RESUMEN
: Signal transduction at the neuromuscular junction (NMJ) is affected in many human diseases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert-Eaton myasthenic syndrome, Isaacs' syndrome, Schwartz-Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-density lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and connective tissue growth factor (Ctgf)) that we recently identified in the Wnt/ß-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway.
Asunto(s)
Proteínas Musculares/metabolismo , Fármacos Neuromusculares/metabolismo , Enfermedades de la Unión Neuromuscular/fisiopatología , Unión Neuromuscular/fisiología , Animales , Humanos , Transducción de SeñalRESUMEN
The neuromuscular junction (NMJ) is a specialized structure that works as an interface to translate the action potential of the presynaptic motor neuron (MN) in the contraction of the postsynaptic myofiber. The design of appropriate experimental models is essential to have efficient and reliable approaches to study NMJ development and function, but also to generate conditions that recapitulate distinct features of diseases. Initial studies relied on the use of tissue slices maintained under the same environment and in which single motor axons were difficult to trace. Later, MNs and muscle cells were obtained from primary cultures or differentiation of progenitors and cocultured as monolayers; however, the tissue architecture was lost. Current approaches include self-assembling 3D structures or the incorporation of biomaterials with cells to generate engineered tissues, although the incorporation of Schwann cells remains a challenge. Thus, numerous investigations have established different NMJ models, some of which are quite complex and challenging. Our review summarizes the in vitro models that have emerged in recent years to coculture MNs and skeletal muscle, trying to mimic the healthy and diseased NMJ. We expect our review may serve as a reference for choosing the appropriate experimental model for the required purposes of investigation.
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Potenciales de Acción/fisiología , Neuronas Motoras/fisiología , Enfermedades de la Unión Neuromuscular/fisiopatología , Unión Neuromuscular/fisiología , Unión Neuromuscular/fisiopatología , Células de Schwann/fisiología , Animales , Humanos , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Enfermedades de la Unión Neuromuscular/diagnósticoRESUMEN
The heterozygous deletion of 15q13.3 is a recurrently observed microdeletion syndrome associated with a relatively mild phenotype including learning disability and language impairment. In contrast, the homozygous deletion of 15q13.3 is extremely rare and is associated with a much severer phenotype that includes epileptic encephalopathy, profound intellectual disability, and hypotonia. Which of the genes within the deleted interval is responsible for the more severe features when biallelically deleted is currently unknown. Here, we report a patient with profound hypotonia, severe intellectual disability, and seizures who had biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del, p.(Glu375Aspfs*11). Unexpectedly, both aberrations occurred de novo. Our experiment using Caenorhabditis elegans showed that worms carrying a corresponding homozygous variant in the homolog OTUB-2 exhibited weakened muscle contraction suggestive of aberrant neuromuscular transmission. We concluded that the biallelic complete loss of OTUD7A in humans represents a presumably new autosomal recessive disorder characterized by profound hypotonia, severe intellectual disability, and seizures.
Asunto(s)
Enzimas Desubicuitinizantes/genética , Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Enfermedades de la Unión Neuromuscular/embriología , Animales , Caenorhabditis elegans/genética , Preescolar , Mutación del Sistema de Lectura/genética , Homocigoto , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/fisiopatología , Pérdida de Heterocigocidad/genética , Masculino , Contracción Muscular/genética , Contracción Muscular/fisiología , Hipotonía Muscular/fisiopatología , Enfermedades de la Unión Neuromuscular/complicaciones , Enfermedades de la Unión Neuromuscular/genética , Enfermedades de la Unión Neuromuscular/fisiopatología , Convulsiones/complicaciones , Convulsiones/genética , Convulsiones/fisiopatología , Tioléster Hidrolasas/genéticaRESUMEN
Skeletal muscle channelopathies are rare genetic neuromuscular conditions that include the nondystrophic myotonias and periodic paralyses. They cause disabling muscle symptoms and can limit educational potential, work opportunities, socialization, and quality of life. Effective therapy is available, making it essential to recognize and treat this group of disorders. Here, the authors highlight important aspects regarding diagnosis and management using illustrative case reports.
