I am going to be talking with you today about synaptic transmission. Since, this is a topic that involves many areas in neuroscience, and could easily be made into a semester length course, I am just going to give you a survey of what is involved in synaptic transmission. In later courses, you will go into much greater detail on each topic I discuss today. So, what is synaptic transmission and what does it entail? Well, simply put, it is the method by which neurons communicate with one another. In order for any movement, sensation, thought, or emotion to occur, many neurons have to relay and integrate messages to one another. This involves many processes both on the electrophysiological and molecular levels. If you have any questions along the way, please do not hesitate to ask. I do not mind being interrupted. If you would like background reference information to this lecture please read Part 2 of Principles of Neural Science (Kandel & Schwartz).
Cns Mg Davidson 07.
Dr.Mohammad Shaikhani DISORDERS OF THE NEUROMUSCULAR JUNCTION MYASTHENIA GRAVIS
Definition: <ul><li>Progressive fatigable weakness, particularly of the ocular, neck, facial & bulbar muscles. </li></ul>
Aetiology / pathology: <ul><li>Most commonly caused by autoantibodies to Ach receptors in the post-junctional membrane of NMJ. </li></ul><ul><li>These antibodies block neuromuscular transmission & initiate a complement-mediated inflammatory response which reduces the number of Ach receptors & damages the end plate. </li></ul><ul><li>A minority have other auto Abs to other epitopes, sp to a muscle-specific kinase (MuSK), an agrin receptor involved in the regulation /maintenance of the Ach receptors. </li></ul><ul><li>15% (mainly late onset) have a thymoma&the majority of the remainder have thymic follicular hyperplasia. </li></ul><ul><li>Increased incidence of other autoimmune diseases&it is linked with certain HLA haplotypes. </li></ul><ul><li>Penicillamine causes an Ab-mediated myasthenic syndrome & aminoglycosides /ciprofloxacin exacerbate it &all avoided. </li></ul>
Clinical features <ul><li>Usually presents between 15-50 years. </li></ul><ul><li>Women affected > men in younger ages &reverse at older ages. </li></ul><ul><li>It has relapsing / remitting course, esp during the early years. </li></ul><ul><li>The cardinal symptom is abnormal fatigable weakness of the muscles (different from a sensation of muscle fatigue); movement is initially strong but rapidly weakens. </li></ul><ul><li>Worsening towards the end of the day or following exercise is characteristic. </li></ul><ul><li>There are no sensory signs or signs of CNS involvement, although weakness of the oculomotor muscles may mimic a central eye movement disorder. </li></ul><ul><li>The first symptoms are usually intermittent ptosis or diplopia, but weakness of chewing, swallowing, speaking or limb movement also occurs. </li></ul>
Clinical features <ul><li>Any limb muscle may be affected, most commonly those of the shoulder girdle; unable to undertake tasks above shoulder level, as combing the hair, without frequent rests. </li></ul><ul><li>Respiratory muscles may be involved& respiratory failure is a not uncommon cause of death & may be the first presentation, in which case the diagnosis is difficult if not thought of. </li></ul><ul><li>Aspiration may occur if the cough is ineffectual. </li></ul><ul><li>Sudden weakness from a cholinergic or myasthenic crisis may require ventilatory support. </li></ul>
Investigations <ul><li>Tensilon test: IV short-acting anticholinesterase, edrophonium bromide, is a valuable diagnostic aid; 2 mg initially, with a further 8 mg given half a minute later if there are no undesirable side-effects. Improvement in muscle power occurs within 30 seconds & usually persists for 2-3 minutes. </li></ul><ul><li>Ice pack test: is simple & less risky than tensilon test with improvement in ptosis in 2 mins. </li></ul><ul><li>EMG with repetitive stimulation may show the characteristic decremental response. </li></ul><ul><li>Anti-acetylcholine receptor antibody (AChRA) is found in > 80%, < in purely ocular myasthenia (50%). </li></ul><ul><li>Anti-MuSK antibodies are found especially in AChRA-negative patients with prominent bulbar involvement. </li></ul><ul><li>Positive anti-skeletal muscle antibodies suggest the presence of thymoma, but all patients should have a thoracic CT to exclude this condition, which may not be visible on plain X-ray. </li></ul><ul><li>Screening for other autoimmune disorders, particularly thyroid disease, is important. </li></ul>
