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Brain Sciences Nov 2021About 25-35% of United States veterans who fought in the 1990-1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness...
About 25-35% of United States veterans who fought in the 1990-1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness (GWI). Thirty years later, there is little consensus on the causes or biological underpinnings of GWI. The Gulf War Era Cohort and Biorepository (GWECB) was designed to investigate genetic and environmental associations with GWI and consists of 1343 veterans. We investigate candidate gene-toxicant interactions that may be associated with GWI based on prior associations found in human and animal model studies, focusing on SNPs in or near , , and genes to replicate results from prior studies. was also considered as a candidate gene. CDC Severe GWI, the primary outcome, was observed in 26% of the 810 deployed veterans included in this study. The interaction between the candidate SNP rs662 and pyridostigmine bromide (PB) pills was found to be associated with CDC Severe GWI. Interactions between PB pill exposure and rs3917545, rs3917550, and rs2299255, all in high linkage disequilibrium in , were also associated with respiratory symptoms. These SNPs could point toward biological pathways through which GWI may develop, which could lead to biomarkers to detect GWI or to better treatment options for veterans with GWI.
PubMed: 34942860
DOI: 10.3390/brainsci11121558 -
Brain, Behavior, and Immunity Aug 2019Gulf War Illness (GWI) is characterized by a constellation of symptoms that includes cognitive dysfunction. While the causes for GWI remain unknown, prophylactic use of...
Gulf War Illness (GWI) is characterized by a constellation of symptoms that includes cognitive dysfunction. While the causes for GWI remain unknown, prophylactic use of the acetylcholinesterase inhibitor pyridostigmine bromide (PB) in combination with the stress of deployment has been proposed to be among the causes of the cognitive dysfunction in GWI. Mechanistically, clinical studies suggest that altered immune function may be an underlying factor in the neurochemical and neurobehavioral complications of GWI. Accordingly, the goal of this study was to determine how responses to an immune challenge (lipopolysaccharide; LPS) or stress impacts inflammation, acetylcholine (ACh) neurochemistry and behavior in an experimental model of GWI. Rats with a history of PB treatment exhibited potentiated increases in C-reactive protein levels in response to a submaximal LPS challenge compared to control rats, indicating that prior treatment with this cholinesterase inhibitor leads to exacerbated inflammatory responses to a subsequent immune challenge. ACh responses to LPS administration were decreased in the hippocampus, but not prefrontal cortex (PFC), in rats with a prior history of PB treatment or stress exposure. Additionally, ACh release in response to acute immobilization stress was attenuated in the PFC and hippocampus in these groups. These attenuated cholinergic responses were accompanied by impairments in contextual and cue-based fear learning. The results of this study suggest that stress and LPS challenges adversely affect central ACh neurochemistry in a rodent model of GWI and support the hypothesis that dysregulated immune responses are mechanistically linked to the neurological complications of GWI.
Topics: Acetylcholine; Animals; Behavior, Animal; C-Reactive Protein; Cholinesterase Inhibitors; Conditioning, Classical; Disease Models, Animal; Fear; Hippocampus; Inflammation; Lipopolysaccharides; Male; Persian Gulf Syndrome; Prefrontal Cortex; Pyridostigmine Bromide; Rats, Sprague-Dawley; Stress, Psychological
PubMed: 30953774
DOI: 10.1016/j.bbi.2019.04.015 -
Neuropharmacology Jul 2020Gulf War Illness (GWI) is a chronic multi-symptom disorder, characterized by symptoms such as fatigue, pain, cognitive and memory impairment, respiratory, skin and... (Review)
Review
Gulf War Illness (GWI) is a chronic multi-symptom disorder, characterized by symptoms such as fatigue, pain, cognitive and memory impairment, respiratory, skin and gastrointestinal problems, that is experienced by approximately one-third of 1991 Gulf War veterans. Over the nearly three decades since the end of the war, investigators have worked to elucidate the initiating factors and underlying causes of GWI. A significant portion of this research has indicated a strong correlation between GWI and exposure to a number of different acetycholinesterase inhibitors (AChEIs) in theater, such as sarin and cyclosarin nerve agents, chlorpyrifos and dichlorvos pesticides, and the anti-nerve agent prophylactic pyridostigmine bromide. Through studying these exposures and their relationship to the symptoms presented by ill veterans, it has become increasingly apparent that GWI is the likely result of an underlying neuroimmune disorder. While evidence indicates that AChEIs are a key exposure in the development of GWI, particularly organophosphate AChEIs, the mechanism(s) by which these chemicals instigate illness appears to be related to "off-target", non-cholinergic effects. In this review, we will discuss the role of AChEI exposure in the development and persistence of GWI; in particular, how these chemicals, combined with other exposures, have led to a chronic neuroimmune disorder. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.