Asunto(s)
Síndrome de Andersen/diagnóstico , Síndrome de Andersen/genética , Canalopatías/diagnóstico , Canalopatías/genética , Parálisis Periódica Hipopotasémica/diagnóstico , Parálisis Periódica Hipopotasémica/genética , Adolescente , Síndrome de Andersen/fisiopatología , Canalopatías/fisiopatología , Humanos , Parálisis Periódica Hipopotasémica/fisiopatología , Masculino , Músculo Esquelético/fisiopatología , Mutación/genética , Trastornos Miotónicos/diagnóstico , Trastornos Miotónicos/genética , Trastornos Miotónicos/fisiopatología , Enfermedades de la Unión Neuromuscular/diagnóstico , Enfermedades de la Unión Neuromuscular/genética , Enfermedades de la Unión Neuromuscular/fisiopatologíaRESUMEN
Early-onset hypertonia is characteristic of developmental neuromotor disorders, including cerebral palsy (CP). The spa transgenic mouse displays early-onset spasticity, abnormal gait, and motor impairments that are remarkably similar to symptoms of human CP. Previously, we showed that spa mice have fewer motor neurons innervating the tibialis anterior (TA). An expanded innervation ratio may result in increased susceptibility to neuromuscular transmission failure (NMTF). We assessed NMTF in an ex vivo TA muscle nerve preparation from spa and wild-type (WT) mice by comparing forces elicited by nerve versus muscle stimulation. TA muscle innervation ratio was assessed by counting the number of muscle fibers and dividing by the number of TA motor neurons. Muscle fiber cross-sectional areas were also assessed in the TA muscle. We observed that NMTF was immediately present in spa mice, increased with repetitive stimulation, and associated with increased innervation ratio. These changes were concomitant with reduced TA muscle fiber cross-sectional area in spa mice compared with WT. Early-onset hypertonia is associated with increased innervation ratio and impaired neuromuscular transmission. These disturbances may exacerbate the underlying gait abnormalities present in individuals with hypertonia.NEW & NOTEWORTHY Nerve-muscle interaction is poorly understood in the context of early-onset spasticity and hypertonia. In an animal model of early-onset spasticity, spa mice, we found a marked impairment of tibialis anterior neuromuscular transmission. This impairment is associated with an increased innervation ratio (mean number of muscle fibers innervated by a single motor neuron). These disturbances may underlie weakness and gait disturbances observed in individual with developmental hypertonia and spasticity.
Asunto(s)
Neuronas Motoras/fisiología , Hipertonía Muscular/fisiopatología , Músculo Esquelético/inervación , Músculo Esquelético/fisiopatología , Unión Neuromuscular/fisiopatología , Transmisión Sináptica/fisiología , Animales , Parálisis Cerebral/fisiopatología , Modelos Animales de Enfermedad , Femenino , Trastornos Neurológicos de la Marcha/fisiopatología , Masculino , Ratones Noqueados , Fibras Musculares Esqueléticas/fisiología , Enfermedades de la Unión Neuromuscular/fisiopatologíaRESUMEN
A 27 year-old Canadian man suffered from fluctuating muscle weakness in the past several years. The patient had a past history of intestinal bleeding, bifid uvula and hypothyroidism in his childhood. Repetitive nerve stimulation tests showed a decrement pattern in the left deltoid muscle. The single fiber electromyography of the left extensor digitorum muscle showed an increment of jitter. Both findings were improved by the edrophonium test. He was diagnosed as having phosphoglucomutase 1 (PGM1) deficiency, as the compound heterozygote mutation of the PGM1 gene was recognized in the whole-exome sequencing and the enzyme activity of PGM1 was defective in the biopsied muscle. Treatment with the galactose lead to improvement of the fluctuating muscle weakness and decremental pattern in the repetitive stimulation test. PGM1 deficiency should be listed in the differential diagnosis of the neuromuscular junction disorder, when the patient is seronegative for antibodies related with myasthenia gravis and shows symptoms or signs consistent with PGM1 deficiency.
