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F1000Research 2022Pulmonary alveolar proteinosis is a very rare diffuse lung disease characterized by the accumulation of amorphous and periodic acid Schiff-positive lipoproteinaceous...
Pulmonary alveolar proteinosis is a very rare diffuse lung disease characterized by the accumulation of amorphous and periodic acid Schiff-positive lipoproteinaceous material in the alveolar spaces due to impaired surfactant clearance by alveolar macrophages. Three main types were identified: Autoimmune, secondary and congenital. Pulmonary alveolar proteinosis has been previously reported to be associated with several systemic auto-immune diseases. Accordingly, we present the first case report of pulmonary alveolar proteinosis associated with myasthenia gravis. A 27-year-old female patient, ex-smoker, developed a dyspnea on exertion in 2020. The chest X-ray detected diffuse symmetric alveolar opacities. Pulmonary infection was ruled out, particularly COVID-19 infection. The chest scan revealed the "crazy paving" pattern. The bronchoalveolar lavage showed a rosy liquid with granular acellular eosinophilic material Periodic acid-Schiff positive. According to the lung biopsy results, she was diagnosed with pulmonary alveolar proteinosis. The granulocyte macrophage colony-stimulating factor autoantibodies were negative. Nine months later, she was diagnosed with bulbar seronegative myasthenia gravis, confirmed with the electroneuromyography with repetitive nerve stimulation showing significant amplitude decrement of the trapezius and spinal muscles. She was treated with pyridostigmine, oral corticosteroids and azathioprine. Given the worsening respiratory condition of the patient, a bilateral whole lung lavage was performed with a partial resolution of symptoms. Thus, this previously unreported association was treated successfully with rituximab, including improvement of dyspnea, diplopia and muscle fatigability at six months of follow-up. This case emphasizes on the possible association of auto-immune disease to PAP, which could worsen the disease course, as the specific treatment does not exist yet. Hence, further studies are needed to establish clear-cut guidelines for PAP management, particularly when associated to auto-immune diseases.
Topics: Humans; Pulmonary Alveolar Proteinosis; Female; Adult; Myasthenia Gravis
PubMed: 38779463
DOI: 10.12688/f1000research.127299.2 -
Neuromuscular Disorders : NMD Jul 2024Patients with myasthenia gravis (MG) can present with respiratory dysfunction, ranging from exercise intolerance to overt respiratory failure, increased fatigue, or...
Patients with myasthenia gravis (MG) can present with respiratory dysfunction, ranging from exercise intolerance to overt respiratory failure, increased fatigue, or sleep-disordered breathing. To investigate the value of multiple respiratory tests in MG, we performed clinical and respiratory assessments in patients with mild to moderate generalized disease. One-hundred and thirty-six patients completed the myasthenia gravis quality-of-life score(MG-QOL-15), myasthenia gravis impairment index(MGII), Epworth sleepiness scale(ESS), University of California-San Diego Shortness of Breath Questionnaire(UCSD-SOB), Modified Medical Research Council Dyspnea Scales(MRC-DS), supine and upright forced vital capacity(FVC), maximal inspiratory pressures(MIPs) and sniff nasal inspiratory pressures(SNIP). Seventy-three (54 %) had respiratory and/or bulbar symptoms and 45 (33 %) had baseline abnormal FVC, with no significant postural changes (p = 0.89); 55 (40.4 %) had abnormal MIPs and 50 (37 %) had abnormal SNIPs. Overall, there were low scores on respiratory and disability scales. Females had increased odds of presenting with abnormal FVC (OR 2.89, p = 0.01) and MIPs (OR 2.48, p = 0.022). There were significant correlations between MIPs, FVC and SNIPs; between MGII/MG-QOL15 and UCSD-SOB/MRC-DS and between ESS and respiratory scales in the whole group. Our data suggests that office-based respiratory measurements are a useful screening method for stable MG patients, even when presenting with minimal respiratory symptoms and no significant disability.
