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Neurology Nov 2020To find determinants of the occurrence of repetitive compound muscle action potential (R-CMAP) and to assess the efficacy of channel blocker therapy in slow-channel...
OBJECTIVE
To find determinants of the occurrence of repetitive compound muscle action potential (R-CMAP) and to assess the efficacy of channel blocker therapy in slow-channel congenital myasthenic syndrome (SCCMS).
METHODS
Neurologic examination, EMG study, laboratory test, muscle biopsy, and next-generation and Sanger sequencing; literature review of reported patients with SCCMS, including EMG, kinetics of mutant acetylcholine receptors (AChRs), and response to therapy; and simulation of the decay phase of endplate potential (EPP) were performed.
RESULTS
Three newly characterized and 57 reported patients with SCCMS with mutations of AChR subunits were included. In patients with R-CMAP, the length of channel opening bursts of mutant AChR was increased 8.68 ± 2.82 (mean ± SD)-fold compared to wild-type; in patients without R-CMAP, the length was increased 3.84 ± 0.65-fold (95% confidence interval 3.18-6.50, = 0.000014). The EPP amplitude after refractory period of action potential in muscle fiber is above the threshold in patients with R-CMAP but below the threshold in patients without R-CMAP. In patients with good results from channel blocker therapy, treatment was initiated 11.60 ± 5.17 years after onset of symptoms; in patients with no to moderate benefit from channel blocker therapy, treatment was initiated 30.70 ± 12.72 years after onset (95% confidence interval -28.57 to -9.63, = 0.00089).
CONCLUSIONS
In SCCMS, the R-CMAP occurrence is related to the extent of prolongation of the opening episodes of mutant AChR channel. Channel blocker treatment is more effective the sooner it is started after the onset of symptoms.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that channel blocker therapy in patients with SCCMS improves symptoms.
Topics: Adult; Cholinesterase Inhibitors; Electromyography; Female; Humans; Membrane Transport Modulators; Middle Aged; Muscle, Skeletal; Myasthenic Syndromes, Congenital; Pedigree; Pyridostigmine Bromide; Receptors, Cholinergic; Young Adult
PubMed: 32907971
DOI: 10.1212/WNL.0000000000010734 -
Neurologia Sep 2020Myasthenia 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.
PubMed: 32900528
DOI: 10.1016/j.nrl.2020.06.011 -
European Journal of Pharmacology Nov 2020Acute intoxication with organophosphorus cholinesterase inhibitors (OPs) can trigger seizures that rapidly progress to life-threatening status epilepticus. Diazepam,...
Acute administration of diazepam or midazolam minimally alters long-term neuropathological effects in the rat brain following acute intoxication with diisopropylfluorophosphate.
Acute intoxication with organophosphorus cholinesterase inhibitors (OPs) can trigger seizures that rapidly progress to life-threatening status epilepticus. Diazepam, long considered the standard of care for treating OP-induced seizures, is being replaced by midazolam. Whether midazolam is more effective than diazepam in mitigating the persistent effects of acute OP intoxication has not been rigorously evaluated. We compared the efficacy of diazepam vs. midazolam in preventing persistent neuropathology in adult male Sprague-Dawley rats acutely intoxicated with the OP diisopropylfluorophosphate (DFP). Subjects were administered pyridostigmine bromide (0.1 mg/kg, i.p.) 30 min prior to injection with DFP (4 mg/kg, s.c.) or vehicle (saline) followed 1 min later by atropine sulfate (2 mg/kg, i.m.) and pralidoxime (25 mg/kg, i.m.), and 40 min later by diazepam (5 mg/kg, i.p.), midazolam (0.73 mg/kg, i.m.), or vehicle. At 3 and 6 months post-exposure, neurodegeneration, reactive astrogliosis, microglial activation, and oxidative stress were assessed in multiple brain regions using quantitative immunohistochemistry. Brain mineralization was evaluated by in vivo micro-computed tomography (micro-CT). Acute DFP intoxication caused persistent neurodegeneration, neuroinflammation, and brain mineralization. Midazolam transiently mitigated neurodegeneration, and both benzodiazepines partially protected against reactive astrogliosis in a brain region-specific manner. Neither benzodiazepine attenuated microglial activation or brain mineralization. These findings indicate that neither benzodiazepine effectively protects against persistent neuropathological changes, and suggest that midazolam is not significantly better than diazepam. Overall, this study highlights the need for improved neuroprotective strategies for treating humans in the event of a chemical emergency involving OPs.