Asunto(s)
Electrofisiología , Enfermedad del Almacenamiento de Glucógeno/complicaciones , Enfermedad del Almacenamiento de Glucógeno/diagnóstico , Debilidad Muscular/etiología , Enfermedades de la Unión Neuromuscular/complicaciones , Enfermedades de la Unión Neuromuscular/diagnóstico , Adulto , Humanos , Masculino , Enfermedades de la Unión Neuromuscular/fisiopatologíaRESUMEN
The neuromuscular junction (NMJ) is a cholinergic synapse where quantal release of acetylcholine (ACh) from motor nerve terminals generates a local endplate potential (EPP) on the muscle fiber. EPPs that reach threshold depolarize the entire muscle fiber and initiate the process of excitation-contraction coupling. Deficits of neuromuscular transmission result in clinical weakness that is fatigable and may fluctuate. Repetitive nerve stimulation (RNS) testing can unmask the reduced safety factor common to all NMJ disorders via depletion of immediate ACh stores at the presynaptic motor nerve terminal with decremental responses to low-frequency RNS (LF-RNS). The facilitated responses characterizing presynaptic NMJ disorders can be revealed by brief exercise or high stimulation rates that augment presynaptic calcium levels. Activation with isometric exercise may increase the sensitivity of RNS testing. Attention to technical detail and reproducibility of findings are essential in generating valid results in RNS testing. Motor unit potential (MUP) instability or jiggle is the main finding seen in NMJ disorders on conventional needle EMG and reflects the moment-to-moment variability in the number and synchrony of muscle fiber action potentials (MFAPs) that compose a MUP. Single fiber EMG (SFEMG) is a highly selective technique that assesses jitter, the temporal variability in MFAPs generated in response to motor nerve action potentials.
Asunto(s)
Enfermedades de la Unión Neuromuscular/diagnóstico , Enfermedades de la Unión Neuromuscular/fisiopatología , HumanosRESUMEN
With resurgence of multidrug resistance (MDR) bacteria and no new novel broad-spectrum antibiotic in research pipeline, usage of older generation antibiotics, once discarded due to their toxicity profile are becoming popular again. Often these drugs are the only option left in managing MDR bacteria-related sepsis. Colistin is one of such antibiotic which is often used in recent times after decades of its avoidance due to its diverse toxicity profile. In this case report, we present a rare myasthenic syndrome like neuromuscular complication developed in a patient after receiving colistin for treatment of MDR Klebsiella-related urosepsis.
Asunto(s)
Antibacterianos/efectos adversos , Colistina/efectos adversos , Fallo Renal Crónico/complicaciones , Infecciones por Klebsiella/tratamiento farmacológico , Debilidad Muscular/inducido químicamente , Enfermedades de la Unión Neuromuscular/inducido químicamente , Unión Neuromuscular/efectos de los fármacos , Infecciones Urinarias/tratamiento farmacológico , Farmacorresistencia Bacteriana Múltiple , Femenino , Humanos , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/terapia , Infecciones por Klebsiella/complicaciones , Infecciones por Klebsiella/diagnóstico , Infecciones por Klebsiella/microbiología , Persona de Mediana Edad , Debilidad Muscular/diagnóstico , Debilidad Muscular/fisiopatología , Debilidad Muscular/terapia , Unión Neuromuscular/fisiopatología , Enfermedades de la Unión Neuromuscular/diagnóstico , Enfermedades de la Unión Neuromuscular/fisiopatología , Enfermedades de la Unión Neuromuscular/terapia , Recuperación de la Función , Síndrome , Resultado del Tratamiento , Infecciones Urinarias/complicaciones , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/microbiologíaRESUMEN
The safety factor of neuromuscular transmission can be assessed by measuring the neuromuscular jitter, which reflects the time variability of processes in the motor end-plate. Jitter is increased in any condition with disturbed end-plate function, such as myasthenic conditions and ongoing reinnervation. Jitter is increasingly being measured with concentric needle (CN) electrodes, which are more prone to artefacts than single fiber EMG recordings. The objective of this review is to identify and demonstrate pitfalls that can be seen with CN jitter measurements, made with both voluntary activation and electrical stimulation. With voluntary activation, errors are caused by poor signal quality; inappropriate time reference points on the signal; an irregular firing rate; and signals with dual latencies, i.e., "flip-flop." With electrical stimulation, additional errors result from insufficient stimulation intensity; from abrupt change in firing rate; and from axon reflexes. Many pitfalls cannot be avoided during recording and can only be detected during post-processing. It is critical to be aware of these artefacts when measuring jitter with CN electrodes.
