1、神经肌接头病(Disorders of neuromuscular transmission)重症肌无力 Lambert-Eaton 综合征 Dep.of Neurology The 2nd Hospital Harbin Medical UniversityNeuromuscular Disorders Definition The diseases of neuromuscular junction(NMJ)describes a sets of disease caused by circulating factors such as neurotoxins or autoantibod
2、ies which bind with high affinity to specific proteins at the NMJ and disturb the neuromuscular transmission.Neuromusuclar Junction(NMJ)Physiologynthe nerve AP reaches the nerve terminal which inflated and without myelin and leads to the opening of calcium channel and release of ACh into the synapti
3、c cleft by exocytosis.Neuromusuclar Junction(NMJ)Physiologyn1/3 of the ACh diffuses rapidly to the postsynaptic membrane and binds to the AChRs,leading to opening of the AChR-associated cation channel and depolarization called the end-plate potential(EPP).nIf the EPP exceeds certain threshold,voltag
4、e gated sodium channel at the postsynaptic membrane are opened.nThis generates the muscle action potential(CMAP)that propagates along the muscle fiber and activates contraction.Neuromusuclar Junction(NMJ)PhysiologynAnother 1/3 of the ACh is hydrolyzed by cholinesterase(ChE).nThe remaining 1/3 of the
5、 ACh is recaptured by the presynaptic membrane.重症肌无力(Myasthenia Gravis,MG)概念 病因及发病机制 病理临床表现 诊断及鉴别诊断 治疗Myasthenia gravis(MG)DefinitionnMG was originated from Latin,meaning very severe weakness.nacquired MG is an antibody and complement-mediated,T cell-dependent autoimmune disease leading to a defect
6、in neuromuscular transmission.Myasthenia gravis(MG)EpidemiologynIt is the prototypic neuromuscular disorders with an incidence of 80-200 per million and prevalence about 500 per million.nIn China,it is estimated that 0.6 million people were diagnosed as MG and most of them lives in the South of Chin
7、a.nIt had been a life-threatening disease before 1970s,though nowadays the incidence of death has been greatly reduced to about 0.2%.Myasthenia Gravis(MG)EtiologynThe autoimmune origin of MG is proposed long before it was established in 1973 by the direct evidence provided by Patrick and Lindstrom,w
8、ho have immunized rabbit with affinity-purified Torpedo AChR with CFA and reproduced the animal models representing human MG(EAMG).nThe AChR is the autoantigen.Myasthenia Gravis(MG)EtiologynThe presence of anti-AChR Abs can be demonstrated in 80%-90%of MG patients.nThere is a 3:1 female-male ratio f
9、or patients who develop MG in early adult life.nOverall,the above makes MG fulfills the criteria for autoimmune diseases.Myasthenia Gravis(MG)EtiologynMost of the patients with MG have abnormalities in the thymus,e.g.thymic hyperplastic or thymoma.nAlthough the primary antiself event being unclear,t
10、hymus appears to be the place where it initiates.nThe general opinion is that virus infection or other nonspecific factors invades the thymus in genetically predisposed individuals leading to the development of MG.Myasthenia Gravis(MG)PathologynLymphoid folliculus can be seen in thymus.About 10%of M
11、G patients has thymoma of epithelia type.nLymphorage,defined by aggregated lymphoid cells around the blood vessels,is sometimes seen in otherwise normal musculature in MG patients.Myasthenia Gravis(MG)PathologynAt the NMJ,grossly simplified postsynaptic folds with deposition of immune-complex and th
12、e anti-AChR Abs is demonstrated by immunochemical studies.There is also considerable debris within the widened synaptic cleft.Normal NMJ、NMJ in MG patients（示意图）（电镜）Myasthenia Gravis(MG)Clinical ManifestationsnMG can arise at any age,although young females and old males are more vulnerable to it.nPre
