PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome.

The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.

Isolated Optic Neuritis: Etiology, Characteristics, and Outcomes in a US Mountain West Cohort.

BACKGROUND: The diagnosis and treatment of autoimmune optic neuritis (ON) has improved with the accessibility and reliability of aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody testing, yet autoantibody-negative ON remains common. This study describes the demographic, clinical, and outcome data in patients with isolated ON across the pediatric and adult cohort. METHODS: A retrospective chart review of University of Utah Health patients with the International Classification of Diseases (ICD) code of ICD-9 377.30 (ON unspecified), ICD-9 377.39 (other ON), or ICD-10 H46 (ON) and at least 2 ophthalmologic evaluations were conducted between February 2011 and July 2023. Only isolated cases of ON without other brain or spinal demyelinating lesions were evaluated. Differences in demographic and clinical characteristics between AQP4, MOG, and Other-ON were determined. RESULTS: Of the 98 patients (15 children and 83 adults), 9 (9.2%) were positive for AQP4-IgG and 35 (35.7%) tested positive for MOG-IgG. Fifty-four were classified into Other-ON, of which 7 (13.0%) had recurrence or new demyelinating lesions during a median follow-up of 12.5 months-2 were ultimately diagnosed with recurrent isolated ON (RION), 1 with chronic relapsing inflammatory ON (CRION), 2 with multiple sclerosis, 1 with collapsin response-mediator protein (CRMP)-5-ON, and 1 with seronegative neuromyelitis optica spectrum disorder. Four patients were treated with long-term immunosuppressive therapy. No patients with RION or CRION had preceding infections; they had first recurrences of ON within 2 months. At presentation, AQP4-ON (75%) and MOG-ON (48.8%) had more severe vision loss (visual acuity <20/200) than Other-ON (23.2%, P = 0.01). At the 1-month follow-up, 93.0% of patients with MOG-ON and 89.3% of patients with Other-ON demonstrated a visual acuity ≥20/40, compared with only 50% of patients with AQP4-ON (P < 0.01). By the last follow-up, 37.5% of the AQP4-ON still exhibited visual acuity <20/40, including 25% who experienced severe vision loss (visual acuity <20/200). By contrast, over 95% of patients with MOG-ON and Other-ON maintained a visual acuity of ≥20/40. In our cohort, over a quarter of pediatric cases presented with simultaneous bilateral ON, 40% had a preceding infection, and 44.4% initially presented with a visual acuity <20/200. Two pediatric cases had recurrence, and both were MOG-ON. By their last follow-up, all pediatric cases had achieved a visual acuity of 20/40 or better. In addition, pediatric cases were more likely to exhibit disc edema compared with adult cases (100% vs 64%, P < 0.01). CONCLUSIONS: Despite recent advances in identification and availability of testing for AQP4-IgG and MOG-IgG, over half of patients who presented with isolated ON remained with an "idiopathic" diagnostic label. As more than 1 in 10 patients with AQP4-IgG and MOG-IgG negative ON experienced recurrence or develop new demyelinating lesions, clinicians should provide anticipatory guidance and closely monitor for potential long-term outcomes. In addition, it is crucial to re-evaluate the diagnosis in cases of poor recovery, ON recurrence, and the emergence of new neurological symptoms, as ON can often be the initial presentation of other conditions.

Stiff person syndrome with Anti-GAD65 antibodies within the national veterans affairs health administration.

INTRODUCTION: Stiff person syndrome (SPS) is a neurological disorder characterized by muscle rigidity primarily in the truncal muscles, commonly associated with autoantibodies to the glutamic acid-decarboxylase 65 kD receptor (GAD65). There is limited epidemiological information on patients with SPS. METHODS: We performed a retrospective case review using the National United States Veterans Affairs Health Administration electronic medical record system. We analyzed prevalence, demographics, disease characteristics, and treatment outcomes in SPS patients who were anti-GAD65 antibody positive. RESULTS: Fifteen patients met our criteria. Point prevalence was 2.06 per million, and period prevalence was 2.71 per million. Men to women ratio was 14:1. All patients benefitted from treatment with symptomatic antispasmodic agents. Ten of 15 patients received intravenous immunoglobulin, with a majority demonstrating stable or improved modified Rankin scores. DISCUSSION: This investigation was a large North American epidemiological study of SPS with predominantly male patients. Symptomatic therapy was beneficial for most patients, with less clear sustained benefit of immunotherapy. Muscle Nerve 58:801-804, 2018.

