Neuromuscular junction

ANATOMY, PHYSIOLOGY OF NEUROMUSCULAR JUNCTION & ITS DISORDERS ----MAYURI GOLHAR

ANATOMY OF THE NEUROMUSCULAR JUNCTION

MOTOR UNIT: a motor neuron innervates a muscle dividing into many nerve fibers each of which supplies 1 muscle fiber. the combination of motor neuron & the muscle fiber it innervates is a motor unit.

SYNAPSE: is the area on the nerve lying closets to the muscle cell, situated opposite a specialized area of the muscle cell called endplate. The synaptic cleft is only 20nm wide.

MOTOR ENDPLATE: is a small specialized area of the muscle that is rich in Ach receptors. The surface of the muscle at the endplate is deeply folded with many ridges & secondary clefts. The ridges have high concentration of Ach receptors on the crest of their folds. There are 1-10 million receptors at the endplate.

NEUROMUSCULAR JUNCTION ANATOMY

The NMJ consists of prejunctional motar nerve ending separated from a highly folded postjunctional membrane of the skeletal muscle fiber by a synaptic cleft that is 20-30 nm wide & filled with extracellular fluid.

The nonmyelinated nerve endings contains mitochondria,endoplasmic reticulum, and synaptic vesicles necessary to synthesize the neurotransmitter acetylcholine

The resting membrane potential of approx -90 mv across nerve and skeletal muscle membranes is maintained by the unequal distribution of potassium and sodium ions across the membrane.

ANATOMY OF NMJ (CONT..)

The NMJ contains 3 types of nicotinic cholinergic receptors:- 2 are postsynaptic on the skeletal muscle surface, 1 junctional and the other extrajunctional-and one is presynaptic on the nerve ending.

The extrajunctional are not involved in the normal neurotransmission but may proliferate if the skeletal muscle is diseased, damaged, or denervated.

The postsynaptic receptors are concentrated on the junctional folds, immediately opposite the sites on the nerve endings where Ach is released.

ACETYLCHOLINE The neurotransmitter at the NMJ is quaternary

ammonium ester acetylcholine. Ach in motor nerve ending is synthesized by the acetylation of choline under the control of enzyme choline acetylase.

Ach is stored in synaptic vesicles in the motor nerve endings and released into the synaptic clefts as packets (quanta) each of which contain atleast 1000 molecules of Ach.

The amount of acetylcholine released by each nerve impulse is large, at least 200 quanta of about 5000 molecules each, and the number of AChRs activated by transmitter released by a nerve impulse is also large, about 500,000 molecules.

ACETYLCHOLINE

There seem to be two pools of vesicles that release acetylcholine, a readily releasable pool and a reserve pool, sometimes called VP2 and VP1, respectively

Arrival of nerve impulse causes the opening of calcium channels & Ca enters the nerve terminal & there is Ca dependant synchronous release of hundreds of quantas of Ach that bind to nicotinic cholinergic receptors on the postsynaptic membrane causing a change in the membrane permeability to ions.

ACETYLCHOLINE (CONTI..) Ach receptors bind to the pentameric complex & induce

a conformational change in the proteins of the alpha subunits which open the channel & K ion leaks outside whereas Na ion moves inside.

Inside the cell the resting membrane potential is -90mv.Na ions are attracted to the inside of the cell which induces depolerization. Once the threshold of -50mv is reached voltage gated Na channels on the sarcolemma are opened & allow the flow of Na ions into the muscle. This increases the rate of depolerization forming AP that passes around the whole sarcolemma causing muscle contraction.

In the absence of AP, quanta of Ach are released randomly producing miniature endplate potentials of <1mv that are insufficient to trigger depolerization of the skeletal muscle membrane.

NERVE ACTION POTENTIAL Nerve signals are transmitted by action

potentials which are rapid changes in the membrane potential.

STAGES: Resting stage: before the action potential. The

membrane is said to be polerised because of large negative memb potential that is present.

Depolerization stage: the memb becomes permeable to Na ions allowing a large no of positively charged Na ions to flow into the interior of the axon.The normal polerised state of -90mv is lost & potential rises rapidly in the positive direction, this is called depolerisation.

NERVE ACTION POTENTIAL

Repolerization stage: within a few seconds after the membrane has become permeable to Na ions the Na channel begins to close& K channel open more than they normally do. The rapid diffusion of K ions to the exterior re-establishes the normal negative resting membrane potential.