Management <ul><li>The principles of treatment are: </li></ul><ul><li>1.Maximise the activity of acetylcholine at remaining receptors in the neuromuscular junctions </li></ul><ul><li>2.Limit or abolish the immunological attack on motor end plates. </li></ul>
Management : 1.Ach estrase inhibs <ul><li>The duration of action of acetylcholine is greatly prolonged by inhibiting its hydrolysing enzyme, acetylcholinesterase. </li></ul><ul><li>The most commonly used anticholinesterase drug is pyridostigmine, orally 30-120 mg, usually 6-hourly. </li></ul><ul><li>Muscarinic side-effects, including diarrhoea/ colic, controlled by propantheline (15 mg as required). </li></ul><ul><li>Over-dosage of anticholinesterases may cause a cholinergic crisis due to depolarisation block of motor end plates, with muscle fasciculation, paralysis, pallor, sweating, excessive salivation & small pupils, distinguished from severe weakness due to exacerbation of myasthenia (myasthenic crisis) by the clinical features & if necessary, by the injection of a small dose of edrophonium. </li></ul>
Management: 2. IMMUNOLOGICAL Trt <ul><li>Thymectomy </li></ul><ul><li>in early stages leads to a much better overall prognosis, whether a thymoma is present or not. </li></ul><ul><li>Should be performed as soon as feasible in any antibody-positive patient < 45 years with symptoms not confined to extraocular muscles, unless the disease established for > 7 years. </li></ul><ul><li>Plasma exchange </li></ul><ul><li>Removing antibody from the blood may produce marked improvement but, usually brief, so normally reserved for myasthenic crisis or for pre-operative preparation </li></ul><ul><li>IV immunoglobulin </li></ul><ul><li>An alternative to plasma exchange in severe myasthenia </li></ul><ul><li>Corticosteroid treatment </li></ul><ul><li>Improvement is commonly preceded by marked exacerbation of myasthenic symptoms So should be initiated in hospital </li></ul><ul><li>It is usually necessary to continue treatment for months or years, often resulting in adverse effects </li></ul><ul><li>Other immunosuppressant treatment </li></ul><ul><li>Azathioprine 2.5 mg/kg can reduce the dosage of steroids necessary & may allow steroids to be withdrawn. </li></ul><ul><li>The effect on clinical disease is often delayed for several months </li></ul>
Prognosis <ul><li>Variable. </li></ul><ul><li>Remissions sometimes occur spontaneously. </li></ul><ul><li>When myasthenia is confined to the eye muscles, the prognosis is excellent & disability slight. </li></ul><ul><li>Young female patients with generalised disease have high remission rates after thymectomy, whilst older patients are less likely to have a remission despite treatment. </li></ul><ul><li>Rapid progression of the disease > 5 years after its onset is uncommon. </li></ul>
OTHER MYASTHENIC SYNDROMES <ul><li>Other conditions present with muscle weakness due to impaired transmission across NMJ. </li></ul><ul><li>The most common is the Lambert-Eaton myasthenic syndrome (LEMS), in which transmitter release is impaired, often in association with antibodies to pre-junctional voltage-gated calcium channels. </li></ul><ul><li>Patients may have autonomic dysfunction (& dry mouth) in addition to muscle weakness, but the cardinal clinical sign is absence of tendon reflexes, which can return immediately after sustained contraction of the relevant muscle. </li></ul><ul><li>The condition is associated with underlying malignancy in a high percentage of cases& investigation must be directed towards detecting such a cause. </li></ul><ul><li>The condition is diagnosed electrophysiologically by the presence of post-tetanic potentiation of motor response to nerve stimulation at a frequency of 20-50/s. </li></ul><ul><li>Treatment is with 3,4-diaminopyridine </li></ul>
Differences between MG & Myasthenic (Eaton-Lamberts) syndrome: MS MG 1.Autoimmune immunological attack on presynaptic membrane limiting the release of ACH. 2.Mosrly paraneoplastic : in 2/3 of cases due to oat cell Ca. of the lungs > 40 ys . of age & 1/3 non neoplastic occuring at any age. 3.Realative sparing of extra ocular & bulbar muscles . 4.Autonomic dysfunction occur in 50% of cases. 5. EMG shows decreases amplitude of contraction with single nerve stimulation , but repetitive stimulation at frequencies > 10htz produces normal amplitude. 6. Treatment: ACH estrase inhibitors has minimal effect. Paraneoplastic type needs management of underlying cancer with guanidine & diaminopyridine having some benefits. For nonneoplastic type steroids + atzathioprine can control immuologocal attack. 1. Postsynaptic ACH receptors Abs. 2.All autoimmune type 3. 3.Common . 4.Not present, 5.Just contrary to that. 6.Good response to ACH estrase inhibitors.