Infection, Immunodeficiency, and Inflammatory Diseases in Autoimmune Neurology.

When patients present with neurological syndromes, such as encephalopathy/encephalitis, meningitis, and/or myelopathy/myelitis, the differential diagnosis is often broad, including infectious, inflammatory, autoimmune, vascular, and neoplastic etiologies. Just with inflammatory and autoimmune etiologies alone, there are numerous causative diseases. A comprehensive history and physical examination investigating for extraneurologic manifestations of immune-mediated disease is often necessary. Moreover, evaluating for an underlying infection and/or immunodeficiency becomes a critical aspect to the workup. This article will focus on the association of viral infections and dysregulation of the immune system as triggers of autoimmunity, in addition to various systemic inflammatory diseases that can cause neurological disease either with or without an established rheumatological disorder.

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica.

Pathogenic autoantibodies associated with neuromyelitis optica (NMO) induce disease by targeting aquaporin-4 (AQP4) water channels enriched on astrocytic endfeet at blood-brain interfaces. AQP4 is also expressed at cerebrospinal fluid (CSF)-brain interfaces, such as the pial glia limitans and the ependyma and at the choroid plexus blood-CSF barrier. However, little is known regarding pathology at these sites in NMO. Therefore, we evaluated AQP4 expression, microglial reactivity, and complement deposition at pial and ependymal surfaces and in the fourth ventricle choroid plexus in 23 autopsy cases with clinically and/or pathologically confirmed NMO or NMO spectrum disorder. These findings were compared to five cases with multiple sclerosis, five cases of choroid plexus papilloma, and five control cases without central nervous system disease. In the NMO cases, AQP4 immunoreactivity was reduced relative to control levels in the pia (91%; 21/23), ependyma (56%; 9/16), and choroid plexus epithelium (100%; 12/12). AQP4 immunoreactivity was normal in MS cases in these regions. Compared to MS, NMO cases also showed a focal pattern of pial and ependymal complement deposition and more pronounced microglial reactivity. In addition, AQP4 loss, microglial reactivity, and complement deposition colocalized along the pia and ependyma only in NMO cases. Within the choroid plexus, AQP4 loss was coincident with C9neo immunoreactivity on epithelial cell membranes only in NMO cases. These observations demonstrate that NMO immunopathology extends beyond perivascular astrocytic foot processes to include the pia, ependyma, and choroid plexus, suggesting that NMO IgG-induced pathological alterations at CSF-brain and blood-CSF interfaces may contribute to the occurrence of ventriculitis, leptomeningitis, and hydrocephalus observed among NMO patients. Moreover, disruption of the blood-CSF barrier induced by binding of NMO IgG to AQP4 on the basolateral surface of choroid plexus epithelial cells may provide a unique portal for entry of the pathogenic antibody into the central nervous system.

Lambert-Eaton myasthenic syndrome: Epidemiology and therapeutic response in the national veterans affairs population.

INTRODUCTION: One nationwide study (The Netherlands) of Lambert-Eaton myasthenic syndrome (LEMS) has been published. We report LEMS epidemiology and its therapeutic response in the United States Veterans Affairs (VA) population. METHODS: Medical records for all active patients (12.5 million) in the VA health system were queried for relevant ICD-9 codes for the period October 1, 1999 to September 30, 2013. Clinical, electrophysiologic, and serologic features were evaluated to confirm diagnosis; epidemiologic and treatment data were collected. RESULTS: Point prevalence was estimated at 2.6 per 1,000,000 (confirmed cases) and 3.3 per 1,000,000 (combined confirmed and probable cases). Crude prevalence was similarly estimated at 9.2 and 10.9 per 1,000,000 respectively. A total of 18 of 48 (38%) patients received 3,4-diaminopyridine (3,4-DAP); 14 of 18 (78%) improved. CONCLUSIONS: This investigation was a large North American epidemiologic study of LEMS. LEMS prevalence in the national VA population was found to be similar to previously published rates in other large international populations. Most patients experienced improvement with therapy, including a majority with 3,4-DAP. Muscle Nerve 56: 421-426, 2017.

Neuronal uptake of anti-Hu antibody, but not anti-Ri antibody, leads to cell death in brain slice cultures.