Topics: Animals; Brain Diseases; Cholinesterase Inhibitors; Diazepam; GABA Modulators; Gliosis; Isoflurophate; Male; Microglia; Midazolam; Neurodegenerative Diseases; Neurotoxicity Syndromes; Oxidative Stress; Rats; Rats, Sprague-Dawley; Seizures; X-Ray Microtomography
PubMed: 32898549
DOI: 10.1016/j.ejphar.2020.173538 -
Revista de Neurologia Sep 2020Slow-channel congenital myasthenic syndrome is an autosomal dominant inherited progressive neuromuscular disorder caused by abnormal gating of mutant acetylcholine...
INTRODUCTION
Slow-channel congenital myasthenic syndrome is an autosomal dominant inherited progressive neuromuscular disorder caused by abnormal gating of mutant acetylcholine receptors in the neuromuscular junction. Its pathological hallmark is selective degeneration of the endplate and postsynaptic membrane due to calcium overload. Pyridostigmine should be avoided in this syndrome, being quinidine or fluoxetine the current recommended therapies.
CASE REPORT
An 11-year-old girl with a limb-girdle phenotype of slow-channel congenital myasthenic syndrome presenting with a slowly progressive fatigable weakness at the age of 8 years. After a clinical worsening with pyridostigmine, empirically started before the exome sequencing results were available, a dramatic and sustained response to ephedrine monotherapy was observed. Whole exome sequencing revealed a de novo heterozygous mutation in CHRNB1 gene: c.865G>A; p.Val289Met (NM_000747.2). An abnormal decrement in amplitude (23.9%) from the first to fifth intravollley waveform was revealed after repetitive peroneal nerve stimulation at low frequencies. In addition, a second smaller compound muscle action potential after the peak of the main M-wave in median, ulnar and peroneal motor nerves was observed.
CONCLUSION
Favorable responses to adrenergic agonists added to fluoxetine had been reported. However, to the best of our knowledge this is the first report on effective monotherapy with ephedrine in a slow-channel congenital myasthenic syndrome patient. Adrenergic agonists may be considered as a therapeutic option in patients with this syndrome.
Topics: Alleles; Child; Electromyography; Ephedrine; Female; Heterozygote; Humans; Muscle Weakness; Mutation, Missense; Myasthenic Syndromes, Congenital; Phenotype; Point Mutation; Pyridostigmine Bromide; Receptors, Nicotinic
PubMed: 32895905
DOI: 10.33588/rn.7106.2020265 -
Journal of Occupational and... Sep 2020This analysis examined the relationship between Gulf War (GW) exposures and health symptoms reported in three time periods over 20 years in Ft. Devens Cohort veterans.
OBJECTIVE
This analysis examined the relationship between Gulf War (GW) exposures and health symptoms reported in three time periods over 20 years in Ft. Devens Cohort veterans.
METHODS
Repeated logistic regression models examined the association of exposures and health symptoms over time. Models included baseline age, active duty status, post-traumatic stress disorder status, sex, and time since deployment as covariates.
RESULTS
Exposure to tent heaters was associated with increased odds of crying easily and muscle twitching. Exposure to pyridostigmine bromide (PB) pills was associated with increased odds of depression and fatigue. Exposure to the Khamisiyah sarin plume was associated with increased odds of trouble concentrating and crying easily.
CONCLUSION
This longitudinal analysis demonstrated an association between neurotoxicant exposures and increased odds of cognitive/mood, fatigue, and neurological symptoms. In addition, most symptoms increased over time since deployment regardless of exposure.
Topics: Cohort Studies; Gulf War; Humans; Longitudinal Studies; Neurotoxins; Occupational Exposure; Persian Gulf Syndrome; Pyridostigmine Bromide; Sarin; Veterans
PubMed: 32890202
DOI: 10.1097/JOM.0000000000001910 -
BMC Neurology Aug 2020Myasthenia gravis (MG) is an autoimmune disease caused by antibodies that block or destroy nicotinic acetylcholine receptors at the neuromuscular junction. Most of MG...
BACKGROUND
Myasthenia gravis (MG) is an autoimmune disease caused by antibodies that block or destroy nicotinic acetylcholine receptors at the neuromuscular junction. Most of MG patients need immunosuppression agents in addition to treatments that alleviate the symptoms. Intravenous immunoglobulin (IVIg) and plasma exchange are specific treatments given to patients with severe MG and myasthenia gravis crisis. IVIg therapy can cause an increase in serum viscosity; therefore, the risk for thromboembolic events, such as stroke, myocardial infarction, and pulmonary embolism, are reported after IVIg therapy.
