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BACKGROUND AND OBJECTIVES: Conventional magnetic resonance imaging (MRI) used for detecting possible antibody-negative autoimmune encephalitis (AIE) often fails to meet the diagnostic requirements of this disease. Positron emission tomography (PET) with a translocator protein radioligand can help visualize microglia distribution density in inflammation-related diseases, thereby offering potentially incremental value to conventional MRI for the in vivo assessment of possible antibody-negative AIE. METHODS: In this prospective study, 15 participants diagnosed with possible antibody-negative AIE and 10 healthy controls were enrolled (ClinicalTrials.gov: NCT05293405, dated March 15, 2022). All participants underwent hybrid 18F-DPA714 PET/MRI and evaluation for modified Rankin scale (mRS) score, clinical assessment scale for AIE (CASE), and appropriate antibodies. A positive finding was defined as the intensity of 18F-DPA714 uptake that was above a threshold of mean standardized uptake value ratio (SUVR) + two standard deviations of SUVR within the corresponding brain regions of healthy controls. RESULTS: The positive detection rate of 18F-DPA714 PET for possible antibody-negative AIE was significantly higher than that of brain MRI (10/15 [67%] vs. 3/15 [20%]; P = 0.039). In addition, both the intensity and extent of 18F-DPA714 uptake were significantly associated with the CASE score (P = 0.002 and 0.001). Meanwhile, SUVR levels in the cerebellar region were significantly higher in patients with ataxia than in those without ataxia (P = 0.006). Furthermore, 18F-DPA714 uptake decreased in 5/10 [50%] patients who underwent follow-up PET/MRI, which mirrored their symptom relief. CONCLUSION: 18F-DPA714 PET demonstrated its potentially incremental value to conventional MRI for detecting possible antibody-negative AIE.

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Purpose: To delineate the characteristics of probable antibody-negative pediatric autoimmune encephalitis (probable Ab-negative AE), we compared the clinical features of probable Ab-negative AE to those of major antibody-positive AE. Methods: We retrospectively reviewed the clinical features of 18 patients with probable Ab-negative AE, 13 with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE), and 13 with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Clinical characteristics, neuroimaging findings, treatments, and outcomes were analyzed. Results: The age of onset and length of hospital stay were significantly higher in the NMDARE group than in the other groups (p = 0.02 and p < 0.01). Regarding initial neurological symptoms, acute symptomatic seizures in the probable Ab-negative AE group (67%) were significantly more frequent than in the NMDARE (15%) and MOGAD (23%) groups (p < 0.01). Paraclinical evidence of neuroinflammation within 1 month of disease onset revealed that single-photon emission computed tomography (SPECT) detected abnormal alterations in 14/14 (100%), cerebrospinal fluid (CSF) analysis in 15/18 (83%), and magnetic resonance imaging (MRI) in 11/18 (61%) in patients with probable Ab-negative AE. In the probable Ab-negative AE group, seven patients (39%) developed autoimmune-associated epilepsy, whereas one patient (8%) had both NMDARE and MOGAD (not statistically significant, p = 0.07). Conclusion: Patients with probable Ab-negative AE exhibited acute symptomatic seizures as initial neurological symptoms significantly more frequently. They developed autoimmune-associated epilepsy more frequently than those with NMDARE and MOGAD, which was not statistically significant. SPECT within 1 month of disease onset might be a valuable surrogate marker of ongoing neuroinflammation and neuronal dysfunction, even in patients with negative MRI findings.

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A 72-year-old female presented with bilateral pulmonary nodules before undergoing surgery for hysteroptosis. Transbronchial biopsy did not lead to a definitive diagnosis. The right mass in the upper lobe was resected through video-assisted thoracic surgery. Pathological findings showed granulomatosis with polyangiitis. However, the patient was negative for serum proteinase 3-anti-neutrophil cytoplasmic antibody. Although the nodule in the left lower lobe progressed, the serum inflammatory reaction yielded negative results. Resection of the nodule in the left lower lobe revealed identical pathological findings with those of the right pulmonary mass. Following total hysterectomy for hysteroptosis, the pathological findings indicated granulomatosis with polyangiitis.