. A, THE ION CHANNEL IS INACTIVE AND DOES NOT OPEN IN THE ABSENCE OF ACETYLCHOLINE. B, EVEN BINDING OF ONE ACETYLCHOLINE MOLECULE (FILLED CIRCLE) TO ONE OF TWO BINDING SITES DOES NOT OPEN THE CHANNEL. C, WHEN ACETYLCHOLINE BINDS TO THE RECOGNITION SITES OF BOTH Α-SUBUNITS SIMULTANEOUSLY (FILLED CIRCLES), A CONFORMATION CHANGE IS TRIGGERED THAT OPENS THE CHANNEL AND ALLOWS IONS TO FLOW ACROSS THE MEMBRANE

ACETYLCHOLINE (CONT..) It is speculated that nerve AP activates adenylate cyclase

in membranes of nerve terminals leading to formation of cyclic adenosine monophosphate (cAMP).cAMP subsequently opens Ca ion channels causing synaptic vesicles to fuse with nerve membrane & release Ach.

Situated in close proximity is enzyme acetylcholinesterase. Acetylcholinesterase at the junction is the asymmetric or A12-form protein made in the muscle, under the end plate. It is a type B carboxylesterase enzyme. There is a smaller concentration of it in the extrajunctional area.

The enzyme is secreted from the muscle but remains attached to it by thin stalks of collagen fastened to the basement membrane This enzyme is responsible for the rapid hydrolysis of Ach in <1ms to acetic acid & choline.

Choline then re-enters motor nerve endings to again participate in the synthesis of new Ach.

POSTJUNCTIONAL NICOTINIC RECEPTORS

Postjunctional membranes contain 2types of receptors- junctional and extrajunctional , nicotinic cholinergic receptors are largely present on the postjunctional membranes.

Postjunctional nicotinic cholinergic receptors are glycoproteins with mol.wt of 25,0000 daltons. Each receptor consists of 5 subunits that are arranged concentrically and designated alpha, beta, gamma ,delta & e.There are 2 alpha subunits and these receptors are concentrated on the shoulders of postjunctional membrane folds which places them precisely opposite prejunctional release sites for Ach.

NICOTINIC RECEPTORS CONT..

Nicotinic cholinergic receptors extend throughout the skeletal muscle membrane and approx 2nm into the cytoplasm. The subunits of the receptor are assembled like barrel staves into cylindrical receptors which has a central funnel shaped core, so as to form a channel to allow the flow of ions along a concentration gradient.

Each NMJ contains millions of postjunctional receptors & a burst of Ach from the nerve ending open atleast 400,000 recptors. As a result sufficient flow through these receptors to depolarize the endplate to create AP.

DIAGRAM

EXTRAJUNCTIONAL & PREJUNCTIONAL CHOLINERGIC RECEPTORS

They are not present in large numbers as their synthesis is supressed by neural activity. Whenever motor nerve are less active due to trauma or denervation they proliferate

The prejunctional receptors differ from the postjunctional nicotinic receptors in 1) chemical binding characteristics 2) the nature of the ion channel they control 3) their preferential blockade during high frequency stimulation.

ACTIONS OF DPMR & NDMR

Classic Actions of Nondepolarizing Muscle Relaxants : Neurotransmission occurs when acetylcholine released by

the nerve action potential binds to AChRs. All NDMRs impair or block neurotransmission by competitively preventing the binding of acetylcholine to its receptor. The final outcome (i.e., block or transmission) depends on the relative concentrations of the chemicals and their comparative affinities for the receptor

Classic Actions of Depolarizing Muscle Relaxants Depolarizing relaxants, at least initially, simulate the

effect of acetylcholine and can therefore be considered agonists despite the fact that they block neurotransmission after initial stimulation. Structurally, succinylcholine is two molecules of acetylcholine bound together. It binds to the receptor , open the channel, pass current, and depolarize the end plate.

NEUROMUSCULAR DISORDERS MYASTHENIA GRAVIS: It is an NM disorder affecting the NMJ & it is

characterized by impaired neuromuscular transmission & muscle weakness.Prevalence is 1/20000-30000. F/M ratio is 6:4. Age: any age Most patients have circulating autoantibodies to the postsynaptic nicotinic Ach receptors. A thymoma is found in approx 10% of patients & hyperplasia of the thymus is found in young patients, although the precise etiology is unknown.

1. Features : weakness on exertion that improves with rest.

2. Ocular, bulbar & facial muscles are commonly involved-ptosis, reduced facial expression,dysarthria & dysphagia.

NMJ- DISORDERS…

Limb weakness, when present is usually proximal, & weakness of the small muscles of the hand may occur.