13、cipitating factors:concurrent infection,stress,weariness,menses,pregnancy or parturition.nThe disease initiates insidious and follows a slowly progressive course.Myasthenia Gravis(MG)Clinical ManifestationsnClinically,MG features with fluctuated muscular weakness in intensity during the day and easy
14、 fatigability.nTypically,the weakness varies in distribution and severity from day to day.nCharacterized by abnormal weakness,which being worse at the end of the day or after exertion and tends to improve after rest or AChE treatment.Myasthenia Gravis(MG)Clinical ManifestationsnThe weakness often be
15、gins with the lateral or bilateral extra-ocular muscles,leading to asymmetric ocular palsies(e.g.diplopia,strabismic)and ptosis.nPupillary responses are not affected.Myasthenia Gravis(MG)Clinical ManifestationsnThe patients may present with less wrinkles,amimia,difficulty in closing the eyes or disc
16、losing tooth;ndifficulty in chewing or swallowing,nasal speech;nweakness of the neck or the proximal upper limbs.Myasthenia Gravis(MG)CrisisdefinitionnCrisis describes a rapidly developed weakness in the bulbar muscles and respiratory insufficiency that necessitates assisted ventilation.nIt is the l
17、eading cause of death in patients with MG.Myasthenia Gravis(MG)CrisisclassificationnMyasthenic crisis:able to react to AChE drugs and being hypersensitive to the curare.nCholinergic crisis:1.overmedication can lead to increased weakness,which,unlike myasthenic weakness,is unaffected or enhanced by i
18、ntravenous edrophonium.2.It may be accompanied by pallor,sweating,nausea,vomiting,salivation,colic,and diarrhea(muscarinic syndrome).nBrittie crisis:unresponsive to AChE.Myasthenia Gravis(MG)Osserman ClassificationnFive subgroups can be defined among patients with myasthenia.I.Ocular IIa.Mild genera
19、lized IIb.Moderate generalized III.Progressively severe IV.late severeMyasthenia Gravis(MG)Other classificationnMG can also be subdivided into adolescent and adult type,neonatal MG,congenital myasthenia,D-Penicillamine induced myasthenia:a similar disorder in patients receiving penicillamine for rhe
20、umatoid arthritis frequently remits when the drug is discontinued.Myasthenia Gravis(MG)InvestigationnRoutine examination on the blood,urea and CSF are normal.nX-rays and CT scans of the chest may reveal a coexisting thymoma in patients over 40 years.Myasthenia Gravis(MG)InvestigationnEMG:increased d
21、ecrement(10%)of the evoked CMAP upon repeated stimuli at 3 or 5 Hz.nSingle fiber myography shows reduced amplitude of MEPP and increased variability(jitter)or more blockade of impulses.Myasthenia Gravis(MG)InvestigationnThe anti-AChR Abs present in 85-90%of patients with generalized MG and in 50%of
22、patients with ocular MG,but not present in healthy individuals.nWhen the anti-AChR Abs are identified,the diagnosis is established.nautoantibodies against striated muscles.Myasthenia Gravis(MG)Diagnosisn疲劳试验（Jolly试验）n抗胆碱酯酶药物试验1.腾喜龙（tensilon）试验2.新斯的明（neostigmine）试验n重复神经电刺激nAChR抗体滴度测定：特征性意义Myasthenia
23、Gravis(MG)Diagnosisnedrophonium in 2-3 dose(totally 10mg)given i.v.give a rapid(within 2)but short-lived(less than 5)improvement in strength in most patients with MG.nneostigmine of 1.5mg given i.m.improves muscle strength within 30 and lasts for 2 hs.nfalse-positive and false-negative results can o
24、ccur.nthere is a small risk of cardiorespiratory collapse.Myasthenia Gravis(MG)DiagnosisnOnce the diagnosis has been made,CT or MRI of the chest should be done to exclude an associated thymoma.nThyroid function and thyroid Abs should be measured,because of the increased frequency of thyroid disease.