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Key Clinical Message: Systemic lupus erythematosus is difficult to diagnose in patients who are antinuclear antibody (ANA) negative and lack typical clinical manifestations. For such patient who presented ANA-negative severe lupus-like manifestations, the diagnosis and treatment are a huge challenge. Histological findings may provide clues to diagnosis. Abstract: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by formation of autoantibodies to nuclear and cytoplasmic antigens. It was reported that a small subset of patients had typical clinical features of SLE with consistently negative antinuclear antibody (ANA), but such disease is usually mild and rarely involves multisystem. At present, there are no reports about severe lupus with ANA continued negative. Our report describes a 34-year-old Chinese woman who presented renal failure, multiple serous cavity effusion, and epilepsy, without malar rash, photosensitivity, lymphopenia, and arthritis. Further renal biopsy pathology revealed lupus-like nephritis. Autoantibodies, including ANA, antibodies against Smith and against double stranded DNA, were negative. Such a ANA negative and lack of typical clinical symptoms of SLE patient, but with severe lupus-like manifestations, whether it was lupus or not is worth discussing.

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The prevalence of antibody-negative chronic autoimmune thyroiditis (SN-CAT) is increasing. The early diagnosis of SN-CAT can effectively prevent its further development. Thyroid ultrasound can diagnose autoimmune thyroiditis and predict hypothyroidism. Primary hypothyroidism with a hypoechoic pattern suggested by thyroid ultrasound and negative thyroid serum antibodies is the main basis for the diagnosis of SN-CAT. However, for early SN-CAT, only hypoechoic thyroid changes and serological antibodies are currently available. This study explored how to achieve an accurate and early diagnosis of SN-CAT and prevent the development of SN-CAT combined with hypothyroidism. The diagnosis of a hypoechoic thyroid by artificial intelligence is expected to be a breakthrough in the accurate diagnosis of SN-CAT.

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BACKGROUND: Our study aimed to characterize seizure incidence and seizure outcome of pediatric autoimmune encephalitis (AE) focusing on subgroup analysis based on antibody (Ab). METHODS: Among 110 pediatric patients with AE, we compared seizure characteristics and outcomes in 68 patients with seizure, who satisfied the proposed criteria of pediatric AE. Accordingly, patients were classified into three groups, anti-myelin oligodendrocyte glycoprotein (anti-MOG) AE, anti-N-methyl-D-aspartic acid receptor (anti-NMDAR) AE, and Ab-negative AE. Univariate and multivariate analyses were performed to evaluate the risk factors for postencephalitic seizures, defined as persisting seizures six months after onset. RESULTS: Seizure incidence in the anti-NMDAR (88.9%) and Ab-negative (71.1%) groups differed from anti-MOG group (37.8%). Median seizure frequency within six months was higher in the Ab-negative group (6.0, interquartile range [IQR] 3.0 to 13.0) than in the anti-NMDAR group (3.0, IQR 2.0 to 4.5) and anti-MOG group (2.0, IQR 1.0 to 5.0). Patients in the Ab-negative group tended to develop postencephalitic seizures more frequently and have a lower seizure freedom rate than those in the anti-NMDAR and anti-MOG groups. Ab-negative status, high seizure frequency within six months, and the presence of status epilepticus were associated with the development of postencephalitic seizures on univariate analysis. On multivariate analysis, Ab-negative status remained the only significant variable linked with postencephalitic seizure (odds ratio, 4.17; 95% confidence interval, 1.02 to 18.05). CONCLUSIONS: We delineated the seizure incidence, evolution, and outcome of pediatric patients with Ab-positive and Ab-negative AE. Ab-negative status is predictive of higher seizure burden, more frequent development of postencephalitic seizures, and less favorable seizure outcome than anti-NMDAR and anti-MOG Ab-positive status.