BACKGROUND: Anti-Hu and anti-Ri antibodies are paraneoplastic immunoglobulin (Ig)G autoantibodies which recognize cytoplasmic and nuclear antigens present in all neurons. Although both antibodies produce similar immunohistological labeling, they recognize different neuronal proteins. Both antibodies are associated with syndromes of central nervous system dysfunction. However, the neurological deficits associated with anti-Hu antibody are associated with neuronal death and are usually irreversible, whereas neurological deficits in patients with anti-Ri antibody may diminish following tumor removal or immunosuppression. METHODS: To study the effect of anti-Hu and anti-Ri antibodies on neurons, we incubated rat hippocampal and cerebellar slice cultures with anti-Hu or anti-Ri sera from multiple patients. Cultures were evaluated in real time for neuronal antibody uptake and during prolonged incubation for neuronal death. To test the specificity of anti-Hu antibody cytotoxic effect, anti-Hu serum IgG was incubated with rat brain slice cultures prior to and after adsorption with its target Hu antigen, HuD. RESULTS: We demonstrated that: 1) both anti-Hu and anti-Ri antibodies were rapidly taken up by neurons throughout both cerebellum and hippocampus; 2) antibody uptake occurred in living neurons and was not an artifact of antibody diffusion into dead cells; 3) intracellular binding of anti-Hu antibody produced neuronal cell death, whereas uptake of anti-Ri antibody did not affect cell viability during the period of study; and 4) adsorption of anti-Hu antisera against HuD greatly reduced intraneuronal IgG accumulation and abolished cytotoxicity, confirming specificity of antibody-mediated neuronal death. CONCLUSIONS: Both anti-Hu and anti-Ri antibodies were readily taken up by viable neurons in slice cultures, but the two antibodies differed markedly in terms of their effects on neuronal viability. The ability of anti-Hu antibodies to cause neuronal death could account for the irreversible nature of paraneoplastic neurological deficits in patients with this antibody response. Our results raise questions as to whether anti-Ri antibody might initially induce reversible neuronal dysfunction, rather than causing cell death. The ability of IgG antibodies to access and react with intracellular neuronal proteins could have implications for other autoimmune diseases involving the central nervous system.

Epidemiology of paraneoplastic neurologic syndromes.

Paraneoplastic neurologic syndromes (PNS), initially depicted as seemingly cryptic remote manifestations of malignancy, were first described clinically in the early 20th century, with pathophysiologic correlates becoming better elucidated in the latter half of the century. There remain many questions not only about the pathophysiology but also regarding the epidemiology of these conditions. The continuous discovery of novel autoantigens and related neurologic disease has broadened the association in classical PNS to include conditions such as paraneoplastic cerebellar degeneration. It has also brought into focus several other neurologic syndromes with a putative neoplastic association. These conditions are overall rare, making it difficult to capture large numbers of patients to study, and raising the question of whether incidence is increasing over time or improved identification is driving the increased numbers of cases. With the rise and increasing use of immunotherapy for cancer treatment, the incidence of these conditions is additionally expected to rise and may present with various clinical symptoms. As we enter an era of clinical trial intervention in these conditions, much work is needed to capture more granular data on population groups defined by socioeconomic characteristics such as age, ethnicity, economic resources, and gender to optimize care and clinical trial planning.

Network Meta-analysis of Ravulizumab and Alternative Interventions for the Treatment of Neuromyelitis Optica Spectrum Disorder.