25、Myasthenia Gravis(MG)Differential diagnosisThe differential diagnosis of MG is wide.nAcquired MG v.s.congenital MG and neurotoxins e.g.botulism,venoms.nOcular MG(of whom about 50%are AChR Ab-negative)v.s.ocular muscular dystrophy and mitochodrial cytopathy.nBulbar myasthenia v.s.brain stem stroke an
26、d motor-neuron disease(e.g.ALS).Myasthenia Gravis(MG)Differential diagnosispatients with generalized weakness but are negative for AChR Abs v.s.neuropathies and myopathies myasthenic syndromes(other disorders of the NMJ which neurophysiological studies might show changes similar to those of MG).Myas
27、thenia Gravis(MG)TreatmentnAChE drugs provides symptomatic benefit without influencing the course of the underlying disease.npyridostigmine,at doses individually determined but usually between 60 and 180 mg q.q.d.nSmall doses of atropine may attenuate side effects such as diarrhea.Myasthenia Gravis(
28、MG)Treatmentnthymectomy should be performed in patients under 60 years of age.nusually leads to symptomatic benefit or remissionnHowever,its beneficial effect may not be evident immediately.Myasthenia Gravis(MG)Treatmentncorticosteriods are indicated for patients who have responded poorly to AChE an
29、d have already under thymectomy.nTreatments are initiated with the patient in hospital,since weakness may initially be exacerbated.nAn initial high dose of predinisone(60-80mg/d orally)can gradually be tapered to a relatively low maintenance level(10-20 mg/d)as improvement occurs.Myasthenia Gravis(M
30、G)TreatmentnImmunosuppressant,e.g.azathioprine,is used as steriod-sparing agent.nIt can also be given in place of corticosteroids to patients who show no sustained benefit with low doses.nThe usual dose is 1-3 mg/kg/d,increased from a lower initial dose.Myasthenia Gravis(MG)Treatmentnplasmapheresis(
31、PE)may be used during an acute exacerbation,myasthenic crisis,or under certain special circumstances,e.g.prior to surgery.nintravenous immunoglobulins(IVIG)have been used to provide temporary benefit in circumstances similar to those in which PE is used.Myasthenia Gravis(MG)TreatmentnCrisis:respirat
32、ory and bulbar complications require appropriate supportive measures,e.g.assisted ventilation and/or nasogastric feeding.nPE and IVIG are needed.Lambert-Eaton Syndrome(LEMS)概念 病因及发病机制 临床表现 诊断及鉴别诊断 治疗Lambert-Eaton Syndrome(LEMS)DefinitionnIn the paraneoplastic disorder,Abs against tumor antigens cros
33、s-react with voltage-gated calcium channels involved in acetylcholine release,leading to a disturbance of NMT.Lambert-Eaton Syndrome(LEMS)EtiologynIn 1957,Lambert and Eaton described a myasthenic syndrome that was electrophysiologically distinct from MG.nan archetypal paraneoplastic neurologic disor
34、der,frequently associated with SCLC.noccasionally associated with pernicious anemia.Lambert-Eaton Syndrome(LEMS)Clinical ManifestationsnLEMS is more common in males than females.nWeakness involves predominantly proximal muscles of the limbs and nearly always affects the legs first.nStrength may incr
35、ease during the first few seconds of a voluntary contraction.Lambert-Eaton Syndrome(LEMS)Clinical ManifestationsnOcular syndromes are far less common than in MG.Weakness and fatigue of hip muscles with aching back and thigh muscles are common.nReflexes are absent.nAutonomic disturbances,such as dry
36、mouth,constipation,and impotence,may also occur.Lambert-Eaton Syndrome(LEMS)InvestigationnCMAP amplitude is decreased at low rates of repetitive nerve stimulation.nthe CMAP shows an increment following high-frequency(10 Hz)stimulation or a few seconds of voluntary contraction.nThe findings contraste
37、d with those in MG.nautoantibodies against the P/Q subtype of voltage-gated calcium channels(VGCC)is highly sensitive and specific.nAChR-Ab(-).Lambert-Eaton Syndrome(LEMS)Diagnosis and differential diagnosisn肌无力、腱反射减低、自主收缩后肌力增加。n典型的电生理改变。n通过检测VGCC抗体加以验证(阳性率90%)。n表17-1TreatmentnTherapy based on the etiology.nPE.nIVIG.本课重点本课重点MG的临床表现 肌肉病态疲劳，晨轻暮重MG危象的概念及分型MG的诊断MG和LEMS的鉴别