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BACKGROUND: Autoimmune encephalitis (AE) is a group of immune-mediated brain diseases. However, new diagnostic criteria for AE in children indicate that partial pediatric patients with AE may be diagnosed without evidence of positive autoantibodies. Therefore, the clinical characteristics and prognosis of children with antibody-negative but probable AE require further investigation. METHODS: Forty-one children with AE admitted to our hospital from April 2014 to January 2021 were retrospectively enrolled in this study. Children were divided into two groups according to positive or negative antibody tests. Clinical characteristics, cerebrospinal fluid, video electroencephalography, brain magnetic resonance imaging, and prognosis were analyzed, and the correlation between modified Rankin scale (mRS) and neutrophil-to-lymphocyte ratio (NLR) was examined. RESULTS: Of 41 children, 16 cases tested positive for autoantibodies. The main features were psychiatric symptoms, cognitive disturbances, speech disturbances, movement disorders, and seizures. All the children were given a combination of intravenous methylprednisolone pulses with intravenous immunoglobulin therapy; 26 cases (63%) had a good outcome, and 15 cases (37%) had a poor outcome. Antibody-positive and antibody-negative but probable AE were analyzed by univariate analysis and showed lower lymphocyte counts and higher NLR and mRS scores in the antibody-negative group (P < 0.05). The Spearman rank correlation analysis showed a positive correlation between NLR level and mRS scores (P < 0.05). CONCLUSIONS: Antibody-negative but possible AE is frequent in children who may have a more severe neurological impairment and higher NLR than antibody-positive AE. Aggressive immunotherapy in antibody-negative AE is essential to achieve a good prognosis.

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Introduction: Neuromyelitis Optica (NMO; Devic syndrome,1894) is a CNS demyelinating syndrome. Significant proportion of neuromyelitis optica spectrum disorder is associated with Anti AQ4 Ab. The revised diagnostic criteria for neuromyelitis optica spectrum disorder (2015) has been proposed on the basis of Anti AQ4 Ab status. Most of cases reported has been found in females. It presents with multiple remissions. Common features of acute myelitis and optic neuritis seems to be the usual presentation. Case presentation: Herein we report a case of a 35-year-old male with longitudinally extending transverse myelitis and Optic Neuritis with confirmation of Anti AQ4 Ab negative status with presentation of bilateral below knee weakness and incontinence of bowel and bladder. It was confirmed by Magnetic Resonance Imaging. Clinical discussion: Seronegative neuromyelitis optica spectrum disorder recently classified by 2015 diagnostic criteria associated with strict clinical presentations neuroimaging findings and exclusions of differentials. It presents with a poor prognosis particularly in relapsing course. Conclusion: We report a case of seronegative neuromyelitis optica spectrum disorder. The prognosis of relapsing course is poor. Early diagnosis and immunomodulators are required to decrease chances of recurrence. Further development of diagnostic modalities in seronegative neuromyelitis optica spectrum disorder is required.

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Autoimmune encephalitis is a group of central nervous system (CNS) inflammatory disorders that most commonly affect young adults and children. These disorders are closely associated with antibodies against neuronal cell-surface proteins, receptors, and ion channels; however, some forms of the disorder have no known antibody at this time. In children, neurological manifestations such as seizure, movement disorders, and focal neurological deficits are more prominent at initial presentation than psychiatric or behavioral symptoms. When psychiatric symptoms do occur, they often manifest as temper tantrums, aggression, agitation, and rarely psychosis. Prompt diagnosis and early treatment can lead to improved outcomes and decreased relapses. First-line therapies include intravenous steroids, intravenous immunoglobulin, and plasmapheresis, whereas rituximab and cyclophosphamide are utilized for refractory or relapsing disease. This review highlights the different forms of this disorder, discusses approach to diagnosis and treatment, and reviews the outcome and prognosis of children diagnosed with different forms of autoimmune encephalitis.

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Non-Hodgkin's lymphoma (NHL) is the fifth most common hematologic disorder in the United States, and its prevalence has been rising in Western countries. Among the subtypes of NHL, diffuse large B-cell lymphoma (DLBCL) mostly involves the lymph nodes, stomach, and gastrointestinal tract, whereas hepatic involvement of DLBCL is rare. On serologic testing, elevated immunoglobulin G (IgG) levels can be observed in DLBCL; however, elevated IgG levels are mainly observed in autoimmune hepatitis. A targeted-lesion biopsy is required for the diagnosis of DLBCL. Based on a final diagnosis, the patient was treated with rituximab-based chemotherapy, including cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP). Herein, we report a case of DLBCL mimicking antinuclear antibody-negative autoimmune hepatitis, which was finally diagnosed as DLBCL involving the liver, and was confirmed by liver biopsy.