Topics: Chemical Warfare Agents; Cholinesterase Inhibitors; Encephalitis; Gulf War; Humans; Persian Gulf Syndrome; Veterans
PubMed: 32247728
DOI: 10.1016/j.neuropharm.2020.108073 -
The Journal of International Medical... Jul 2022Myasthenia gravis (MG) is an acquired autoimmune disease. Its clinical manifestations comprise ptosis, diplopia, dysarthria, dysphagia, limb weakness, and in severe... (Review)
Review
Myasthenia gravis (MG) is an acquired autoimmune disease. Its clinical manifestations comprise ptosis, diplopia, dysarthria, dysphagia, limb weakness, and in severe cases, respiratory muscle involvement. Dysarthria as an exclusive initial and primary complaint in MG is rare and seldom reported. In this paper, we report a case of type IIIb MG with isolated dysarthria as the only clinical manifestation and we review the relevant literature. The patient was a 62-year-old man who presented with episodes of slurred speech for 20 days that had worsened in the previous 9 days. His medical history comprised hypertension, diabetes mellitus, and coronary heart disease. The initial diagnosis on admission was transient ischemic attack. Careful re-examination of the patient's history revealed that his symptoms mainly involved increasingly worse slurred speech episodes without drinking or swallowing difficulties, and no significant improvement with rest was observed. Electromyography and autoantibody profiling led to a diagnosis of type IIIb MG. His symptoms improved after the oral administration of pyridostigmine bromide 60 mg. Laryngeal MG is important to differentiate from stroke. It is necessary to perform a computerized voice analysis when encountering patients with atypical symptoms of MG.
Topics: Blepharoptosis; Deglutition Disorders; Dysarthria; Humans; Male; Middle Aged; Myasthenia Gravis; Pyridostigmine Bromide
PubMed: 35915860
DOI: 10.1177/03000605221109395 -
Child's Nervous System : ChNS :... Oct 2022Achondroplasia is the commonest skeletal dysplasia of autosomal dominant inheritance caused by "gain of function" mutations in the fibroblast growth factor receptor 3... (Review)
Review
BACKGROUND
Achondroplasia is the commonest skeletal dysplasia of autosomal dominant inheritance caused by "gain of function" mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum compression due to accelerated ossification and spinal canal stenosis secondary to reduced interpedicular distance is a hallmark of achondroplasia, driven by G380R nucleotide pair substitution. In severe cases, limb weakness and neurogenic claudication will require surgical decompression. Rarely, a neurological condition may mimic the compressive spinal dysfunction and therefore, non-surgical causes must also be considered in cases of acute neurological deterioration in children with achondroplasia. Myasthenia gravis (MG) is an autoimmune condition resulting in fatigable muscle weakness. There are no reported cases of myasthenia gravis in achondroplasia in the literature.
RESULTS
We report a child with achondroplasia scheduled for decompressive surgery for severe lumbar canal stenosis presenting with neurological claudication and knee weakness. While waiting for surgery during the COVID-19 pandemic, she developed generalized fatigability and severe weakness raising concerns of acute worsening of cord compression. Urgent investigations ruled out spinal cord compression but identified an unexpected concurrent myasthenia gravis with positive antibodies to acetylcholine receptors. The surgical intervention was postponed averting the potential risk of life-threatening anaesthetic complications. She was successfully managed with a combination of pyridostigmine, steroids, azathioprine, and plasma exchange.