INTRODUCTION: Anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) is a complement-mediated autoimmune disease in which unpredictable and relapsing attacks on the central nervous system cause irreversible and accumulating damage. Comparative efficacy of new NMOSD therapies, such as ravulizumab, with established therapies is critical in making informed treatment decisions. METHODS: Efficacy of ravulizumab relative to established AQP4-Ab+ NMOSD treatments, such as eculizumab, inebilizumab, and satralizumab, was evaluated in a Bayesian network meta-analysis (NMA). Data were extracted from trials identified by a systematic literature review. The final evidence base consisted of 17 publications representing five unique and global studies (PREVENT, N-MOmentum, SAkuraSky, SAkuraStar, and CHAMPION-NMOSD). The primary endpoint was time-to-first relapse; other outcomes included annualized relapse rates (ARRs). RESULTS: For patients receiving monotherapy (monoclonal antibody only), ravulizumab was associated with a lower risk of relapse than inebilizumab (hazard ratio [HR] 0.09, 95% credible interval [CrI] 0.02, 0.57) or satralizumab (HR 0.08, 95% CrI 0.01, 0.55) and was comparable to eculizumab (HR 0.86, 95% Crl 0.16, 4.52). Ravulizumab + immunosuppressive therapy (IST) was associated with a lower risk of relapse than satralizumab + IST (HR 0.15, 95% CrI 0.03, 0.78); the comparison with eculizumab + IST suggested no difference. No patients treated with inebilizumab received background IST and were thus excluded from analysis. The ARR with ravulizumab monotherapy was 98% lower compared with inebilizumab (rate ratio [RR] 0.02, 95% Crl 0.00, 0.38) and satralizumab (RR 0.02, 95% Crl 0.00, 0.42) monotherapies. The ARR with ravulizumab ± IST showed the strongest treatment-effect estimates compared with other interventions. CONCLUSION: In the absence of head-to-head randomized controlled trials, NMA results suggest ravulizumab, a C5 inhibitor, is likely to be more effective in preventing NMOSD relapse in patients with AQP4-Ab+ NMOSD when compared with other treatments having different methods of action.

Anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, also called AQP4-Ab+ NMOSD, is a rare autoimmune disease that causes repeated episodes of symptoms such as blindness, arm/leg weakness, painful spasms, vomiting, and hiccups, among other symptoms. Each episode can cause nervous system damage to worsen, making it more difficult to recover back to regular abilities. Repeated episodes are likely to cause permanent damage, such as blindness and paralysis. Medical treatments that reduce episodes also reduce the damage and the chances symptoms will become permanent. One treatment, ravulizumab, is being studied to treat adults with AQP4-Ab+ NMOSD. This analysis looked at information from published clinical studies to compare ravulizumab with three other treatments (eculizumab, inebilizumab, and satralizumab) to determine how well each treatment reduced NMOSD episodes. There are no studies that have tested all four treatments in one study. Here, the treatments were compared by a method used to estimate the likelihood of a treatment being better than the others. While all four treatments successfully reduced episodes in their own studies, this analysis predicts that ravulizumab would likely be best in preventing episodes compared with inebilizumab or satralizumab when used alone or in combination with other immunosuppressive treatments. These findings, in consideration along with other relevant factors such as cost, safety, dosing delivery method, and frequency of treatment, may help doctors and patients decide what is the best treatment option for each individual patient to prevent attacks in adults with AQP4-Ab+ NMOSD.

Electroconvulsive therapy in N-methyl-d-aspartate receptor encephalitis: A retrospective cohort and scoping review of literature.

Neuropsychiatric symptoms in N-methyl-d-aspartate receptor encephalitis (NMDARE) have led some to pursue empiric trials of electroconvulsive therapy (ECT). A scoping review identified 39 patients diagnosed with NMDARE undergoing ECT. Separately, a retrospective cohort was reviewed to characterize 21 patients. Clinical improvement was attributed to ECT in 49% of patients in the scoping review and 19% of patients in the retrospective cohort; timing of immunotherapies was a confounding factor. Worsening of clinical course following ECT was reported in 28% of patients in the scoping review and 38% of patient in the retrospective review. There is currently insufficient data supporting a beneficial effect of ECT in NMDARE.