Myasthenia may be unmasked by anesthesia which may result in hypoventilation or apnoea postop.

Treatment: *oral anticholinesterases-pyridostigmine

*Immunosupression-corticosteriods or azathioprine

*Thymectomy – young onset, Ab positive pt, thymoma.

*Plasmapheresis .

NMJ DISORDERS..

IMPLICATIONS FOR ANESTHESIA: Increased sensitivity to non-depolerizing

muscle relaxants Resistance to depolerizing muscle relaxants Increased sensitivity to neuromuscular

effects of volatile agents Risk of aspiration with bulbar weakness Risk of postop resp failure with resp muscle

wkn Risk of cholinergic crisis with excessive doses

of cholinesterases Effects of immunosupressant therapy.

NMJ DISORDERS… Anaesthesia : the management of anesthesia depends

on severity of disease, type of surgery & need of muscle relaxants. A short acting non-depolerizing muscle relaxant administered in increments or by infusion with careful monitoring of the neuromuscular blockade is advised for patients in whome muscle relaxation is deemed necessary.

Many surgical procedures like thymectomy may be performed without the use of muscle relaxants & this may facilitate early extubation.

Volatile agents specially isoflurane,decrease the availability of Ach at the NMJ & potentiate the effects of non-depolerising muscle relaxants.sevoflurane is rapidly eliminated & is probably the volatile agent of choice.

NMJ- MYASTHENIA GRAVIS CONTI..

Maintenance of anesthesia with propofol has the advantage of avoiding the neuromuscular effects of volatile agents,& in combination with thoracic epidural analgesia has been reported to reduce the requirement of post-op ventilatory support after thymectomy.

Cautious use of other respiratory depressants like opiates is recomended. Non-opiate analgesics & local analgesic should be used wherever possible.Neostigmine should be used cautiously because of its risk of precipitating cholinergic crises .All patients of MG should be monitered closely & some may require ventilatory support post-op.

NMD- MULTIPLE SCLEROSIS..

Multiple Sclerosis Multiple sclerosis (MS) is an autoimmune

disorder characterized by T-cell–mediated autoantibodies against myelin and a subsequent inflammatory response within the central nervous system (CNS: brain and spinal cord). Thus, MS is a disorder of the myelinated part of the axon that leads to secondary nerve conduction failure. The disease affects mainly women, primarily between 20 and 40 or 45 and 60 years of age. Although the etiology is unknown, it has been speculated that MS is caused by environmental factors combined with a genetic predisposition

MULTIPLE SCLEROSIS Patients with MS frequently report paresthesias,

muscle weakness, and sensory disturbances. Typically, there is a localized or, late in the course of disease, generalized muscle weakness with the legs affected more than the arms.

In severe cases, respiration may be involved with the development of hypoxemia. Diplopia and other cranial nerve–dependent impairments are early and frequent signs, along with sensory abnormalities and sometimes disturbed bowel and bladder function.

As a rule, symptoms are closely related to the site affected within the CNS, and the amount of symptoms is related to the extent of sclerosing CNS plaque. Notably, MS can be associated with impaired autonomic function, which may lead to adverse reactions to sympathomimetic drugs.

MULTIPLE SLCEROSIS Diagnosis of MS is currently based on a

combination of clinical and laboratory tests, including cerebrospinal fluid (CSF) antibody analysis and radiology (detection of CNS plaque by magnetic resonance imaging). Medication consists of various combinations of immunosuppression modalities.

ANESTHETIC CONSIDERATIONS. Its speculated that general anesthesia& surgery

may increase the risk for aggravation of MS. Patients should therefore be informed of the potential for aggravated symptoms in the postoperative period. In general, preoperative chronic immunosuppressive medication should be continued during the perioperative period.

MULTIPLE SCLEROSIS Patients with MS are sensitive to physical (pain,

fever, infection) and emotional stress, which makes it more likely that symptoms will be intensified in the perioperative period.

Great care must be exercised to minimize changes in body temperature, fluid homeostasis, and central hemodynamics (preload, afterload) and to maintain respiration. Although intravenous induction agents and volatile anesthetics have been used safely, it is wise to avoid administering depolarizing neuromuscular blocking drugs to MS patients. MS-induced denervation or misuse myopathy may lead to a risk for succinylcholine-induced hyperkalemia, which can result in fatal cardiac arrhythmias

MULTIPLE SCLEROSIS Use of nondepolarizing NM blockers appears to

be safe. Regional anesthesia, including epidural application of low concentrations of local anesthetics, has been used in MS patients. Spinal anesthesia exacerbates symptoms in MS and is therefore not recommended for MS patients by most authorities.

