Tissue-based assay-confirmed, antibody-negative autoimmune encephalitis responsive to low-dose rituximab in an elderly patient

Objective: This study aimed to conduct a comprehensive literature review and meta-analysis of antibody-negative Autoimmune encephalitis (AE) and to quantitatively compare the clinical features of antibody-negative versus antibody-positive AE patients. Methods: Systematic searches of the PubMed, Embase, Web of Science, and Chinese databases (China National Knowledge Infrastructure, Wanfang, and VIP) were conducted up to December 2023. Relevant articles including references and similar documents from retrieved papers, were further screened. Standardized mean differences (SMD) or odds ratios (OR) with 95% confidence intervals (CI) were calculated using fixed-effect or random-effect models for demographic characteristics, clinical manifestations, magnetic resonance imaging (MRI) and electroencephalogram (EEG) abnormalities, and cerebrospinal fluid (CSF) parameters. Subgroup analyses were performed to identify sources of heterogeneity. Results: Six studies (one prospective and five retrospective case-control studies) detailing the clinical features of antibody-negative AE were included in the meta-analysis. Compared to patients with antibody-positive AE, those with antibody- negative AE had a significantly older age at onset (SMD = 0.26, 95% CI: 0.04, 0.49; P = 0.02), a lower incidence of concurrent tumors (OR = 0.57, 95% CI: 0.31, 1.07; P = 0.08), and a lower CSF pleocytosis rate (OR = 0.46, 95% CI: 0.27, 0.79; P = 0.01). No significant differences were observed in sex distribution, clinical manifestations, MRI or EEG abnormality rates, or CSF protein concentrations. Furthermore, subgroup analysis demonstrated a lower prevalence of epileptic seizures among Western populations with antibody-negative AE compared to their Asian counterparts (P = 0.03). Conclusion: This meta-analysis revealed significant differences in age of onset, tumor comorbidity, and CSF pleocytosis rate between patients with antibody-negative and antibody-positive AE, contributing to a more nuanced understanding of antibody-negative AE among clinicians.

Background and Aims Elderly patients with Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) tend to have higher rates of mortality and treatment-related adverse events. Rituximab is now widely used in the treatment of patients with AAV based on the results of remission induction (RITUXVAS and RAVE) and remission maintenance (MAINRITSAN) randomized controlled trials. Elderly patients were relatively under-represented in these trials. In this observational study we aimed to examine the outcome of elderly patients who received Rituximab (either as low dose Rituximab (LDR) or standard dose Rituximab (SDR)) for remission induction and maintenance. Method We investigated the outcome of three treatment strategies in elderly (age>65 years) patients who presented with AAV to our Vasculitis clinic from 1 July 2007 to 9 of July 2017. These strategies included: LDR (17 patients), SDR (14 patients) and Cyclophosphamide/Azathioprine (Cyc/A) 26 patients. LDR patients received two dose of 500mg Rituximab fortnightly followed by six monthly 500mg doses for 2 years. SDR patients received 1g Rituximab fortnightly followed by six monthly 1g doses for 2 years. Cyc/A patients received 1.5mg/kg oral Cyclophosphamide for 3 months followed by 18 months of Azathioprine. Results Among 57 AAV patients, 56% were females and mean age of 79.6 +/- 4 (LDR), 72.4 +/- 7.2 (SDR), and 71.1 +/- 5 (Cyc/A) (p=0.001). The distribution of MPA and GPA was 11/6 in LDR, 7/7 in SDR and 18/8 in Cyc, respectively. Relapsing GPA was significantly higher in SDR 12/2 compared to LDR 3/14, and Cyc/A 0/26 (p=0.0001). There were no significant differences in serum creatinine, BVAS scores or CRP between groups at initiation of treatment. Patients survival at 24 months was 88% (LDR), 92% (SDR), and 77% (Cyc), p=0.3. The mean corticosteroids dose at 3 months from onset of treatment was significantly lower in the LDR (7.6 +/- 1.7) and SDR (8.6 +/- 3.1) compared with Cyc/A (12.5 +/- 3.6), p=0.001. 1 patients relapsed in the SDR group and 4 patients in the Cyc/A group. Hospitalization for infections were significantly lower in the LDR (3 episodes) compared to Cyc/A (17 episodes), p=0.004. The number of patients with hypogammaglobulinemia was not significantly different between LDR and SDR. Conclusion In this single centre observational study, we found that low dose Rituximab for remission induction and maintenance associated with similar patient outcome to SDR. The findings of this study needs to be replicated with longer duration of follow-up.