Asunto(s)
Enfermedades de la Unión Neuromuscular/diagnóstico , Unión Neuromuscular/fisiopatología , Transmisión Sináptica/fisiología , Electrodiagnóstico , Electromiografía , Humanos , Miastenia Gravis/diagnóstico , Miastenia Gravis/fisiopatología , Enfermedades de la Unión Neuromuscular/fisiopatologíaRESUMEN
Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.
Asunto(s)
Laminina/genética , Síndromes Miasténicos Congénitos/genética , Enfermedades de la Unión Neuromuscular/genética , Adulto , Cara/diagnóstico por imagen , Cara/fisiopatología , Femenino , Homocigoto , Humanos , Síndromes Miasténicos Congénitos/complicaciones , Síndromes Miasténicos Congénitos/diagnóstico por imagen , Síndromes Miasténicos Congénitos/fisiopatología , Miopía/complicaciones , Miopía/diagnóstico por imagen , Miopía/genética , Miopía/fisiopatología , Enfermedades de la Unión Neuromuscular/complicaciones , Enfermedades de la Unión Neuromuscular/diagnóstico por imagen , Enfermedades de la Unión Neuromuscular/fisiopatología , Tics/complicaciones , Tics/diagnóstico por imagen , Tics/genética , Tics/fisiopatología , Adulto JovenRESUMEN
Previously, we found that brain-derived neurotrophic factor (BDNF) signaling through the high-affinity tropomyosin-related kinase receptor subtype B (TrkB) enhances neuromuscular transmission in the diaphragm muscle. However, there is an age-related loss of this effect of BDNF/TrkB signaling that may contribute to diaphragm muscle sarcopenia (atrophy and force loss). We hypothesized that chronic treatment with 7,8-dihydroxyflavone (7,8-DHF), a small molecule BDNF analog and TrkB agonist, will mitigate age-related diaphragm neuromuscular transmission failure and sarcopenia in old mice. Adult male TrkBF616A mice (n = 32) were randomized to the following 6-month treatment groups: vehicle-control, 7,8-DHF, and 7,8-DHF and 1NMPP1 (an inhibitor of TrkB kinase activity in TrkBF616A mice) cotreatment, beginning at 18 months of age. At 24 months of age, diaphragm neuromuscular transmission failure, muscle-specific force, and fiber cross-sectional areas were compared across treatment groups. The results did not support our hypothesis in that chronic 7,8-DHF treatment did not improve diaphragm neuromuscular transmission or mitigate diaphragm muscle sarcopenia. Taken together, these results do not exclude a role for BDNF/TrkB signaling in aging-related changes in the diaphragm muscle, but they do not support the use of 7,8-DHF as a therapeutic agent to mitigate age-related neuromuscular dysfunction.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Diafragma/inervación , Flavonas/farmacología , Enfermedades de la Unión Neuromuscular/fisiopatología , Receptor trkB/antagonistas & inhibidores , Envejecimiento/metabolismo , Envejecimiento/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/farmacología , Diafragma/efectos de los fármacos , Diafragma/fisiopatología , Flavonas/administración & dosificación , Flavonas/metabolismo , Masculino , Ratones , Enfermedades de la Unión Neuromuscular/tratamiento farmacológico , Pirazoles/administración & dosificación , Pirazoles/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Receptor trkB/metabolismo , Receptor trkB/farmacología , Sarcopenia/patología , Transducción de SeñalRESUMEN
Diseases of the neuromuscular junction comprise a wide range of disorders. Antibodies, genetic mutations, specific drugs or toxins interfere with the number or function of one of the essential proteins that control signaling between the presynaptic nerve ending and the postsynaptic muscle membrane. Acquired autoimmune disorders of the neuromuscular junction are the most common and are described here. In myasthenia gravis, antibodies to acetylcholine receptors or to proteins involved in receptor clustering, particularly muscle-specific kinase, cause direct loss of acetylcholine receptors or interfere with the agrin-induced acetylcholine receptor clustering necessary for efficient neurotransmission. In the Lambert-Eaton myasthenic syndrome (LEMS), loss of the presynaptic voltage-gated calcium channels results in reduced release of the acetylcholine transmitter. The conditions are generally recognizable clinically and the diagnosis confirmed by serologic testing and electromyography. Screening for thymomas in myasthenia or small cell cancer in LEMS is important. Fortunately, a wide range of symptomatic treatments, immunosuppressive drugs, or other immunomodulating therapies is available. Future research is directed to understanding the pathogenesis, discovering new antigens, and trying to develop disease-specific treatments.