Cardiac Involvement in Neurosarcoidosis: A Single-Center Investigation

BACKGROUND AND OBJECTIVES: Sarcoidosis is a multisystem inflammatory granulomatous disease. Among systemic sarcoidosis manifestations, cardiac or nervous system involvement can result in significant morbidity and mortality. We describe the overlapping incidence of cardiac sarcoidosis (CS) within a neurosarcoidosis (NS) cohort and determine the frequency of other nonsarcoid cardiac diseases in these patients. METHODS: We performed a retrospective chart review of patients evaluated at the University of Utah from 2010 to 2022. Patients were included if they had (1) at least one instance of a diagnostic code for sarcoidosis in their medical record-International Classification of Diseases (ICD) 9 code 135 or ICD 10 code D86; (2) at least one outpatient visit in the Neurology Department within the University of Utah electronic health record with a diagnosis of definite, probable, or possible NS based on 2018 consensus criteria; (3) at least one outpatient visit in the Cardiology Department within the University of Utah electronic health record; and (4) ECG available in their medical record for review. Of 64 definite, probable, or possible patients with NS in the University of Utah cohort, 52 met our inclusion criteria and were included in this study. RESULTS: Of 52 patients with NS who met our inclusion criteria, 65.38% were female, with an average age of 60.9 years (range 38-84). More than half (58%) were obese (BMI ≥ 30). CS was diagnosed in 6 patients with NS (12%). Symptoms suggestive of possible cardiac dysfunction included lower extremity edema (50%), palpitations (46%), chest pain (44%), and shortness of breath (27%). ECG abnormalities included nonspecific T-wave change (40%) and right bundle branch block (17%). Three patients experienced ventricular tachycardia: sustained in one patient and nonsustained in 2 patients. Cardiac MRI was performed in 17 patients (32.7%) and in 3 patients (17.6%), which revealed diffuse myocardial enhancement suggesting CS. DISCUSSION: In this cohort, 12% of patients with NS also had confirmed CS. In addition, these patients had a high burden of cardiovascular disease not directly attributed to sarcoidosis. Our data suggest that patients with NS require comprehensive cardiac evaluation. Future studies are needed to clarify the extent of the direct contribution of granulomatous inflammation on the cardiovascular system from the indirect contribution of treatments such as glucocorticoids that lead to increased risk of cardiovascular disease in sarcoidosis.

Vasculitis in the Central Nervous System: Etiology, Characteristics, and Outcomes in a Large Single-Center Cohort.

Background and Purpose: For the management of central nervous system (CNS) vasculitis, it is crucial to differentiate between primary and secondary CNS vasculitis and to understand the respective etiologies. We assessed the etiology, characteristics, and outcomes of patients with CNS vasculitis. Methods: A single-center retrospective chart review was conducted at the University of Utah, Department of Neurology, between February 2011 and October 2022. Results: The median age of the 44 included patients at diagnosis was 54 years; 25.0% were men. Compared to primary CNS vasculitis, secondary CNS vasculitis exhibits higher fever incidence (observed in infectious and connective tissue disorder [CTD]-associated vasculitis), low glucose levels (mostly in infectious vasculitis) and unique cerebrospinal fluid oligoclonal bands (observed in infectious and CTD-associated vasculitis). Patients with inflammatory cerebral amyloid angiopathy (CAA) were older and more commonly had microhemorrhage than primary angiitis of the CNS (PACNS). All patients with CTD-associated vasculitis had a known history of CTD at presentation. Brain biopsies were performed on 10 of 17 PACNS patients and 4 of 8 inflammatory CAA patients, confirming vasculitis in 7 and 4 patients, respectively. Intravenous methylprednisolone was the predominant induction therapy (63.6%), and cyclophosphamide was the most used adjunctive therapy. Cyclophosphamide, rituximab, azathioprine, and mycophenolate mofetil were utilized as maintenance therapy, often with concurrent prednisone. Patients with inflammatory CAA had a higher tendency for relapse rates than PACNS. Conclusions: This study highlights the variations in patients' characteristics, symptoms, and treatment for CNS vasculitis. Understanding these differences can lead to more efficient diagnostic and management strategies.

High level of agreement in a fixed vs. live cell-based assay for antibodies to myelin oligodendrocyte glycoprotein in a real-world clinical laboratory setting.

Introduction: As recognition of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease becomes more widespread, the importance of appropriately ordering and interpreting diagnostic testing for this antibody increases. Several assays are commercially available for MOG testing, and based on a few small studies with very few discrepant results, some have suggested that live cell-based assays (CBA) are superior to fixed CBA for clinical MOG antibody testing. We aimed to determine the real-world agreement between a fixed and live CBA for MOG using two of the most commonly available commercial testing platforms. Methods: We compared paired clinical samples tested at two national clinical reference laboratories and determined the real-world agreement between the fixed CBA and live CBA. Results: Of 322 paired samples tested on both platforms, 53 were positive and 246 were negative by both methodologies (agreement 92.9%, Cohen's kappa 0.78, [0.69-0.86]). Spearman correlation coefficient was 0.80 (p < 0.0001). Of the discrepant results, only 1 of 14 results positive by the live CBA had a titer greater than 1:100, and only 1 of 9 results positive by the fixed CBA had a titer of greater than 1:80. Lower titers on the fixed CBA correlate to higher titers on the live CBA. Conclusion: Overall, there is excellent agreement between fixed and live CBA for MOG antibody testing in a real-world clinical laboratory setting. Clinicians should be aware of which method they use to assess any given patient, as titers are comparable, but not identical between the assays.