ObjectiveThis study aimed to compare clinical features, laboratory findings, and immunotherapy responses between antibody-positive and antibody-negative Autoimmune encephalitis (AE) patients.MethodsA retrospective analysis of clinical data from 60 AE patients (33 antibody-positive, 27 antibody-negative) diagnosed at Zhongshan Hospital of Xiamen University between January 1, 2016, and March 1, 2024 was conducted. Disease severity and treatment response were assessed using the modified Rankin Scale (mRS) and the Clinical Assessment Scale for Autoimmune Encephalitis (CASE).ResultsAntibody-positive AE patients more frequently presented with multiple symptoms (≥4 symptoms: 39.4% vs. 14.8%, p = 0.036). They demonstrated significantly elevated serum IgG concentrations (p = 0.010) and cerebrospinal fluid (CSF) leukocyte counts (p = 0.014). Conversely, antibody-negative AE patients presented with higher CSF total protein levels (p = 0.025) and albumin quotients (p = 0.018), indicative of more severe blood–brain barrier disruption. Antibody-positive AE patients more frequently received combination first-line immunotherapy (75.8% vs. 48.1%, p = 0.027) and exhibited superior treatment outcomes (90.9% vs. 70%, p = 0.022). Among critically ill patients (peak mRS score: 4–5), improvement in CASE scores was markedly greater in the antibody-positive cohort (median: 4.50 vs. 1.00, p = 0.024).ConclusionAntibody-positive AE patients manifested a more diverse symptom spectrum, elevated serum IgG concentrations and CSF leukocyte counts, and superior responses to immunotherapy. In contrast, antibody-negative AE patients demonstrated more severe blood–brain barrier dysfunction, as evidenced by higher CSF total protein concentrations and albumin quotients.

Context:Autoimmune encephalitis (AE) is an emerging cause of non-infective encephalitis, presentations of which vary widely. Traditionally the diagnosis of AE is based on detection of antibodies in a patient with clinical picture suggestive of AE.Aim:To evaluate the clinical characteristics and response to immunotherapy in patients with antibody negative autoimmune encephalitis and to compare them with definite cases.Settings and Design:A prospective follow-up study was done in patients presenting with presumptive symptoms of AE from January 2017 to January 2019. The study was done in a tertiary care institute of Northern India.Patients and Methods:Demographic and clinical parameters were noted and relevant investigations for management were done according to well-defined protocol. The patients were treated with immunomodulatory therapy in the form of steroids and/or intravenous immunoglobulins (IVIg). They were followed up for treatment response and relapse at 2 monthly intervals.Statistical Analysis Used:The data was expressed as either proportions or mean/median. Chi-square test/Independent T test was used to compare antibody positive and antibody negative group.Results:Out of 31 patients with presumptive AE, 16 patients tested positive for autoimmune antibodies (definite AE). Incidences of seizure, behavioral abnormalities, dementia and altered sensorium were similar between the 2 groups (p > 0.05). Complete or partial response was seen in all treated patients in both groups with no significant difference (p 0.716). CSF protein concentration and cellularity were higher in the definite group although only high protein concentration could reach statistical significance (p 0.002). Malignancy could be confirmed after extensive search in 2 out of 16 patients with definite AE and in 1 out of 15 antibody negative AE patients.Conclusions:Clinical presentation of antibody negative cases does not differ significantly from definite ones. Since treatment response is also similar in both the groups, starting immunotherapy in a patient presenting with presumptive symptoms of AE, while ruling out other common mimickers, seems to be the need of the hour in the management of this evolving entity.