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Background: Chorea as a symptom of late-onset post-infectious autoimmune encephalitis has been reported with HSV-1 but not HSV-2 encephalitis. Extrapyramidal symptoms are typically associated with the presence of anti-NMDA receptor antibodies but may also exist in antibody-negative individuals. Case: This case highlights a patient who presented with mental status changes and chorea as the initial manifestation of HSV-2 encephalitis. The choreiform movements failed to respond to antiviral medications but were rapidly responsive to plasmapheresis, which, together with abnormal intrathecal immunoglobulin synthesis, suggests a potential contribution of parainfectious immune-mediated process. The patient made a full recovery and a complete resolution of the chorea. Discussion: This is the first case associating HSV-2 encephalitis presentation with chorea. The neurological complications, including chorea, are largely related to active CNS HSV-2 infection, possibly together with triggered CNS autoimmunity despite undetectable CSF neuronal autoantibodies and normal neuroimaging. Early diagnosis and treatment with antiviral agent and immune therapies might be pivotal to optimize the clinical outcome.

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Antibody-negative autoimmune encephalitis (AE) is challenging to diagnose because clinically suspected antibody-negative AE cases are difficult to confirm. If not treated properly, like antibody-positive AE, antibody-negative AE can cause irreparable damage to patients. Previously, immunotherapy was effective in treating patients with antibody-negative AE. We present the case of a 63-year-old man who was admitted to our hospital with altered cognition. He was diagnosed with antibody-negative AE based on CSF, brain MRI, and B-cell counts; autoimmune diseases with similar clinical symptoms were ruled out. He was treated with immunotherapy, especially rituximab, for antibody-negative AE. After 3 weeks of treatment, his mental state and brain MRI results, concomitant with a decrease in CD19+/CD20+ B-cell counts. This case report shows that patients with antibody-negative AE may respond to rituximab, similar to those with antibody-positive AE. Thus, potentially undetected antibodies could be responsible for the treatment outcome.

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A 74-year-old woman with a history of asthma and allergic rhinitis rapidly developed multiple mononeuropathy. Although anti-neutrophil cytoplasmic antibodies were negative, the presence of eosinophilia and eosinophilic infiltrations in the sural nerve led to a diagnosis of eosinophilic granulomatosis with polyangiitis. A motor nerve conduction study on admission revealed conduction block, which promptly disappeared after initiating immunotherapy without findings suggestive for remyelination or axonal degeneration. This electrophysiological change distinct from that of Wallerian degeneration. A biopsy of the sural nerve showed many eosinophil infiltrations and degranulation of eosinophilic cationic protein within nerve fascicles, whereas findings of necrotizing vasculitis were absent. These findings suggest that a direct effect of eosinophilic cationic protein, rather than ischemic damage due to vasculitis, was the main mechanism of transient nerve conduction failure in this patient.

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A 66-year-old woman with a history of bronchial asthma had shortness of breath and fatigue upon mild exercise. She was diagnosed as congestive heart failure. A blood test showed eosinophilia without the presence of anti-neutrophil cytoplasmic antibody (ANCA), and a myocardial biopsy specimen revealed eosinophilic infiltration in the myocardium. Eosinophilia was improved when she was administered short-term methylprednisolone. After that, she had numbness and pain in her lower limbs with re-elevation of eosinophils. She had dysesthesia and hypalgesia in the distal part of the limbs. Sural nerve biopsy revealed axonal degeneration and thickness of the arterial wall, indicating a diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA). Two courses of steroid pulse therapy were performed, resulting in marked improvement of her sensory symptoms. ANCA-negative EGPA might be associated with myocarditis and peripheral neuropathy. A sufficient immunotherapy should have been considered to prevent rapid progression.

