkpoint inhibitors.

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum.

Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined. ANN NEUROL 2020;87:659-669.

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.

Paraneoplastic cochleovestibulopathy: clinical presentations, oncological and serological associations.

OBJECTIVE: Cochleovestibulopathy is a distinguishable paraneoplastic phenotype. In this study, we evaluate clinical presentation, serological/cancer associations and outcomes of paraneoplastic cochleovestibulopathy. METHODS: Retrospective chart review of patients with hearing impairment and/or vestibulopathy who underwent serological evaluations for paraneoplastic antibodies between January 2007 and February 2021 was performed. RESULTS: Twenty-six patients were identified (men, n=23; median age, 45 years, range: 28-70). Biomarkers detected included: KLHL11-IgG| |(n=20,| |77% (coexisting LUZP4-IgG, n=8)),| ||ANNA1-IgG| | |(n=3,| |12%),| |amphiphysin-IgG|| |(n=2,| |8%)| |and| |LUZP4-IgG|| |(n=1,| |4%). Most common neoplastic association was |testicular|/|extra-testicular| |seminoma| | (n=13,| |50%).|| Hearing| impairment (bilateral, 62%) was |present| |in| |all| |patients.| |Fifteen patients (58%) had cochleovestibular dysfunction as their initial presentation before rhombencephalitis/encephalomyelitis manifestations (hearing loss, four; acute vertigo, eight; both, three). |Brain| |MRI| |demonstrated| |internal| |auditory| |canal| |enhancement| |in| |four |patients.| Audiometry commonly revealed severe-profound bilateral sensorineural hearing loss. Most patients |had| a refractory course |despite| |immunotherapy| |and/or| |cancer| |treatment|. CONCLUSION: Cochleovestibulopathy commonly presents with rapidly progressive bilateral hearing loss and/or acute vertigo. However, in some patients, these symptoms present along with or following brainstem/cerebellar manifestations. KLHL11-IgG and seminoma are the most common serological and cancer associations, respectively. Recognition of this phenotype may aid in earlier diagnosis of paraneoplastic autoimmunity and associated cancer.

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.

Frequency and characteristics of MRI-negative myelitis associated with MOG autoantibodies.

BACKGROUND: Myelitis accompanied by a negative spinal cord MRI may lead to diagnostic uncertainty. OBJECTIVE AND METHODS: We retrospectively investigated the frequency of negative spinal cord MRI (performed <6 weeks from onset) in Mayo Clinic patients with myelin oligodendrocyte glycoprotein (MOG)-IgG-associated myelitis (2000-2019). RESULTS: The initial spinal cord MRI was negative in 7/73 (10%) patients, despite severe acute disability (median EDSS, 7 (range, 4.5-8)); myelitis symptoms/signs were frequent (paraparesis, neurogenic bladder, sensory level, Lhermitte's phenomenon). Myelitis lesions became overt at follow-up MRI in three patients. CONCLUSIONS: A negative spinal cord MRI should not dissuade from MOG-IgG testing in patients with acute/subacute myelitis.