Pearls & Oy-sters: ATX-FGF14 Mimicking Autoimmune Pathology.

ATX-FGF14 (formerly spinocerebellar ataxia 27, OMIM #193003) is an autosomal dominant condition caused by a pathogenic variant in the fibroblast growth factor 14 (FGF14, OMIM #601515) gene located on chromosome 13. The phenotypic expression can vary in patients with the same genotype, often delaying diagnosis, especially in probands without known affected relatives and/or with limited available family history. We describe 2 cases of ATX-FGF14 in 1 family with a focus on the importance of differentiating episodic manifestations of neurogenetic conditions from inflammatory/autoimmune neurologic conditions. A 68-year-old male patient (case 1) presented with episodic dysarthria, dizziness, imbalance, and encephalopathy, creating suspicion for a possible autoimmune etiology. At the first evaluation, the patient reported no significant family history. Four years later, on revisiting the family history, he noted that his 49-year-old niece (case 2) had also developed neurologic symptoms of an unclear etiology. On evaluation, she had tremor and ataxia. Both patients also had coexistent evidence of systemic autoimmunity that likely contributed to the initial suspicion of neurologic autoimmunity, and neither had cerebellar or brainstem volume loss. Ultimately, their genetic testing revealed a pathogenic structural variant in the FGF14 gene, consistent with ATX-FGF14. These 2 cases highlight the importance of a detailed interval family history at each visit, especially in undiagnosed adult patients, as well as the importance of objectively analyzing the impact of immunotherapy diagnostic treatment trials to avoid unnecessary immunomodulatory medications.

PNMA2 forms non-enveloped virus-like capsids that trigger paraneoplastic neurological syndrome.

The paraneoplastic Ma antigen (PNMA) genes are associated with cancer-induced paraneoplastic syndromes that present with neurological symptoms and autoantibody production. How PNMA proteins trigger a severe autoimmune disease is unclear. PNMA genes are predominately expressed in the central nervous system with little known functions but are ectopically expressed in some tumors. Here, we show that PNMA2 is derived from a Ty3 retrotransposon that encodes a protein which forms virus-like capsids released from cells as non-enveloped particles. Recombinant PNMA2 capsids injected into mice induce a robust autoimmune reaction with significant generation of autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, while capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies present in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic neurologic disease show similar preferential binding to PNMA2 "spike" capsid epitopes. These observations suggest that PNMA2 capsids released from tumors trigger an autoimmune response that underlies Ma2 paraneoplastic neurological syndrome.

Neurologic involvement in seronegative primary Sjögren's syndrome with positive minor salivary gland biopsy: a single-center experience.

Objective: To assess the demographics, neurologic manifestations, comorbidities, and treatment of patients with seronegative primary Sjögren's syndrome (pSS). Patients and methods: We conducted a retrospective chart review on patients with seronegative pSS evaluated by a neurologist at the University of Utah Health between January 2010 and October 2018. The diagnosis was based on characteristic symptoms, positive minor salivary gland biopsy according to the American-European Consensus Group 2002 criteria, and seronegative antibody status. Results: Of 45 patients who met the study criteria, 42 (93.3%) were Caucasian, and 38 (84.4%) were female. The patients' mean age at diagnosis was 47.8 ± 12.6 (range 13-71) years. Paresthesia, numbness and dizziness, and headache were noted in 40 (88.9%), 39 (86.7%), and 36 patients (80.0%), respectively. Thirty-four patients underwent brain magnetic resonance imaging. Of these, 18 (52.9%) showed scattered nonspecific periventricular and subcortical cerebral white matter T2/fluid-attenuated inversion recovery hyperintense foci. Twenty-nine patients (64.4%) presented to the neurology clinic prior to pSS diagnosis, and the median delay in diagnosis from the first neurology clinic visit was 5 (interquartile ranges 2.0-20.5) months. Migraine and depression were the most common comorbidities in 31 patients (68.9%). Thirty-six patients received at least one immunotherapy, and 39 were on at least one medication for neuropathic pain. Conclusion: Patients often display various nonspecific neurological symptoms. Clinicians should express a high degree of skepticism regarding seronegative pSS and consider minor salivary gland biopsy to avoid delaying diagnosis, as undertreatment can affect patients' quality of life.