CONCLUSION
We report the first case of myasthenia gravis in achondroplasia and review implications in the management.
Topics: Achondroplasia; Anesthetics; Azathioprine; COVID-19; Child; Constriction, Pathologic; Female; Humans; Myasthenia Gravis; Nucleotides; Pandemics; Pyridostigmine Bromide; Receptor, Fibroblast Growth Factor, Type 3; Receptors, Cholinergic; Spinal Cord Compression
PubMed: 35908138
DOI: 10.1007/s00381-022-05617-1 -
Brain, Behavior, and Immunity Jul 2020Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of...
Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes. Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HC, n = 8), were examined using integrated [C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n = 13). Whether compared to the whole HC group, or only the HC subgroup, veterans with GWI demonstrated widespread cortical elevations in [C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines. Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.
Topics: Astrocytes; Gulf War; Humans; Persian Gulf Syndrome; Pyridostigmine Bromide; Receptors, GABA; Veterans
PubMed: 32027960
DOI: 10.1016/j.bbi.2020.01.020 -
Neurotoxicology Mar 2020Gulf War Illness (GWI) manifests a multitude of symptoms, including neurological and immunological, and approximately a third of the 1990-1991 Gulf War (GW) veterans...
Gulf War Illness (GWI) manifests a multitude of symptoms, including neurological and immunological, and approximately a third of the 1990-1991 Gulf War (GW) veterans suffer from it. This study sought to characterize the acute neurochemical (monoamine) and neuroinflammatory profiles of two established GWI animal models and examine the potential modulatory effects of the novel immunotherapeutic Lacto-N-fucopentaose III (LNFPIII). In Model 1, male C57BL/6 J mice were treated for 10 days with pyridostigmine bromide (PB) and permethrin (PM). In Model 2, a separate cohort of mice were treated for 14 days with PB and N,N-Diethyl-methylbenzamide (DEET), plus corticosterone (CORT) via drinking water on days 8-14 and diisopropylfluorophosphate (DFP) on day 15. LNFPIII was administered concurrently with GWI chemicals treatments. Brain and spleen monoamines and hippocampal inflammatory marker expression were examined by, respectively, HPLC-ECD and qPCR, 6 h post treatment cessation. Serotonergic (5-HT) and dopaminergic (DA) dyshomeostasis caused by GWI chemicals was apparent in multiple brain regions, primarily in the nucleus accumbens (5-HT) and hippocampus (5-HT, DA) for both models. Splenic levels of 5-HT (both models) and norepinephrine (Model 2) were also disrupted by GWI chemicals. LNFPIII treatment prevented many of the GWI chemicals induced monoamine alterations. Hippocampal inflammatory cytokines were increased in both models, but the magnitude and spread of inflammation was greater in Model 2; LNFPIII was anti-inflammatory, more so in the apparently milder Model 1. Overall, in both models, GWI chemicals led to monoamine disbalance and neuroinflammation. LNFPIII co-treatment prevented many of these disruptions in both models, which is indicative of its promise as a potential GWI therapeutic.
Topics: Amino Sugars; Animals; Biogenic Monoamines; Brain; Brain Chemistry; DEET; Disease Models, Animal; Encephalitis; Humans; Immunotherapy; Male; Mice, Inbred C57BL; Permethrin; Persian Gulf Syndrome; Pesticides; Polysaccharides; Pyridostigmine Bromide; Spleen
PubMed: 31866310
DOI: 10.1016/j.neuro.2019.12.012 -
The Turkish Journal of Pediatrics 2023Myasthenia gravis is a chronic, autoimmune disease with muscle weakness. Acetylcholinesterase inhibitors are used in the symptomatic treatment of the disease. Allergic...
BACKGROUND
Myasthenia gravis is a chronic, autoimmune disease with muscle weakness. Acetylcholinesterase inhibitors are used in the symptomatic treatment of the disease. Allergic reaction to pyridostigmine bromide is rare. In the literature, no allergic reaction to pyridostigmine bromide has been reported in the pediatric population.