Asunto(s)
Enfermedades de la Unión Neuromuscular , Unión Neuromuscular/patología , Autoanticuerpos/metabolismo , Electromiografía , Humanos , Unión Neuromuscular/fisiopatología , Enfermedades de la Unión Neuromuscular/diagnóstico , Enfermedades de la Unión Neuromuscular/inmunología , Enfermedades de la Unión Neuromuscular/fisiopatología , Receptores Colinérgicos/inmunologíaRESUMEN
Aging is associated with a progressive loss of muscle strength and mass, and a decline in neurophysiologic functions, which are characteristic features of neuromuscular disorders (NMDs). Understanding aging induced neuromuscular junction (NMJ) dysfunction is very crucial to understand the mechanism underlying NMDs. Morphological and physiological changes result in remodelling of the motor unit and a decline in the number of motor neuron muscle fibres. These alterations lead to excitation-contraction uncoupling and a loss of communication between the neuromuscular system, causing a decline in skeletal muscle strength and muscle mass. Understanding the molecular basis of NMJ dysfunction is essential in search for new treatment options. Besides structural and molecular studies, search for animal models to establish connection between brain and muscle is needed. Among various factors it has been observed that stress is one of the leading causes of NMDs. In the present review, we aim to explore various factors linking stress and NMDs neuromuscular disorders which gets aggravated by aging, with a special emphasis on mitochondrial connection. This in turn will help us gain new insights in the treatment of NMDs by aiding in improved symptoms, increased mobility and prolonged life.
Asunto(s)
Fuerza Muscular/fisiología , Enfermedades de la Unión Neuromuscular/fisiopatología , Estrés Oxidativo/fisiología , Humanos , Enfermedades de la Unión Neuromuscular/patología , Estrés MecánicoRESUMEN
BACKGROUND: Pipecuronium is a steroidal neuromuscular blocking agent. Sugammadex, a relaxant binding γ-cyclodextrin derivative, reverses the effect of rocuronium, vecuronium, and pancuronium. We investigated whether sugammadex reverses moderate pipecuronium-induced neuromuscular blockade (NMB) and the doses required to achieve reversal. METHODS: This single-center, randomized, double-blind, 5-group parallel-arm study comprised 50 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX) according to international standards. When the NMB recovered spontaneously to train-of-four count 2, patients randomly received 1.0, 2.0, 3.0, or 4.0 mg/kg of sugammadex or placebo. Recovery time from sugammadex injection to normalized train-of-four (TOF) ratio 0.9 was the primary outcome variable. The recovery time from the sugammadex injection to final T1 was the secondary end point. Postoperative neuromuscular functions were also assessed. RESULTS: Each patient who received sugammadex recovered to a normalized TOF ratio of 0.9 within 5.0 minutes (95% lower confidence interval for the lowest dose 70.1%; for all doses 90.8%) and 79% of these patients reached a normalized TOF ratio 0.9 within 2.0 minutes (95% lower confidence interval for the lowest dose 26.7%; for all doses 63.7%). T1 recovered several minutes after the TOF ratio. No residual postoperative NMB was observed. CONCLUSIONS: Sugammadex adequately and rapidly reverses pipecuronium-induced moderate NMB during sevoflurane anesthesia. Once the train-of-four count has spontaneously returned to 2 responses following pipecuronium administration, a dose of 2.0 mg/kg of sugammadex is sufficient to reverse the NMB.