Topics: Humans; Myasthenia Gravis; Female; Male; Middle Aged; Adult; Aged; Quality of Life; Respiratory Function Tests; Vital Capacity; Surveys and Questionnaires
PubMed: 38776756
DOI: 10.1016/j.nmd.2024.05.005 -
The Journal of International Medical... May 2024Autoimmune encephalitis (AIE) is a rapid, progressive neurological disorder characterized by nervous system inflammation. While the Graus criteria are the best known... (Review)
Review
Autoimmune encephalitis (AIE) is a rapid, progressive neurological disorder characterized by nervous system inflammation. While the Graus criteria are the best known criteria for AIE diagnosis, other differential diagnoses meeting the Graus criteria must be considered before management. This narrative review discusses the most common etiologies that resemble AIE. We suggest routine exclusion of mimickers meeting the Graus criteria before confirming an AIE diagnosis. We reviewed 28 studies including 356 patients. The main initial diagnosis was AIE, then paraneoplastic limbic encephalitis and anti-N-methyl-D-aspartate receptor encephalitis. Only 194 patients met the possible Graus criteria. The most frequent conditions among the total population were dementia, other neurodegenerative diseases, and psychiatric and functional neurological disorders. AIE is often misdiagnosed, leading to unnecessary treatment. Despite publication of the Graus criteria, medical cases mimicking this condition are being published. Many neurological diseases entering the differential diagnosis of AIE could be excluded through a detailed history, neurological examination, laboratory analysis, and other investigations, including cerebrospinal fluid and brain magnetic resonance imaging. However, some differential diagnoses complied with the possible Graus criteria, with some having concurrent antineuronal antibodies, which were considered true mimickers. AIE diagnosis suspicion is primarily clinical, but a definitive diagnosis requires various diagnostic tools.
Topics: Humans; Diagnosis, Differential; Encephalitis; Hashimoto Disease; Magnetic Resonance Imaging; Limbic Encephalitis; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Autoantibodies
PubMed: 38775376
DOI: 10.1177/03000605241248050 -
Neurology(R) Neuroimmunology &... Jul 2024A positive allosteric modulator of the NMDAR, SGE-301, has been shown to reverse the alterations caused by the antibodies of patients with anti-NMDAR encephalitis...
OBJECTIVES
A positive allosteric modulator of the NMDAR, SGE-301, has been shown to reverse the alterations caused by the antibodies of patients with anti-NMDAR encephalitis (NMDARe). However, the mechanisms involved beyond receptor modulation are unclear. In this study, we aimed to investigate how this modulator affects NMDAR membrane dynamics.
METHODS
Cultured hippocampal neurons were treated with SGE-301 or vehicle, alongside with immunoglobulins G (IgG) from patients with NMDARe or healthy controls. NMDAR surface dynamics were assessed with single-molecule imaging by photoactivated localization microscopy.
RESULTS
NMDAR trajectories from neurons treated with SGE-301 were less confinement, with increased diffusion coefficients. This effect mainly occurred at synapses because extrasynaptic diffusion and confinement were minimally affected by SGE-301. Treatment with patients' IgG reduced NMDAR surface dynamics and increased their confinement. Remarkably, SGE-301 incubation antagonized patients' IgG effects in both synaptic and extrasynaptic membrane compartments, restoring diffusion and confinement values similar to those from neurons exposed to control IgG.
DISCUSSION
We demonstrate that SGE-301 upregulates NMDAR surface diffusion and antagonizes the pathogenic effects of patients' IgG on NMDAR membrane organization. These findings suggest a potential therapeutic strategy for NMDARe.