The need for postoperative care is dependent on the preoperative symptoms, type of surgery, and status of the patient at the end of the surgical procedure. In this context, MS patients with severe weakness and respiratory distress, including pharyngeal dysfunction, may need extended postoperative care, such as respiratory support and intense physiotherapy.

MOTOR NEURON DISORDERS

Motor Neuron Disorders Motor neuron disorders involve either the upper

or the lower motor neurons of the cerebral cortex, brainstem, and spinal cord. Some forms are mixed, whereas others have predominately upper or lower motor neuron involvement. Amyotrophic lateral sclerosis (ALS) is the most common disease within this group and involves both upper and lower motor neurons. Other examples of motor neuron disease are Kennedy's disease (spinobulbar muscular atrophy), Friedreich's ataxia (mixed upper and lower motor neurons), and spinal muscular atrophy (lower motor neurons).

MOTOR NEURON DISORDERS ALS is characterized by progressive and

variable loss of motor neurons within the cerebral cortex, medullary nuclei of cranial nerves, and nuclei of the ventral horn in the spinal cord. Degenerative loss of these neurons leads to progressive muscle weakness, muscle atrophy, and loss of neuronal mass in these locations. Sensory functions, including intellectual capacity and cognition, as well as bowel and bladder function, are not usually affected in ALS.

ALS has an incidence of about 2 in 100,000, and onset of the disease is around 40 to 50 years of age, with males affected more than females

MOTOR NEURON DISORDERS Most cases are sporadic, but rare familial forms) do

exist. The underlying mechanism of motor neuronal death are unclear, but it has recently been suggested that superoxide dismutase mutations may have a key role in the increased formation of free radicals seen in subsets of patients.

The diagnosis is made by electrophysiology (electromyography [EMG] and electroneurography) and by neurologic examination, which demonstrates early spastic weakness of the upper and lower extremities, typical subcutaneous muscle fasciculations, and bulbar involvement affecting pharyngeal function, speech, and the facial muscles. No curative treatment is currently available, and patients are therefore treated symptomatically.

MOTOR NEURON DISOREDERS ANESTHETIC CONSIDERATIONS. Bulbar involvement in combination with

respiratory muscle weakness leads to a risk for aspiration & pulmonary complications. Notably, these patients may have increased sensitivity to the respiratory depressant effects of sedatives and hypnotics. Succinylcholine should be avoided because of the risk for hyperkalemia as a result of denervation and immobilization.

Nondepolarizing NM blocking agents may cause prolonged and pronounced NM blockade & hence should be used with great caution.

General anesthesia combined with epidural anesthesia has been used without complications

GUILLAIN BARRE SYNDROME Guillain-Barré syndrome (GBS) is an acute

inflammatory polyneuritis caused by an immunologic reaction.The etiology is unknown, in many cases a timely association with a viral (influenza-like) or bacterial infection or even lymphomatous disease can be demonstrated.

Symmetric peripheral flaccid muscle weakness and sensory loss develop. The lower extremities are affected first, after which the disease progresses to the upper extremities and cranial nerve–innervated muscles in some cases. Importantly, patients may also have autonomic involvement that could lead to sudden fatal cardiac and circulatory collapse

GUILLIAN BARRE SYNDROME

The diagnosis is made after careful neurologic examination, clinical electrophysiology, and CSF analysis.

CSF analysis may show a typical increase in CSF protein in combination with a normal cell count, which is a classic sign of the disease.

Treatment focuses on respiratory support, nutritional support, and early initiation of plasmapheresis.

GUILLIAN BARRE SYNDROME

ANESTHETIC CONSIDERATIONS. Succinylcholine should not be used

because of the risk of hyperkalemia. Nondepolarizing muscle relaxants are not contraindicated but should be avoided as a result of the increased sensitivity and risk for prolonged muscle weakness in the postoperative period. The risk for autonomic dysfunction, respiratory failure, and aspiration may require assisted or mechanical ventilation, even in the postoperative period

GUILLIAN BARRE SYNDROME

Great care should be taken to maintain circulatory stability, including adequate cardiac preload and afterload. Careful hemodynamic monitoring is therefore essential in these patients.

General anesthesia can be used; however, the combination of general anesthesia and epidural anesthesia is more controversial. Although regional anesthesia is not contraindicated, there are reports of an association between GBS and epidural anesthesia.

DUCHENNE MUSCLE DYSTROPHY

It is the commonest & severest muscular dystrophies. it is a X linked recessive condition that presents in the early childhood with weakness of the lower limbs & pelvic muscles.