Asunto(s)
Anestesia General/métodos , Anestésicos por Inhalación , Antídotos/uso terapéutico , Éteres Metílicos , Bloqueo Neuromuscular/métodos , Bloqueantes Neuromusculares/uso terapéutico , Enfermedades de la Unión Neuromuscular/prevención & control , Unión Neuromuscular/efectos de los fármacos , Pipecuronio/uso terapéutico , gamma-Ciclodextrinas/uso terapéutico , Adulto , Anciano , Periodo de Recuperación de la Anestesia , Método Doble Ciego , Femenino , Humanos , Hungría , Masculino , Persona de Mediana Edad , Bloqueo Neuromuscular/efectos adversos , Bloqueantes Neuromusculares/efectos adversos , Unión Neuromuscular/fisiopatología , Enfermedades de la Unión Neuromuscular/inducido químicamente , Enfermedades de la Unión Neuromuscular/diagnóstico , Enfermedades de la Unión Neuromuscular/fisiopatología , Monitoreo Neuromuscular , Pipecuronio/efectos adversos , Recuperación de la Función , Sevoflurano , Sugammadex , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Postoperative residual neuromuscular blockade (NMB), defined as a train-of-four (TOF) ratio of <0.9, is an established risk factor for critical postoperative respiratory events and increased morbidity. At present, little is known about the occurrence of residual NMB in Canada. The RECITE (Residual Curarization and its Incidence at Tracheal Extubation) study was a prospective observational study at 8 hospitals in Canada investigating the incidence and severity of residual NMB. METHODS: Adult patients undergoing open or laparoscopic abdominal surgery expected to last <4 hours, ASA physical status I-III, and scheduled for general anesthesia with at least 1 dose of a nondepolarizing neuromuscular blocking agent for endotracheal intubation or maintenance of neuromuscular relaxation were enrolled in the study. Neuromuscular function was assessed using acceleromyography with the TOF-Watch SX. All reported TOF ratios were normalized to the baseline values. The attending anesthesiologist and all other observers were blinded to the TOF ratio (T4/T1) results. The primary and secondary objectives were to determine the incidence and severity of residual NMB (TOF ratio <0.9) just before tracheal extubation and at arrival at the postanesthesia care unit (PACU). RESULTS: Three hundred and two participants were enrolled. Data were available for 241 patients at tracheal extubation and for 207 patients at PACU arrival. Rocuronium was the NMB agent used in 99% of cases. Neostigmine was used for reversal of NMB in 73.9% and 72.0% of patients with TE and PACU data, respectively. The incidence of residual NMB was 63.5% (95% confidence interval, 57.4%-69.6%) at tracheal extubation and 56.5% (95% confidence interval, 49.8%-63.3%) at arrival at the PACU. In an exploratory analysis, no statistically significant differences were observed in the incidence of residual NMB according to gender, age, body mass index, ASA physical status, type of surgery, or comorbidities (all P > 0.13). CONCLUSIONS: Residual paralysis is common at tracheal extubation and PACU arrival, despite qualitative neuromuscular monitoring and the use of neostigmine. More effective detection and management of NMB is needed to reduce the risks associated with residual NMB.
