Background and purpose
Autoimmune encephalitis (AE) represents a complex syndrome with diverse clinical manifestations and therapeutic outcomes. The aim of this study was to report the clinical ...characteristics and the long‐term outcome of patients with paraneoplastic and idiopathic AE.
Methods
All patients with subacute encephalopathy admitted to the Neurology Department of our Institution from January 2012 to May 2019 were consecutively enrolled. Patients’ serum and cerebrospinal fluid were tested for neural‐specific autoantibodies by indirect immunofluorescence assays on mouse brain, rat neurons, cell‐based assays and immunoblots. Outcome was assessed by the modified Rankin Scale score.
Results
From 107 adult patients with subacute encephalopathy, 50 patients were finally diagnosed with AE. Neural antibodies (Abs) were detected in 45/50 patients (90%). Leucine‐rich glioma‐inactivated protein 1 immunoglobulin G was the most frequent (6/50, 12%) Ab specific to neural surface antigens detected in adults with AE. Paraneoplastic encephalitis was diagnosed in 16/50 patients (32%). The presence of bilateral temporal lobe lesions on magnetic resonance imaging and cerebrospinal fluid restricted oligoclonal bands was associated with a higher probability to detect cancer at the time of AE diagnosis. All patients with Abs to neural surface antigens had a good outcome at last follow‐up. Severe disability at AE onset and the lack of long‐term immunosuppression predicted a poor outcome.
Conclusions
Leucine‐rich glioma‐inactivated protein 1 immunoglobulin G was the most frequent Ab detected. Patients with bilateral temporal lobe lesions and oligoclonal bands have a higher probability to harbour an occult tumour. In these patients, a strict surveillance and monitoring for cancer detection is recommended.
Background and purpose
Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus‐based ...diagnostic criteria (AE‐DC) allow clinic‐serological subgrouping of AE, with unclear prognostic implications. The impact of AE‐DC on patients’ management was studied, focusing on the subgroup of Ab‐negative‐AE.
Methods
This was a retrospective multicenter study on patients fulfilling AE‐DC. All patients underwent Ab testing with commercial cell‐based assays (CBAs) and, when available, in‐house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab‐positive‐AE N‐methyl‐d‐aspartate‐receptor encephalitis (NMDAR‐E), Ab‐positive limbic encephalitis (LE), definite‐AE or Ab‐negative‐AE (Ab‐negative‐LE, probable‐AE, possible‐AE).
Results
Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab‐negative cases, in‐house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE‐DC, 81 (68.6%) with Ab‐positive‐AE (Ab‐positive‐LE, 40; NMDAR‐E, 32; definite‐AE, nine) and 37 (31.4%) with Ab‐negative‐AE (Ab‐negative‐LE, 17; probable/possible‐AE, 20). Clinical phenotypes were similar in Ab‐positive‐LE versus Ab‐negative‐LE. Twenty‐four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab‐positive or Ab‐negative. Ab‐positive‐AE patients were treated earlier than Ab‐negative‐AE patients (P = 0.045), responded more frequently to treatments (92.3% vs. 65.6%, P < 0.001) and received second‐line therapies more often (33.3% vs. 10.8%, P = 0.01). Delays in first‐line therapy initiation were associated with poor response (P = 0.022; odds ratio 1.02; confidence interval 1.00–1.04).
Conclusions
In‐house diagnostics improved Ab detection allowing better patient management but was available in a patient subgroup only, implying possible Ab‐positive‐AE underestimation. Notwithstanding this limitation, our findings suggest that Ab‐negative‐AE and Ab‐positive‐AE patients share similar oncological profiles, warranting appropriate tumor screening. Ab‐negative‐AE patients risk worse responses due to delayed and less aggressive treatments.
Highlights • We adopted a novel methodology using patients’ long-term clinical course as the gold standard for myasthenia gravis (MG) diagnosis. • The sensitivity of SFEMG in diagnosing MG was 98% ...and the specificity was 70%, with a positive predictive value of 79% and a negative predictive value of 97%. • Patients with normal findings at SFEMG are unlikely to be affected by MG.
Type II topoisomerases (TopoIIs) are ubiquitous enzymes that are involved in crucial nuclear processes such as genome organization, chromosome segregation, and other DNA metabolic processes. These ...enzymes function as large, homodimeric complexes that undergo a complex cycle of binding and hydrolysis of two ATP molecules in their ATPase domains, which regulates the capture and passage of one DNA double-helix through a second, cleaved DNA molecule. This process requires the transmission of information about the state of the bound nucleotide over vast ranges in the TopoII complex. How this information is transmitted at the molecular level to regulate TopoII functions and how protein substitutions disrupt these mechanisms remains largely unknown. Here, we employed extensive microsecond-scale molecular dynamics simulations of the yeast TopoII enzyme in multiple nucleotide-bound states and with amino acid substitutions near both the N and C termini of the complex. Simulation results indicate that the ATPase domains are remarkably flexible on the sub-microsecond timescale and that these dynamics are modulated by the identity of the bound nucleotides and both local and distant amino acid substitutions. Network analyses point toward specific allosteric networks that transmit information about the hydrolysis cycle throughout the complex, which include residues in both the protein and the bound DNA molecule. Amino acid substitutions weaken many of these pathways. Together, our results provide molecular level details on how the TopoII catalytic cycle is controlled through nucleotide binding and hydrolysis and how mutations may disrupt this process.