CASE PRESENTATION
An MG patient was treated with pyridostigmine bromide and prednisolone. The patient's symptoms worsened 26 days after the commencement of treatment and was presented with head drop and dyspnea. The patient was diagnosed with MG crisis and IVIg was initiated. However, the patient reported chest pain and dyspnea 3 days after IVIg had started. An electrocardiogram (ECG) revealed ST elevations in leads II, III, and aVF. A cardiac catheterization was performed and stenosis, obstruction, and sclerosis were ruled out. Glyceryl trinitrate relieved the patient's symptoms, suggesting coronary spastic angina (CSA).
CONCLUSIONS
We report the first case of CSA after IVIg. Practitioners should be aware of the potential risks of CSA when administering IVIg for MG patients, in particular in old patients with vascular risk factors.
Topics: Aged, 80 and over; Antibodies; Coronary Vasospasm; Electrocardiography; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Myasthenia Gravis; Prednisolone; Pyridostigmine Bromide; Receptors, Nicotinic
PubMed: 32859168
DOI: 10.1186/s12883-020-01901-2 -
Frontiers in Psychiatry 2020Gulf War Illness is a chronic multisystem disorder affecting approximately a third of the Veterans of the Gulf War, manifesting with physical and mental health symptoms... (Review)
Review
Gulf War Illness is a chronic multisystem disorder affecting approximately a third of the Veterans of the Gulf War, manifesting with physical and mental health symptoms such as cognitive impairment, neurological abnormalities, and dysregulation of mood. Among the leading theories into the etiology of this multisystem disorder is environmental exposure to the various neurotoxins encountered in the Gulf Theatre, including organophosphates, nerve agents, pyridostigmine bromide, smoke from oil well fires, and depleted uranium. The relationship of toxin exposure and the pathogenesis of Gulf War Illness converges on the innate immune system: a nonspecific form of immunity ubiquitous in nature that acts to respond to both exogenous and endogenous insults. Activation of the innate immune system results in inflammation mediated by the release of cytokines. Cytokine mediated neuroinflammation has been demonstrated in a number of psychiatric conditions and may help explain the larger than expected population of Gulf War Veterans afflicted with a mood disorder. Several of the environmental toxins encountered by soldiers during the first Gulf War have been shown to cause upregulation of inflammatory mediators after chronic exposure, even at low levels. This act of inflammatory priming, by which repeated exposure to chronic subthreshold insults elicits robust responses, even after an extended period of latency, is integral in the connection of Gulf War Illness and comorbid mood disorders. Further developing the understanding of the relationship between environmental toxin exposure, innate immune activation, and pathogenesis of disease in the Gulf War Veterans population, may yield novel therapeutic targets, and a greater understanding of disease pathology and subsequently prevention.
PubMed: 32848904
DOI: 10.3389/fpsyt.2020.00704 -
Neuroscience Insights 2020Neurological disorders are commonly reported among veterans who returned from the Gulf war. Veterans who suffer from Gulf War illness (GWI) complain of continued symptom...
Neurological disorders are commonly reported among veterans who returned from the Gulf war. Veterans who suffer from Gulf War illness (GWI) complain of continued symptom persistence that includes neurological disorders, muscle weakness, headaches, and memory loss, that developed during or shortly after the war. Our recent research showed that chemical exposure associated microbial dysbiosis accompanied by a leaky gut connected the pathologies in the intestine, liver, and brain. However, the mechanisms that caused the symptoms to persist even 30 years after the war remained elusive to investigators. In this study, we used a rodent model of GWI to investigate the persistence of microbiome alterations, resultant chronic inflammation, and its effect on neurotrophic and synaptic plasticity marker BDNF. The results showed that exposure to GW chemicals (the pesticide permethrin and prophylactic drug pyridostigmine bromide) resulted in persistent pathology characterized by the low relative abundance of the probiotic bacteria in the gut, which correlated with high circulatory HMGB1 levels, blood-brain barrier dysfunction, neuroinflammation and lowered neurotrophin BDNF levels. Mechanistically, we used mice lacking the NLRP3 gene to investigate this inflammasome's role in observed pathology. These mice had significantly decreased inflammation and a subsequent increase in BDNF in the frontal cortex. This suggests that a persistently low species abundance of and associated chronic inflammation due to inflammasome activation might be playing a significant role in contributing to chronic neurological problems in GWI. A therapeutic approach with various small molecules that can target both the restoration of a healthy microbiome and decreasing inflammasome activation might have better outcomes in treating GWI symptom persistence.
PubMed: 32832901
DOI: 10.1177/2633105520942480 -
The Journal of Pharmacology and... Oct 2020Earlier reports suggested that galantamine, a drug approved to treat mild-to-moderate Alzheimer's disease (AD), and other centrally acting reversible...