Purpose To evaluate the value of serum and cerebrospinal fluid (CSF) testing in optic neuropathy (ON) patients with malignant tumors. Methods Fourteen patients clinically diagnosed as ON with malignant tumors but without intracranial or orbital mass in MRI were included in this study. Detailed medical records including medical history, complete ophthalmic examination, colour fundus photography, visual field test, orbital MRI examination, serum and CSF testing data were collected and analyzed. The diagnosis of paraneoplastic optic neuropathy (PON) based on the 2004 recommended criteria of the paraneoplastic syndrome- Euronetwork consortium for paraneoplastic neurological disorders, and current adaption for neuropathies. All patients underwent serum tests for pathogens and autoantibodies including antinuclear antibodies, anticardiolipin antibodies, antineutrophil cytoplasmic antibodies, AQP4-Ab and MOG-Ab, as well as CSF tests for malignant cells under microscope. Serum paraneoplastic antibodies were detected in PON patients. Monkey cerebellar tissue-based assay was used to detect unknown serum anti-neuron antibodies in PON patients with negative paraneoplastic antibody testing results. Results Fourteen ON patients were classified as four groups based on their clinical and MRI characteristics, as well as serum and CSF testing results: [1] definite PON, 6 cases (11 eyes); [2] possible PON, 3 case (5 eyes); [3] meningeal carcinomatosis-associated optic neuropathy (MCON), 4 cases (6 eyes); [4] infiltrative optic neuropathy (ION), 2 cases (2 eyes). Malignant cells were found under microscope in CSF samples from MCON and ION patients, contrast to no malignant cells in CSF samples from PON cases. All 14 ON patients with malignant tumors showed negative results in serum tests for pathogens and autoantibodies. Serum paraneoplastic antibodies were tested in PON patients, anti- CV2, anti-Yo, and anti- amphiphysin were detected positive in 2, 1, and 1 case, respectively, in definite PON group, whereas no serum paraneoplastic antibody detected in possible PON group. Two unknown serum antineuronal antibodies (an anti- Purkinje cell antibody and an anti-granular cell antibody) were detected using monkey cerebellar tissue-based assay in 2 of 5 PON patients with negative paraneoplastic antibody test results. Conclusions Serum and CSF tests are of great importance in differentiating different subtypes of ON with malignant tumors. Current diagnosis of PON still depends on combination of clinical and MRI manifestations, as well as serum and CSF tests. Tissue-based assay may help to detect new biomarkers for ON etiology and diagnosis.

Background Rituximab (RTX) has become the first-line therapy for idiopathic membranous nephropathy (IMN). The safety of low-dose and long-course RTX regimen in elderly patients with IMN remains unknown. Methods Sixty-nine IMN patients with anti-M-phospholipase A2 receptor (PLA2R) antibodies-positive were recruited for this study. The patients were categorized into two groups based on their age. The different age groups were further divided into the recommended RTX group and the low-dose and long-course RTX group. Compare the outcomes and adverse events of patients between different groups after 9-month follow-up. Results There was no significant difference in the complete remission rate and composite remission rate in patients with IMN in different age who received different RTX regimens. As expected, the risk of adverse events was higher in the recommended-dose RTX group compared with the low-dose and long-course RTX group in patients with IMN aged ≥60 years (66.7% vs. 19%, p = .006), and the main adverse event was infection (p = .019). Moreover, we found that different regimens were independent risk factor for infection in patients with IMN aged ≥60 years. Furtherly, ROC curve analysis suggest that in the first month after RTX used, compared with the percentage of CD19+ B lymphocytes, the percentage of eosinophilic granulocytes was more sensitive in predicting the risk of infection in elderly IMN patients (AUC = 0.329 vs. AUC = 0.555). Conclusions The low-dose and long-course RTX regimen should be recommended for elderly patients with IMN, and the percentage of eosinophilic granulocytes is a better risk predictor of infections after RTX used in elderly patients with IMN.