Disease of muscles: MUSCULAR DYSTROPHIES <ul><li>A group of inherited disorders characterised by progressive degeneration of muscles, sometimes with heart muscle or conducting tissue& other parts of the nervous system. </li></ul><ul><li>Clinically: </li></ul><ul><li>Wasting weakness are usually symmetrical, there is no fasciculation& no sensory loss& tendon reflexes are preserved until a late stage, except in myotonic dystrophy. </li></ul><ul><li>Investigations </li></ul><ul><li>Confirmed by specific molecular genetic testing, supplemented with EMG& muscle biopsy if necessary. </li></ul><ul><li>Creatine kinase is markedly elevated in Duchenne type, but is normal or only moderately elevated in the other dystrophies. </li></ul><ul><li>Screening for an associated cardiac abns (cardiomyopathy or dysrhythmia) is important. </li></ul>
Disease of muscles: MUSCULAR DYSTROPHIES <ul><li>Management: </li></ul><ul><li>There is no specific therapy for these conditions, but physiotherapy & occupational therapy help patients cope with their disability. </li></ul><ul><li>Treatment of associated cardiac failure or arrhythmia (with pacemaker insertion if necessary) may be required. </li></ul><ul><li>Management of respiratory complications (including nocturnal hypoventilation) can improve quality of life. </li></ul><ul><li>Genetic counselling is important. </li></ul>
Disease of muscles: MUSCULAR DYSTROPHIES Pseudohypertrophy of calves Cardiomyopathy Gower +ve. Proximal/limb girdle LC/EA XL; deled dystrophin gene Becker Pseudohypertrophy of calves Cardiomyopathy, Gower sign +ve:patient climbs thigh by hand to stand Proximal/ limb girdle 1st 5ys XL; deletd dystrophin gene Duchenne As for DM1 but cognition not affected, Muscle pain Proximal, esp thigh, sometimes muscle hypertrophy Adult AD; chr 3q Proximal myotonic myopathy (PROMM; DM2) Myotonia, cognitive dulling, cardiac conduction abnormalities, lens opacities, frontal balding, hypogonadism Face (ptosis), sternomastoids, distal limb, generalised later Any AD; triplet repeat chr19q Myotonic dystrophy (DM1) Other features Muscles affected onset Genetics Type
Disease of muscles: MUSCULAR DYSTROPHIES Contractures early Cardiac involvement leads to sudden death Humero-peroneal, proximal limb girdle later 4-5 years XLR; mutations in emerin gene Emery-Dreifuss Mild lower limb weakness Ptosis, external ophthalmoplegia, dysphagia, tongue weakness 30-50 years AD/AR recessive; chromosome 14q Oculopharyngeal Pain in shoulder girdle common Face/ upper limb girdle 7-30 ys AD; chromosome 4q Facioscapulohumeral (FSH) Some have calf hypertrophy Some have cardiac conduction abnormalities Limb girdle Childhood/early adult AD (type 1) AR (type 2) different chromosomes Limb girdle
Disease of muscles: MUSCULAR DYSTROPHIES <ul><li>Prognosis: </li></ul><ul><li>Patients with Duchenne dystrophy used to die within 10 years of diagnosis, but with improved general care they are now living into the third decade. </li></ul><ul><li>The lifespan in limb girdle & facioscapulohumeral dystrophies is normal. </li></ul><ul><li>In myotonic dystrophy , there is considerable phenotypic variation & the prognosis is very variable, limited by cardiac & respiratory complications. </li></ul>