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INTRODUCTION: STRIVE was a 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative (JCV-negative) relapsing-remitting multiple sclerosis (RRMS) patients with disease duration ≤ 3 years. The objective of STRIVE was to examine no evidence of disease activity (NEDA) status and predictors of NEDA in natalizumab-treated patients with early RRMS. METHODS: Proportions of patients with NEDA were evaluated along with baseline predictors of NEDA, annualized relapse rate, 24-week confirmed disability worsening (CDW), magnetic resonance imaging assessments (T2 and gadolinium-enhancing lesions), and serious adverse events. RESULTS: In years 1 and 2, 56.1% (95% confidence interval [CI] 48.7-63.4%) and 73.6% (95% CI 66.2-80.2%) of patients (intent-to-treat population [N = 222]), respectively, achieved NEDA. In years 3 and 4, 84.6% (95% CI 78.0-89.9%) and 91.9% (95% CI 86.4-95.8%) of patients, respectively, achieved Clinical NEDA (no relapses or 24-week CDW). Baseline predictors of NEDA in year 4 were Expanded Disability Status Scale score ≤ 2.0 (odds ratio [OR] = 3.85 [95% CI 1.54-9.63]; p = 0.004) and T2 lesion volume > 4 cc (OR = 0.39 [95% CI 0.15-0.98]; p = 0.046), with the latter also predicting Clinical NEDA in year 4 (OR = 0.21 [95% CI 0.05-0.92]; p = 0.038). The cumulative probability of CDW at year 4 was 19.3%. Serious adverse events were reported in 11.3% of patients. CONCLUSION: These results support the long-term safety and effectiveness of natalizumab. Baseline predictors of NEDA help to inform benefit-risk assessments of natalizumab treatment in JCV-negative patients with early RRMS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01485003.

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Atopic dermatitis and bronchial asthma are common diseases in children. We report the development of eosinophilic polyangiitis granulomatosis (EGPA) in a young girl being treated for both atopic dermatitis, diagnosed at 1 year of age, and bronchial asthma, diagnosed at 4 years of age. Her eruption did not result in lichenification and was not fully responsive to corticosteroid ointment. Asthma lightened by treatment of inhalational steroids. Hypereosinophilia was detected at 5 years of age, at least 20% of white blood cells, and 44% at 8 years of age. At 10 years of age, she was diagnosed with anti-neutrophil cytoplasmic antibody-negative EGPA. The diagnosis was based on findings of eosinophil-infiltrating granulomatous vasculitis of the skin accompanied by notable peripheral blood eosinophilia, sinusitis, and pulmonary nodules on radiographic evaluation. Asymptomatic myocardial involvement was also detected utilizing dual perfusion and metabolic scintigraphy with 201Tl/123I-BMIPP, which was relieved by 1-year treatment of glucocorticoid combined with immunosuppressive drugs. EGPA is an extremely rare vasculitis that develops several years after preceding allergic disorders. Pediatric-onset EGPA has a poorer prognosis than adult-onset EGPA, which can be attributed to a high prevalence of cardiac involvement. Therefore, accurate diagnosis is critical for improving prognosis. EGPA should be considered when atypical findings are noted in management of atopic dermatitis and bronchial asthma.

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AIM: Subclinical hypothyroidism is thought to be associated with adverse pregnancy outcomes but the data is conflicting and generally depends on antibody positivity and treatment. We evaluated the pregnancy outcomes in Turkish population with untreated, antibody negative subclinical hypothyroidism for the first time. METHODS: We searched for 30 015 patients between January 2016 and May 2017 retrospectively. Finally, a total of 930 pregnant women with untreated, antibody negative subclinical hypothyroidism and 7986 controls were included. Demographic characteristics, laboratory findings and pregnancy outcomes, including pregnancy loss, impaired glucose tolerance, gestational diabetes, hypertensive disorders of pregnancy, preterm birth, neonatal intensive care unit admission, placenta previa and abruption, cesarean delivery, low birthweight, Apgar score <7 and premature rupture of membranes were recorded. RESULTS: Demographic and laboratory characteristics were similar between two groups except thyroid stimulating hormone levels and previous uterine surgery rates. Subclinical hypothyroidism group had an increased risk of pregnancy loss (odds ratio [OR] 2.583; 95% confidence interval [CI] 1.982-3.365; P < 0.001), impaired glucose tolerance (OR 1.952; 95% CI 1.450-2.627; P < 0.001), hypertensive disorders of pregnancy (OR 1.476; 95% CI 1.113-1.923; P = 0.004), neonatal intensive care unit admission (OR 1.620; 95% CI 1.084-2.420; P = 0.019), placenta previa (OR 12.581; 95% CI 5.046-31.363; P < 0.001) and cesarean delivery (OR 1.263; 95% CI 1.091-1.462; P = 0.002). CONCLUSION: Subclinical hypothyroidism has worse pregnancy outcomes as compared to euthyroid pregnant women even in antibody negativity. Therefore, we suggest that all pregnant women should routinely be screened in their first antenatal visits for thyroid functions.

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