Cardiac muscle involvement leads to hypertrophic cardiomyopathy, progressive respiratory weakness leading to respiratory failure. Scoliosis is common.

ANAESTHETIC IMPLICATIONS: Abnormal metabolic responses to

suxamethonium & volatile agents may lead to clinical syndrome of rhabdomyolysis & hypermetabolism

DUCHNENNE MUSCLE DYSTROPHY

ANAESTHETIC IMPLICATION: Perioperative cardiac events including

arrhythmias, cardiac failure & cardiac arrest may occur either due to cardiomyopathy or metabolic disturbances, particularly hyperkalemia.

The response to non-depolerizing muscle relaxants is variable, but the duration of action may be prolonged, administration of incremental doses & neuromuscular monitoring is needed.

Respiratory complications is more common late in the disease with an increase in the incidence of postop chest infection & respiratory failure.

MYOTONIC DYSTROPHY Myotonic dystrophy (MD) is an inherited

muscular disorder characterized by progressive muscle weakness. MD is caused by expansion of a CTG trinucleotide repeat in the DMPK gene and is inherited in an autosomal dominant manner.There are two types MD1 & MD2

Typical signs and symptoms include muscle weakness and wasting (most prominent in the cranial and distal limb musculature), periodic myotonia, progressive myopathy, insulin resistance, defects in cardiac conduction, neuropsychiatric impairment, cataracts, testicular atrophy, and frontal balding in males.

MYOTONIC DYSTROPHY

The typical cranial muscle weakness and wasting are manifested not only in the facial, temporalis, masseter, and sternocleidomastoid muscles but also in the vocal cord apparatus. Mitral valve prolapse is found in 20% of patients

During pregnancy, the symptoms may be exacerbated. Uterine atony and retained placenta may also complicate vaginal delivery. First-degree atrioventricular heart block is a common finding on the ECG before the onset of symptoms

MYOTONIC DYSTROPHY

ANESTHETIC IMPLICATION: The majority of complications were found to be

pulmonary related and significantly more frequent in patients undergoing upper abdominal operations.The pulmonary complications of MD are the result of hypotonia, chronic aspiration, and central and peripheral hypoventilation Smooth muscle atrophy, which leads to poor gastric motility, when coupled with a diminished cough reflex, promotes aspiration.

Succinylcholine will produce contractions lasting for several minutes, thus making intubation and ventilation a challenge. These contractions are not antagonized by nondepolarizing muscle relaxants

MYOTONIC DYSTROPHY

Triggering factors, such as hypothermia, shivering, and mechanical or electrical stimulation, may cause a myotonic reaction. Careful titration with relatively short-acting anesthetic agents may be beneficial.

Close cardiac monitoring is required for MD patients. Pacing equipments should be readily available because a third of first-degree atrioventricular blocks may not respond to atropine. All patients should be treated as though they have both cardiomyopathy and conduction defects.

EATON –LAMBERT SYNDROME

Eaton-Lambert myasthenic syndrome (ELMS) is an immune-mediated channelopathy caused by decreased release of acetylcholine as a result of autoantibodies against presynaptic voltage-gated calcium channels and other presynaptic elements.

Patients with ELMS have muscle weakness and fatigability, generally of the proximal limb muscles, with the lower extremities affected more often than the extraocular and bulbar muscle groups. The syndrome is frequently part of a paraneoplastic phenomenon, usually combined with small cell lung carcinoma.

EATON-LAMBERT SYNDROME Patients with ELMS are usually worse in the

morning with gradual improvement throughout the day. Improvement of muscle function with exercise is due to the accumulation of presynaptic calcium and subsequent improved release of acetylcholine.

The diagnosis of ELMS is made by careful physical examination combined with clinical electrophysiology showing the typical facilitation with high-frequency nerve stimulation (30 to 50 Hz). Anticholinesterase treatment has little effect on patients with ELMS. Plasmapheresis, immunoglobulin therapy, and 3,4-diaminopyridine (DAP) result in transient improvement.

EATON-LAMBERT SYNDROME

ANESTHETIC CONSIDERATIONS. As in patients with MG, those with ELMS

should be carefully evaluated for the risk of postoperative respiratory failure and the need for prolonged respiratory monitoring in the postoperative period.

Sensitivity to depolarizing and nondepolarizing neuromuscular blocking agents is usually increased. In patients treated with DAP or an anticholinesterase agent, reversal of neuromuscular blockade may be ineffective.

REFERNCES

Miller Barash Lee’s synopsis

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