Neurologic Manifestations of Common Variable Immunodeficiency: Impact on Quality of Life.

BACKGROUND AND OBJECTIVES: Common variable immunodeficiency is a systemic disease and not solely a disease of humoral immunity. Neurologic symptoms associated with common variable immunodeficiency are underrecognized and warrant further study. This work aimed to characterize the neurologic symptoms reported by people living with common variable immunodeficiency. METHODS: We conducted a single academic medical center study of neurologic symptoms reported by adults previously diagnosed with common variable immunodeficiency. We used a survey of common neurologic symptoms to determine the prevalence of these symptoms in a population with common variable immunodeficiency and further assessed these patient-reported symptoms with validated questionnaires and compared symptom burden with other neurologic conditions. RESULTS: A volunteer sample of adults (aged 18 years or older) previously diagnosed with common variable immunodeficiency at the University of Utah Clinical Immunology/Immune Deficiency Clinic who were able to read and comprehend English and willing and able to answer survey-based questions were recruited. Of 148 eligible participants identified, 80 responded and 78 completed the surveys. The mean age of respondents was 51.3 years (range 20-78 years); 73.1% female and 94.8% White. Patients with common variable immunodeficiency reported many common neurologic symptoms (mean 14.6, SD 5.9, range 1-25), with sleep issues, fatigue, and headache reported by more than 85%. Validated questionnaires addressing specific neurologic symptoms supported these results. T-scores on Neuro QoL questionnaires for sleep (mean 56.4, SD 10.4) and fatigue (mean 54.1, SD 11) were higher, indicating more dysfunction, than in the reference clinical population (p < 0.005). The Neuro QoL questionnaire for cognitive function showed a lower T-score (mean 44.8, SD 11.1) than that in the reference general population (p < 0.005), indicating worse function in this domain. DISCUSSION: Among survey respondents, there is a marked burden of neurologic symptoms. Given the impact of neurologic symptoms on health-related quality-of-life measures, clinicians should screen patients with common variable immunodeficiency for the presence of these symptoms and offer referral to neurologists and/or symptomatic treatment when indicated. Frequently prescribed neurologic medications may also affect the immune system, and neurologists should consider screening patients for immune deficiency before prescribing them.

Autoimmune Encephalitis Misdiagnosis in Adults.

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

Adrenal Crisis Presenting as Recurrent Encephalopathy Mimicking Autoimmune, Infectious Encephalitis, and Common Variable Immune Deficiency: A Case Report.

INTRODUCTION: Adrenal crisis can present with life-threatening complications and mimic autoimmune or infectious encephalitis, and common variable immune deficiency (CVID). The literature regarding the neurological complications of adrenal crisis is limited and focuses on patients who present with hypotension and electrolyte abnormalities. CASE REPORT: A 30-year-old man presented 3 times to our hospital with encephalopathy, fever, and left sided weakness with a history of multiple autoimmune diseases and prior hospitalizations for encephalopathy. During his first 2 admissions, he was normotensive and without electrolyte abnormalities. Extensive workup for infectious, paraneoplastic, seizure, metabolic, toxic, and vascular etiologies, and autoimmune encephalitis was negative. His exam returned to baseline with empiric steroid treatment, and he was discharged. He re-presented 2 months later with encephalopathy for a third admission. During this subsequent presentation, he had hyponatremia, low serum osmolality, elevated urine sodium, undetectable morning cortisol, and 21-α hydroxylase autoantibodies. A diagnosis of autoimmune adrenal insufficiency was established, he was treated with physiological doses of hydrocortisone and fludrocortisone, and improved rapidly to near baseline function. He has remained relapse-free at 4-year follow up. During all admissions, he was also found to have low immunoglobulin G levels and met criteria for CVID; however, his immunoglobin levels recovered with steroid replacement. CONCLUSION: The reported patient demonstrated some of the neurological complications of adrenal crisis which can mimic other autoimmune conditions such as CVID. The neurologist should be aware that recurrent encephalopathy from adrenal insufficiency can occur regardless of hemodynamic or electrolyte changes on typical hospital metabolic panels.