Earlier reports suggested that galantamine, a drug approved to treat mild-to-moderate Alzheimer's disease (AD), and other centrally acting reversible acetylcholinesterase (AChE) inhibitors can serve as adjunct pretreatments against poisoning by organophosphorus compounds, including the nerve agent soman. The present study was designed to determine whether pretreatment with a clinically relevant oral dose of galantamine HBr mitigates the acute toxicity of 4.0×LD soman (15.08 µg/kg) in posttreated intramuscularly with the conventional antidotes atropine (0.4 mg/kg), 2-pyridine aldoxime methyl chloride (30 mg/kg), and midazolam (0.32 mg/kg). The pharmacokinetic profile and maximal degree of blood AChE inhibition (∼25%-40%) revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr in these nonhuman primates (NHPs) translate to human-equivalent doses that are within the range used for AD treatment. Subsequent experiments demonstrated that 100% of NHPs pretreated with either dose of galantamine, challenged with soman, and posttreated with conventional antidotes survived 24 hours. By contrast, given the same posttreatments, 0% and 40% of the NHPs pretreated, respectively, with vehicle and pyridostigmine bromide (1.2 mg/kg, oral), a peripherally acting reversible AChE inhibitor approved as pretreatment for military personnel at risk of exposure to soman, survived 24 hours after the challenge. In addition, soman caused extensive neurodegeneration in the hippocampi of saline- or pyridostigmine-pretreated NHPs, but not in the hippocampi of galantamine-pretreated animals. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supralethal doses of soman in NHPs. SIGNIFICANCE STATEMENT: This is the first study to demonstrate that a clinically relevant oral dose of galantamine effectively prevents lethality and neuropathology induced by a supralethal dose of the nerve agent soman in Cynomolgus monkeys posttreated with conventional antidotes. These findings are of major significance for the continued development of galantamine as an adjunct pretreatment against nerve agent poisoning.
Topics: Acetylcholinesterase; Administration, Oral; Animals; Antidotes; Area Under Curve; Chemical Warfare Agents; Galantamine; Hippocampus; Lethal Dose 50; Macaca fascicularis; Male; Organophosphate Poisoning; Soman
PubMed: 32759369
DOI: 10.1124/jpet.120.265843 -
Neuropharmacology Nov 2020Gulf War Illness (GWI) is a chronic multisymptom illness that includes gastrointestinal disorders. Although the exact etiology of GWI is unknown, exposure to the drug...
Pyridostigmine bromide exposure creates chronic, underlying neuroimmune disruption in the gastrointestinal tract and brain that alters responses to palmitoylethanolamide in a mouse model of Gulf War Illness.
Gulf War Illness (GWI) is a chronic multisymptom illness that includes gastrointestinal disorders. Although the exact etiology of GWI is unknown, exposure to the drug pyridostigmine bromide (PB) is considered a major factor. Exposure to PB drives enteric neuroinflammation, promotes immunosuppression, and alters physiological functions of the colon in the short term but whether exposure to PB is sufficient to promote long term dysfunction is not known. Here, we tested whether exposure to PB is sufficient to drive long term changes that reflect GWI, and whether the endogenous anti-inflammatory mediator palmitoylethanolamide (PEA) is sufficient to reduce the detrimental effects of PB in the gut and brain of mice. Exposure to PB alone was not sufficient to cause major changes in neuromuscular transmission but did drive major changes by altering the effects of PEA. Calcium imaging data show that the mechanisms responsible include a shift in receptor signaling mediated by TRPV1, endocannabinoids, and peroxisome proliferator-activated receptors alpha (PPARα). Additional mechanisms include the development of glial reactivity and changes in enteric neurochemical coding and survival. PB and PEA caused major shifts in pro-inflammatory cytokines/chemokines in the brain and colon that persisted up to 5 months following exposure. Many of the effects of PB and PEA exhibit significant sex differences. Together, these results highlight novel mechanisms whereby PB promotes long-lasting changes in nervous system and immune function by inducing occult neuroplasticity that is revealed by subsequent exposure to unrelated drugs in a sex dependent manner.
Topics: Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Cholinesterase Inhibitors; Chronic Disease; Disease Models, Animal; Ethanolamines; Female; Gastrointestinal Tract; Male; Mice; Mice, Inbred C57BL; Neuroimmunomodulation; Palmitic Acids; Persian Gulf Syndrome; Pyridostigmine Bromide
PubMed: 32758565
DOI: 10.1016/j.neuropharm.2020.108264