OBJECTIVETo examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG).
METHODSThis ...study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy MGTX). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody–positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18–65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups.
RESULTSPatients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone.
CONCLUSIONSThymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone.
CLINICALTRIALS.GOV IDENTIFIERNCT00294658.
CLASSIFICATION OF EVIDENCEThis study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.
Abstract Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) ...antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed.
In addition to being a master regulator of cell cycle progression, E2F1 regulates other associated biological processes, including growth and malignancy. Here, we uncover a regulatory network linking ...E2F1 to lysosomal trafficking and mTORC1 signaling that involves v-ATPase regulation. By immunofluorescence and time-lapse microscopy we found that E2F1 induces the movement of lysosomes to the cell periphery, and that this process is essential for E2F1-induced mTORC1 activation and repression of autophagy. Gain- and loss-of-function experiments reveal that E2F1 regulates v-ATPase activity and inhibition of v-ATPase activity repressed E2F1-induced lysosomal trafficking and mTORC1 activation. Immunoprecipitation experiments demonstrate that E2F1 induces the recruitment of v-ATPase to lysosomal RagB GTPase, suggesting that E2F1 regulates v-ATPase activity by enhancing the association of V0 and V1 v-ATPase complex. Analysis of v-ATPase subunit expression identified B subunit of V0 complex, ATP6V0B, as a transcriptional target of E2F1. Importantly, ATP6V0B ectopic-expression increased v-ATPase and mTORC1 activity, consistent with ATP6V0B being responsible for mediating the effects of E2F1 on both responses. Our findings on lysosomal trafficking, mTORC1 activation and autophagy suppression suggest that pharmacological intervention at the level of v-ATPase may be an efficacious avenue for the treatment of metastatic processes in tumors overexpressing E2F1.
Background and purpose
The detection of antibodies binding neural antigens in patients with epilepsy has led to the definition of ‘autoimmune epilepsy’. Patients with neural antibodies not responding ...to antiepileptic drugs (AEDs) may benefit from immunotherapy. Aim of this study was to evaluate the frequency of autoantibodies specific to neural antigens in patients with epilepsy and their response to immunotherapy.
Methods
Eighty‐one patients and 75 age‐ and sex‐matched healthy subjects (HS) were enrolled in the study. Two groups of patients were included: 39 patients with epilepsy and other neurological symptoms and/or autoimmune diseases responsive to AEDs (group 1) and 42 patients with AED‐resistant epilepsy (group 2). Patients' serum and cerebrospinal fluid were evaluated for the presence of autoantibodies directed to neural antigens by indirect immunofluorescence on frozen sections of mouse brain, cell‐based assays and a radioimmunoassay. Patients with AED‐resistant epilepsy and neural autoantibodies were treated with immunotherapy and the main outcome measure was the reduction in seizure frequency.
Results
Neural autoantibodies were detected in 22% of patients (18/81), mostly from the AED‐resistant epilepsy group (P = 0.003), but not in HS. Indirect immunofluorescence on mouse brain revealed antibodies binding to unclassified antigens in 10 patients. Twelve patients received immunotherapy and nine (75%) achieved >50% reduction in seizure frequency.
Conclusions
A significant proportion of patients with AED‐resistant epilepsy harbor neural‐specific autoantibodies. The detection of these antibodies, especially of those binding to synaptic antigens, may predict a favorable response to immunotherapy, thus overcoming AED resistance.
To examine the characteristics of thymoma when associated with MG and to evaluate those conditions that can complicate management and affect survival.
The study includes 207 myasthenic patients who ...were operated on for thymoma, with at least 1-year follow-up from surgery. MG severity and response to treatment, the occurrence of paraneoplastic diseases and extrathymic malignancies, thymoma histologic types and stages, adjuvant therapy, tumor recurrences, and causes of death were recorded.
MG-associated thymoma was predominantly of B type and was invasive in the majority of patients. MG was generally severe, and most patients remained dependent on immunosuppressive therapy. Other paraneoplastic disorders and extrathymic malignancies were found in 9.66 and 11.11% of patients. Thymoma recurrences occurred in 18 of 115 patients with invasive tumors (15.65%) and were often associated with the onset/aggravation of autoimmune diseases. On completion of the study, MG and thymoma accounted for a similar mortality rate.
Thymoma should be considered as a potentially malignant tumor requiring prolonged follow-up. The presence of myasthenic weakness can still complicate its management. Thymoma-related deaths are bound to outnumber those due to MG in the future.
PDF