Topics: Humans; Hippocampus; Receptors, N-Methyl-D-Aspartate; Animals; Neurons; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Immunoglobulin G; Allosteric Regulation; Cells, Cultured; Autoantibodies; Female; Male; Rats; Adult; Single Molecule Imaging
PubMed: 38771989
DOI: 10.1212/NXI.0000000000200261 -
Journal of Investigative Medicine High... 2024Cutaneous paraneoplastic syndromes due to Hodgkin lymphoma present with a wide spectrum of clinical manifestations from generalized pruritus to exfoliative erythroderma....
Cutaneous paraneoplastic syndromes due to Hodgkin lymphoma present with a wide spectrum of clinical manifestations from generalized pruritus to exfoliative erythroderma. We summarize the clinical findings and outcomes of 14 patients with Hodgkin lymphoma and associated cutaneous paraneoplastic syndromes treated at Mayo Clinic over the past 3 decades. Cutaneous paraneoplastic syndromes may be present at the time of lymphoma diagnosis, whereas in other patients, it may appear at the time of relapse, including patients with initial absence of cutaneous manifestations during the initial lymphoma presentation. Our results indicate that complete resolution of the paraneoplastic syndrome is associated with significantly improved overall survival. Recognition of cutaneous paraneoplastic syndromes is a crucial surrogate of relapsed malignancy and treatment requires targeting the underlying malignancy.
Topics: Humans; Hodgkin Disease; Paraneoplastic Syndromes; Male; Female; Middle Aged; Adult; Aged; Young Adult; Skin Diseases; Adolescent
PubMed: 38767173
DOI: 10.1177/23247096241255840 -
BioRxiv : the Preprint Server For... May 2024Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer....
Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain. We found that patient-derived CV2/CRMP5-Abs can bind to their target in rodent dorsal root ganglia (DRG) and superficial laminae of the spinal cord. CV2/CRMP5-Abs induced DRG neuron hyperexcitability and mechanical hypersensitivity in rats that were abolished by preventing binding to their cognate autoantigen CRMP5. The effect of CV2/CRMP5-Abs on sensory neuron hyperexcitability and mechanical hypersensitivity observed in patients was recapitulated in rats using genetic immunization providing an approach to rapidly identify possible therapeutic choices for treating autoantibody-induced pain including the repurposing of a monoclonal anti-CD20 antibody that selectively deplete B-lymphocytes. These data reveal a previously unknown neuronal mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes resulting directly from CV2/CRMP5-Abs-induced nociceptor excitability. CV2/CRMP5-Abs directly sensitize pain responses by increasing sensory neuron excitability and strategies aiming at either blocking or reducing CV2/CRMP5-Abs can treat pain as a comorbidity in patients with paraneoplastic neurological syndromes.
PubMed: 38766071
DOI: 10.1101/2024.05.04.592533 -
Journal of the Neurological Sciences Jun 2024Myasthenia gravis (MG) with MuSK antibodies (MuSK-MG) represents a distinct subtype with different responses to treatments compared to patients with AChR antibodies,...
BACKGROUND
Myasthenia gravis (MG) with MuSK antibodies (MuSK-MG) represents a distinct subtype with different responses to treatments compared to patients with AChR antibodies, especially in terms of tolerance to acetylcholinesterase inhibitors (AChEI). However, AChEI are often used as first line symptomatic treatment in MuSK-MG, despite reports that they are poorly tolerated, seldom effective or even deleterious.
METHODS
We analyzed demographic, clinical and therapeutic responses and side-effects in the large cohort of 202 MuSK-MG patients cared for at the MG Clinic of Azienda Ospedaliero-Universitaria Pisana.
RESULTS
165 patients had received AChEI at first evaluation. Only 7/165 patients (4.2%) reported an initial clinical benefit. Conversely, 76.9% of patients reported at least one side effect, most commonly neuromuscular hyperexcitability (68.4%), gastrointestinal (53.9%) and neurovegetative (35.8%) disturbances. 56 (33.9%) patients reported a concomitant worsening of muscle weakness and twelve patients (7.3%) suffered a cholinergic crisis. According to these patients, the severity of cholinergic side effects was greater at higher doses of AChEI, but side effects occurred regardless of the dose administered and ceased once the drug was discontinued.