Asunto(s)
Androstanoles/efectos adversos , Bloqueo Neuromuscular/efectos adversos , Bloqueantes Neuromusculares/efectos adversos , Enfermedades de la Unión Neuromuscular/epidemiología , Unión Neuromuscular/efectos de los fármacos , Parálisis/epidemiología , Abdomen/cirugía , Adulto , Extubación Traqueal , Periodo de Recuperación de la Anestesia , Anestesia General , Antídotos/uso terapéutico , Canadá/epidemiología , Inhibidores de la Colinesterasa/uso terapéutico , Femenino , Humanos , Incidencia , Laparoscopía , Masculino , Persona de Mediana Edad , Neostigmina/uso terapéutico , Unión Neuromuscular/fisiopatología , Enfermedades de la Unión Neuromuscular/inducido químicamente , Enfermedades de la Unión Neuromuscular/diagnóstico , Enfermedades de la Unión Neuromuscular/fisiopatología , Monitoreo Neuromuscular , Parálisis/inducido químicamente , Parálisis/diagnóstico , Parálisis/fisiopatología , Estudios Prospectivos , Factores de Riesgo , Rocuronio , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
The motoneural control of skeletal muscle contraction requires the neuromuscular junction (NMJ), a midmuscle synapse between the motor nerve and myotube. The formation and maintenance of NMJs are orchestrated by the muscle-specific receptor tyrosine kinase (MuSK). Motor neuron-derived agrin activates MuSK via binding to MuSK's coreceptor Lrp4, and genetic defects in agrin underlie a congenital myasthenic syndrome (an NMJ disorder). However, MuSK-dependent postsynaptic differentiation of NMJs occurs in the absence of a motor neuron, indicating a need for nerve/agrin-independent MuSK activation. We previously identified the muscle protein Dok-7 as an essential activator of MuSK. Although NMJ formation requires agrin under physiological conditions, it is dispensable for NMJ formation experimentally in the absence of the neurotransmitter acetylcholine, which inhibits postsynaptic specialization. Thus, it was hypothesized that MuSK needs agrin together with Lrp4 and Dok-7 to achieve sufficient activation to surmount inhibition by acetylcholine. Here, we show that forced expression of Dok-7 in muscle enhanced MuSK activation in mice lacking agrin or Lrp4 and restored midmuscle NMJ formation in agrin-deficient mice, but not in Lrp4-deficient mice, probably due to the loss of Lrp4-dependent presynaptic differentiation. However, these NMJs in agrin-deficient mice rapidly disappeared after birth, and postsynaptic specializations emerged ectopically throughout myotubes whereas exogenous Dok-7-mediated MuSK activation was maintained. These findings demonstrate that the MuSK activator agrin plays another role essential for the postnatal maintenance, but not for embryonic formation, of NMJs and also for the postnatal, but not prenatal, midmuscle localization of postsynaptic specializations, providing physiological and pathophysiological insight into NMJ homeostasis.
Asunto(s)
Agrina/fisiología , Unión Neuromuscular/enzimología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Agrina/deficiencia , Agrina/genética , Empalme Alternativo , Animales , Diafragma/embriología , Diafragma/crecimiento & desarrollo , Activación Enzimática , Femenino , Proteínas Relacionadas con Receptor de LDL , Longevidad/genética , Masculino , Ratones , Ratones Transgénicos , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/fisiología , Proteínas Musculares/deficiencia , Proteínas Musculares/fisiología , Unión Neuromuscular/embriología , Unión Neuromuscular/crecimiento & desarrollo , Enfermedades de la Unión Neuromuscular/enzimología , Enfermedades de la Unión Neuromuscular/genética , Enfermedades de la Unión Neuromuscular/fisiopatología , Fosforilación , Densidad Postsináptica/fisiología , Procesamiento Proteico-Postraduccional , Receptores Colinérgicos/fisiología , Receptores de LDL/deficiencia , Receptores de LDL/fisiología , Proteínas Recombinantes de Fusión/metabolismo , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Miller Fisher syndrome is defined by a triad of symptoms, namely areflexia, ataxia, and ophthalmoparesis. The ophthalmoparesis is mostly severe, undulating weakness of eye movements with ptosis and increased fatigability resembling a neuromuscular transmission disorder. We present a 52-year-old man with severe Miller Fisher syndrome with a high level of anti-GQ1b antibodies and a presynaptic type of neuromuscular transmission disorder. The diagnosis was confirmed by stimulated single-fiber electromyography with the use of a concentric needle electrode and various stimulation rates.