BackgroundAutoimmune nodopathy with anti-contactin-1 (CNTN1) responds well to rituximab instead of traditional therapies. Although a low-dose rituximab regimen was administered to patients with other autoimmune diseases, such as myasthenia gravis and neuromyelitis optica spectrum disorders, and satisfactory outcomes were obtained, this low-dose rituximab regimen has not been trialed in anti-CNTN1-positive patients.MethodsAnti–CNTN1 nodopathy patients were enrolled in this prospective, open-label, self-controlled pilot study. A cell-based assay was used to detect anti-CNTN1 antibodies and their subclasses in both serum and cerebrospinal fluid. Clinical features were evaluated at baseline, 2 days, 14 days, and 6 months after single low-dose rituximab treatment (600 mg). The titers of the subclasses of anti-CNTN1 antibody and peripheral B cells were also evaluated at baseline, 2 days, and 6 months after the rituximab regimen.ResultsTwo patients with anti–CNTN1 antibodies were enrolled. Both patients had neurological symptoms including muscle weakness, tremor, sensory ataxia, numbness and mild nephrotic symptoms. In the field of neurological symptoms, sensory ataxia markedly improved, and the titer of anti-CNTN1 antibody as well as CD19+ B cells decreased only two days following low-dose rituximab treatment. Other neurological symptoms improved within two weeks of rituximab treatment. At the 6-month follow-up, all neurological symptoms steadily improved with steroid reduction, and both the anti-CNTN1 antibody titer and CD19+ B cells steadily decreased. No adverse events were observed after this single low-dose rituximab treatment.ConclusionsWe confirmed the clinical efficacy of low-dose rituximab by B cell depletion in autoimmune nodopathy with anti-CNTN1 antibody. This rapid and long-lasting response suggests that low-dose rituximab is a promising option for anti-CNTN1 nodopathy.

Aim: Idiopathic intracranial hypertension (IIH) is a disease with signs and symptoms of increased intracranial pressure syndrome without a structural lesion in the brain and an abnormal finding in the cerebrospinal fluid (CSF). IIH is associated with obesity and inflammation. In our study, we aimed to evaluate the correlation between neutrophil-lymphocyte ratios (NLR) and body mass index (BMI) and CSF pressure in IIH. Method: Forty-seven patients consisting of 41 (87.2%) women and 6 (12.8%) men who had headache and papilledema, a CSF opening pressure of 25 cmH2O and above, and normal CSF biochemistry and were newly diagnosed with IHH according to the modified Dandy criteria, and 47 age-and gender-matched healthy volunteers consisting of 39 (83%) women and 8 (17%) men were included in the study, and their BMI, white blood cell counts, NLR, CSF pressures and cranial MRI findings were evaluated. RESULTS: The NLR ratio was 2.3952±1.09 in the patient group and 1.9711±0.74 in the control group and was significantly higher in the patient group (p=0.02) (p=0.02). The white blood cell counts were found to be significantly higher with 7.93±1.91 in the patient group and 7.11±1.42 in the control group (p=0.02). BMI was significantly higher with 30.23±2.84 in the patient group and 26.31±3.97 in the control group (p=0.00). Although there was no correlation between NLR and CSF pressure (p=0.58), the cut-off value for NLR was calculated to be 1.95, and a significant correlation was found between the NLR values of 1.95 and above and the CSF pressure (p=0.04). A positive correlation was found between BMI and CSF pressure and NLR ( p=0.001, r= 0.79; p=0.03, r= 0.21). Conclusion: The etiopathogenesis of IIH has not been fully understood, and the existing findings are associated with obesity and related inflammation. Our results indicate that serum NLR level can be used as a marker to show inflammation in IIH and that increased inflammation may be associated with BMI and CSF pressure.

BackgroundFour times of once-weekly doses of 375 mg/m2 rituximab (RTX) are frequently used as remission induction therapy for ANCA-associated vasculitis (AAV). Since this regimen has been basically generated from experience...

Autoimmune central nervous system disorders: Antibody testing and its clinical utility

Polyarteritis nodosa and Churg-Strauss angiitis: characteristics and outcome in 38 patients over 65 years.