CONCLUSIONS
This is the largest population of MuSK-MG patients reported for perceived responsiveness and tolerance to AChEI treatment. Our obervations strongly suggest avoiding this treatment in MuSK-MG.
Topics: Humans; Myasthenia Gravis; Cholinesterase Inhibitors; Male; Female; Middle Aged; Receptors, Cholinergic; Adult; Receptor Protein-Tyrosine Kinases; Aged; Autoantibodies; Young Adult; Adolescent; Aged, 80 and over; Treatment Outcome; Cohort Studies
PubMed: 38759248
DOI: 10.1016/j.jns.2024.123047 -
Cureus May 2024We present a case of a 76-year-old Caucasian female with a recurrent solitary fibrous tumor (SFT) of the pleura, showcasing a rare manifestation of hypoglycemia...
We present a case of a 76-year-old Caucasian female with a recurrent solitary fibrous tumor (SFT) of the pleura, showcasing a rare manifestation of hypoglycemia associated with Doege-Potter syndrome (DPS). Having undergone two previous surgeries for SFT, the patient presented to the emergency department with severe fatigue, recurrent episodes of loss of consciousness, and hypoglycemia, despite lacking a history of diabetes mellitus. Radiological evaluation revealed a substantial recurrent SFT in the left lung, prompting excision through a left posterolateral thoracotomy. Remarkably, the patient's altered mental status and hypoglycemia resolved postoperatively. The case meets the criteria for aggressive SFT behavior, warranting consideration for adjuvant radiation therapy to control the risk of recurrence. This report highlights the nuanced interplay between SFT recurrence, paraneoplastic syndromes like DPS, and the potential benefits of adjuvant therapeutic strategies in managing these complex clinical scenarios.
PubMed: 38746482
DOI: 10.7759/cureus.60256 -
Frontiers in Immunology 2024Anti-NMDA receptor encephalitis is an autoimmune disorder caused by autoantibodies (abs) against the conformational epitope on GluN1 subunits. GluN1-abs have been...
INTRODUCTION
Anti-NMDA receptor encephalitis is an autoimmune disorder caused by autoantibodies (abs) against the conformational epitope on GluN1 subunits. GluN1-abs have been determined with cell-based assay (CBA) co-expressing GluN1/GluN2 subunits. However, commercial fixed CBA expressing only GluN1 subunit has increasingly been used in clinical practice. The ab titers can be determined with serial dilutions, but its clinical significance remains unclear. We aimed to develop an H-intensity scale (HIS) score to estimate GluN1-ab titers in cerebrospinal fluid (CSF) with one-time immunostaining using both commercial CBA and immunohistochemistry and report its usefulness. "H" is the initial of a patient with high CSF GluN1-ab titers (1:2,048).
METHODS
We first determined the reliability of CBA in 370 patients with suspected autoimmune encephalitis by comparing the results between commercial CBA and established assay in Dalmau's Lab. Then, we made positive control panels using the patient H's CSF diluted in a fourfold serial dilution method (1:2, 1:8, 1:32, 1:128, 1:512, and 1:2,048). Based on the panels, we scored the intensity of ab reactivity of 79 GluN1-ab-positive patients' CSF (diluted at 1:2) on a scale from 0 to 6 (with ≥1 considered positive). To assess inter-assay reliability, we performed immunostaining twice in 21 patients' CSF. We investigated an association between the score of CSF obtained at diagnosis and the clinical/paraclinical features.