CASE
A 12-year-old female patient diagnosed with myasthenia gravis consulted our clinic with the complaint of urticaria due to pyridostigmine bromide. The oral challenge test performed with pyridostigmine bromide was positive. As the patient was required to be continue pyridostigmine bromide with no suitable alternatives, it was decided that the patient had to be desensitized to pyridostigmine. During and after the desensitization protocol, no reaction was observed.
CONCLUSIONS
In this report, a successful desensitization protocol for pyridostigmine bromide in a child with myasthenia gravis is discussed.
Topics: Child; Female; Humans; Pyridostigmine Bromide; Acetylcholinesterase; Myasthenia Gravis; Cholinesterase Inhibitors; Muscle Weakness; Hypersensitivity
PubMed: 37114698
DOI: 10.24953/turkjped.2022.386 -
Journal of Integrative Neuroscience Jun 2020Tolosa-Hunt syndrome is an uncommon disease that exhibits unilateral periorbital pain or headache, accompanied by cranial nerve palsies. Myasthenia gravis is an acquired...
Tolosa-Hunt syndrome is an uncommon disease that exhibits unilateral periorbital pain or headache, accompanied by cranial nerve palsies. Myasthenia gravis is an acquired immune system disease involving the neuromuscular junction. One rare case of Tolosa-Hunt syndrome combined with ocular myasthenia gravis had been reported in the literature, but not general myasthenia gravis. We present a patient with a probable coincidence of Tolosa-Hunt syndrome and general myasthenia gravis. A 63-year-old male exhibited episodes of unilateral headache with double vision, bilateral ptosis, vision decrease in the left eye and left facial hypoesthesia, muscle weakness in limbs and neck. The muscle weakness was fluctuating and could be relieved by rest. Blood analysis, cranial magnetic resonance imaging, magnetic resonance angiography/venogram) and orbit/mediastinum computed tomography demonstrated no abnormalities. Serum myasthenia gravis related antibodies detection showed positive titin- antibodies and ryanodine receptor antibodies. Corticosteroid and pyridostigmine bromide treatments were effective. Each of the patient's symptoms had almost disappeared at the third-month follow-up. We speculate on the etiology of Tolosa-Hunt syndrome with general myasthenia.
Topics: Adrenal Cortex Hormones; Cholinesterase Inhibitors; Humans; Male; Middle Aged; Myasthenia Gravis; Neuroimaging; Tolosa-Hunt Syndrome
PubMed: 32706200
DOI: 10.31083/j.jin.2020.02.1254 -
Neurologia Mar 2023Myasthenia gravis (MG) is an autoimmune disease affecting nerve transmission at the level of the neuromuscular junction, and typically causes fluctuating muscle...
INTRODUCTION
Myasthenia gravis (MG) is an autoimmune disease affecting nerve transmission at the level of the neuromuscular junction, and typically causes fluctuating muscle weakness. Epidemiological studies show an increase in MG prevalence, particularly among the older population.
OBJECTIVE
We performed a retrospective epidemiological study to determine the incidence and prevalence of MG in the province of Ourense (Galicia, Spain), characterised by population ageing.
MATERIAL AND METHODS
Patients were selected from our clinical neuromuscular diseases database by searching for patients with an active prescription for pyridostigmine bromide. Incidence was estimated for the period 2009-2018. We calculated prevalence at 31/12/2018. According to census data for the province of Ourense, the population on 1/1/2019 was 307 651, of whom 96 544 (31.4%) were aged ≥ 65 years.
RESULTS
We identified 80 cases of MG, with a prevalence rate of 260 cases/1 000 000 population (95% CI, 202.7-316.4), rising to 517.9/1 000 000 population in those aged ≥ 65 (95% CI, 363.2-672.9). Cumulative incidence in the study period was 15.4 cases per 1 000 000 person-years. Early onset (≤ 50 years) was recorded in 29.1% of cases.
CONCLUSION
The prevalence of MG in our health district is one of the highest published figures, and the disease is highly prevalent in the older population.
Topics: Humans; Spain; Retrospective Studies; Myasthenia Gravis; Prevalence; Incidence
PubMed: 35249845
DOI: 10.1016/j.nrleng.2020.06.013