Rumination Syndrome in a Patient With Hashimoto's Encephalopathy

PurposeRecently, the role of autoimmune mechanisms in epileptogenesis and intractability has attracted attention. The clinical features of autoimmune encephalitis (AE) vary; thus, diagnosis can be difficult and often delayed. Paraneoplastic neurological syndromes are usually associated with malignant cancers; however, paraneoplastic antibodies (PAs) can be present in the absence of overt cancers. In this single-center, retrospective study, we evaluated the diagnostic significance of PAs in adult Japanese patients with AE.Patients and MethodsWe retrospectively analyzed the medical records of all patients who visited our epilepsy clinic and underwent a thorough diagnostic evaluation for AE between April 2021 and October 2022. Patients who met the criteria for AE and presented to our epilepsy clinic with new-onset seizures or acute or subacute seizure aggravation were included. Data from the PA panel, including anti-amphiphysin (AMPH), CV2, paraneoplastic Ma antigen 2 (PNMA2), Ri, Yo, Hu, recoverin, SRY-related HMG-box gene 1 (SOX1), titin, zic4, glutamate decarboxylase 65 (GAD65), and Tr/DNER antibodies, were evaluated.ResultsOf 32 patients who were investigated, 6 (19.0%; 2 males, age: 38.0 ± 18.0 years) were positive for PAs (anti-AMPH: 1, PNMA2: 1, Yo: 1, recoverin: 2, SOX1: 1). No patients had malignant tumors. Serum anti-SS-A/Ro antibodies were detected in one patient, and the cerebrospinal fluid showed a slightly elevated protein level. Intravenous high-dose methylprednisolone was administered to four patients and was effective in three.ConclusionApproximately one-fifth of AE cases were attributable to PAs, although there were no signs of malignant tumors, in adult epilepsy clinics in Japan.

To explore the safety and efficacy of lower dose of rituximab in the treatment of elderly autoimmune hemolytic anemia (AIHA). From May 2008 to February 2013, a total of 37 patients with newly diagnosed elderly AIHA patients were enrolled in the study, including 25 cases treated with prednisone 1 mg · kg⁻¹ · d⁻¹ for 4 weeks and 12 cases ineligible for glucocorticoid receiving rituximab (100 mg/week for 4 times). Of the 25 patients with conventional glucocorticoid, 5 cases (20.0%) were complete remission (CR), 15 cases with partial remission (PR) and 5 cases without response. The overall response rate was 80.0%. Of the 12 cases with rituximab, 8 cases (66.7%) were CR, 3 cases with PR and 1 without response. The overall response rate was 91.7%. A significantly higher CR rate was seen in lower dose of rituximab, as compared to that in conventional glucocorticoid (P=0.038). A lower dose of rituximab, with satisfactory safety and efficacy, was better than the conventional glucocorticoid in the treatment of elderly AIHA patients.

Autoimmune cerebellar ataxia (ACA) is a cerebellar syndrome induced by autoimmune reactions and its onset is induced by malignant tumors, prodromic infection, and gluten allergy. Its clinical symptoms include gait disorder, limb ataxia, dysarthria, and dysphagia. According to the Chinese Expert Consensus on the Diagnosis and Management of Autoimmune Encephalitis 2024, the diagnosis of ACA is based on the following points: 1. subacute or acute onset of the disease, with cerebellar syndrome as the main manifestation; 2. The cranial magnetic resonance imaging (MRI) in the early stage of the disease (within three months) does not show significant atrophy of the cerebellum and brainstem; 3. presence of either of the following: 1) positive anti-cerebellar antibodies in serum and/or cerebrospinal fluid cell-based assay (CBA), 2) at least two of the following are present: ① the patient or first-degree relative has a history of autoimmune disease, ② cerebrospinal fluid leukocytes >5×106/L, or positive for cerebrospinal fluid specific oligoclonal bands, ③ tissue-based assay (TBA) revealing the characteristic fluorescent form of Purkinje cell antibody, and ④ the presence of systemic autoimmune disease-related antibodies; and 4. the absence of other diseases. Currently, fewer instances of ACA have been associated with positive results for carbonic anhydrase-related protein VIII (CARP VIII). Three case reports have been detected by this antibody in adults with ovarian cancer, breast cancer, or melanoma, and there is no report on this antibody in children. Moreover, neurological diseases associated with mycoplasma pneumoniae infection are increasingly being reported. Therefore, the correlation between this infection and autoimmune encephalitis antibodies needs to be further investigated.