RESULTS
The sensitivity and specificity of CBA were 93.7% (95% CI: 86.0-97.3) and 98.6% (95% CI: 96.5-99.5), respectively. Linear regression analysis showed a good agreement between the scores of the first and second assays. Patients with a typical spectrum, need for mechanical ventilation support, autonomic symptoms/central hypoventilation, dyskinesias, speech dysfunction, decreased level of consciousness, preceding headache, ovarian teratoma, and CSF leukocyte count >20 cells/µL had a higher median HIS score than those without, but HIS score was not associated with sex, age at onset, or seizure. HIS score at diagnosis had a significant effect on 1-year functional status.
DISCUSSION
The severity of disease and four of the six core symptoms were associated with higher GluN1-ab titers in CSF at diagnosis, which may play a role in poor 1-year functional status. An incomplete phenotype can be attributed to low CSF GluN1-ab titers.
Topics: Humans; Female; Autoantibodies; Middle Aged; Adult; Male; Receptors, N-Methyl-D-Aspartate; Aged; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Young Adult; Adolescent; Child; Immunohistochemistry; Child, Preschool; Nerve Tissue Proteins; Reproducibility of Results; Biomarkers; Aged, 80 and over
PubMed: 38745654
DOI: 10.3389/fimmu.2024.1350837 -
Cell Communication and Signaling : CCS May 2024The pathway involving PTEN-induced putative kinase 1 (PINK1) and PARKIN plays a crucial role in mitophagy, a process activated by artesunate (ART). We propose that...
BACKGROUND
The pathway involving PTEN-induced putative kinase 1 (PINK1) and PARKIN plays a crucial role in mitophagy, a process activated by artesunate (ART). We propose that patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis exhibit insufficient mitophagy, and ART enhances mitophagy via the PINK1/PARKIN pathway, thereby providing neuroprotection.
METHODS
Adult female mice aged 8-10 weeks were selected to create a passive transfer model of anti-NMDAR encephalitis. We conducted behavioral tests on these mice within a set timeframe. Techniques such as immunohistochemistry, immunofluorescence, and western blotting were employed to assess markers including PINK1, PARKIN, LC3B, p62, caspase3, and cleaved caspase3. The TUNEL assay was utilized to detect neuronal apoptosis, while transmission electron microscopy (TEM) was used to examine mitochondrial autophagosomes. Primary hippocampal neurons were cultured, treated, and then analyzed through immunofluorescence for mtDNA, mtROS, TMRM.
RESULTS
In comparison to the control group, mitophagy levels in the experimental group were not significantly altered, yet there was a notable increase in apoptotic neurons. Furthermore, markers indicative of mitochondrial leakage and damage were found to be elevated in the experimental group compared to the control group, but these markers showed improvement following ART treatment. ART was effective in activating the PINK1/PARKIN pathway, enhancing mitophagy, and diminishing neuronal apoptosis. Behavioral assessments revealed that ART ameliorated symptoms in mice with anti-NMDAR encephalitis in the passive transfer model (PTM). The knockdown of PINK1 led to a reduction in mitophagy levels, and subsequent ART intervention did not alleviate symptoms in the anti-NMDAR encephalitis PTM mice, indicating that ART's therapeutic efficacy is mediated through the activation of the PINK1/PARKIN pathway.
CONCLUSIONS
At the onset of anti-NMDAR encephalitis, mitochondrial damage is observed; however, this damage is mitigated by the activation of mitophagy via the PINK1/PARKIN pathway. This regulatory feedback mechanism facilitates the removal of damaged mitochondria, prevents neuronal apoptosis, and consequently safeguards neural tissue. ART activates the PINK1/PARKIN pathway to enhance mitophagy, thereby exerting neuroprotective effects and may achieve therapeutic goals in treating anti-NMDAR encephalitis.
Topics: Animals; Artesunate; Mice; Female; Neuroprotective Agents; Disease Models, Animal; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Protein Kinases; Neurons; Microscopy, Electron, Transmission; Mitophagy; Apoptosis; Ubiquitin-Protein Ligases; Mitochondria; Hippocampus
PubMed: 38745240
DOI: 10.1186/s12964-024-01652-4