Asunto(s)
Autoanticuerpos/sangre , Electromiografía , Gangliósidos/inmunología , Síndrome de Miller Fisher/diagnóstico , Enfermedades de la Unión Neuromuscular/complicaciones , Ataxia/etiología , Diplopía/etiología , Electromiografía/métodos , Potenciales Evocados Somatosensoriales , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Miller Fisher/complicaciones , Síndrome de Miller Fisher/inmunología , Síndrome de Miller Fisher/fisiopatología , Enfermedades de la Unión Neuromuscular/fisiopatología , Oftalmoplejía/etiología , Reflejo AnormalRESUMEN
Congenital myopathies are a clinically and genetically heterogeneous group of disorders characterized by early onset hypotonia, weakness and characteristic, but not pathognomonic, structural abnormalities in muscle fibres. The clinical features overlap with muscular dystrophies, myofibrillar myopathies, neurogenic conditions and congenital myasthenic syndromes. We describe a case of cap myopathy with myasthenic features due to a mutation in the TPM2 gene that responded to anticholinesterase therapy. We also review other published cases of congenital myopathies with neuromuscular transmission abnormalities. This report expands the spectrum of congenital myopathies with secondary neuromuscular transmission defects. The recognition of these cases is important since these conditions can benefit from treatment with drugs enhancing neuromuscular transmission.
Asunto(s)
Enfermedades de la Unión Neuromuscular/genética , Enfermedades de la Unión Neuromuscular/fisiopatología , Tropomiosina/genética , Adolescente , Inhibidores de la Colinesterasa/uso terapéutico , Humanos , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Mutación , Miopatías Estructurales Congénitas/tratamiento farmacológico , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Miopatías Estructurales Congénitas/fisiopatología , Enfermedades de la Unión Neuromuscular/tratamiento farmacológico , Enfermedades de la Unión Neuromuscular/patologíaRESUMEN
In rodents exposed to 3,3'-iminodipropionitrile (IDPN), neurofilaments (NFs) accumulate in swollen proximal axon segments; this also occurs in motor neurons of patients with amyotrophic lateral sclerosis. We hypothesized that early loss of NFs in neuromuscular junctions (NMJs) in IDPN proximal neuropathy would result in neuromuscular dysfunction and lead to neuromuscular detachment. Adult male rats were given 0 or 15 mmol/L IDPN in drinking water for up to 1 year. The IDPN-exposed rats dragged their tails and had impaired endurance in a grip test. Neuromuscular junctions and distal axons were examined in the levator auris longus muscle after 3, 6, 9, and 12 months. Neuromuscular junctions showed a progressive reduction in NF immunolabeling, which became undetectable in up to 70% of the NMJs after 12 months. Neurofilament labeling was also reduced in preterminal axons and in a more proximal axon level within the muscle. Triple-label analysis with antisyntaxin demonstrated that the terminals remained in place and usually contained a few minute NF bundles. Electron microscopy revealed the disappearance of terminal NFs, reduced content in synaptic vesicles, and accumulation of multilamellar bodies, but scant degeneration. Thus, IDPN proximal neurofilamentous axonopathy is associated with NF depletion in motor terminals; motor weakness and structural changes in the NMJs suggest impaired synaptic function despite long-term preservation of the NMJs.