Miastenia Gravis

Fiziologia transmiterii sinapticeSinapsa neuromusculara:butonul sinaptic: vezicule cu cuante de Acyfanta sinaptica: parcursa de Acy -> fixare pe R sarcolemei -> descompusa de Acy-esteraza in acetat + colina -> recaptata de axonmembrana postsinaptica (sarcolema): fixarea Acy de R specifici -> depolarizare locala = potential de placa motorie (PPM), daca e mare -> contractie = PAPA -- depinde de PPM - nr. de cuante de Acy:scade la primele stimulari peste 0,1 Hz, apoi Ncreste timp de 30-60 s dupa 10 s de contractie maxima, apoi scade in 2-5 min (epuizare postactivare)Raportul PPM / PA = factor de siguranta -> fiecare PPM va fi urmat de PA functionalitatea sinapseifactor de siguranta variabil (PPM +/- -> PA) = jitter neuromuscular

MGAfectiune autoimuna a musculaturii striate, cu patogenie multipla, caracterizata clinic prin deficit motor declansat de efort si ameliorat dupa repaus.Patofiziologic: reducerea potentialului de placa motorie (PPM) necesar pentru a genera potentialul de actiune (PA) ce determina cuplajul electro-mecanic (contractia musculara)

Patogenia MGMG: Ac anti R-Acy (90%)

Nou: Ac anti MusK = kinaza musculara - in vitro corelat cu agregarea RNu exista corelatie: nivelul seric Ac - severitatea boliiAc - Ig G - 3 mecanisme:mediat de complement - corelat cu grd de distructie a mb postsinapticecresc rata de distructie a Rblocheaza R - deschiderea canalului de Na - deficit sever

Patogenia MGFactorul de siguranta depinde de:eliberarea cuantelor de Acyactivitatea Acy-esterazeifunctionalitatea si densitatea R-Acydensitatea canalelor Na si arhitectura mb postsinaptice

Disfunctionalitatea sinapsei:blocaj presinaptic: toxina botulinica, sindom miastenic (SMi)blocaj sinaptic: inhibitori colinesteraza, hemicolina (- recaptarea colinei)blocaj postsinaptic: curara (R), MG

ClinicOssermanI - forma oculara (15-20%)II A. forma generalizata usoara, lent progresiva, fara crize, responsiva la tratament (30%) B. Forma generalizata medie, cu afectare bulbara, fara crize, raspuns mediu la tratament (25%)III forma acuta fulminanta, cu crize, raspuns prost la tratament, mortalitate crescuta (15%)IV forma severa (III) cu evolutie in 2 ani (10%)

MG Foundation of America

I Forma oculara - 15% (1/2 = seronegativa)Forma generalizata:II - usoara: a - axialb - orofaringian + respiratorIII - medie: a, bIV - severa: a, bV - protezata respirator si alimentar

DiagnosticTensilon (edrofoniu): 1-2 mg IV 45 3mg 5min(+): ameliorare in 1 mm (! SLA, Smi)Testul cu gheata (hT incetineste degradarea Acy):gheata pe pleoapa 5min ridicare > 50%Testul de somn: 30 min ridicarea pleoapeiDozare serica Ac :anti R-Acy + 90%anti-striationali (anti-timici) + intre 20-50 aniCT / RMN timusEMG

Diagnostic diferential

ocular

patologie nucleara si de TC (incl Horner), distrofie oculofaringiana, miastenie congenitala, Graves

bulbar

patologie nucleara si de TC, boala neuronului motor, lez ORL

deficit lateralizat al membrelor

central, radicular, periferic

extremitate distala

miopatii distale, radiculopatii, neuropatii

tulburare respiratorie izolata

boala neuronului motor, Smi, polimiozita, distrofie miotonica, deficit acid-maltaza

deficit cervical

boala neuronului motor, miopatie paraspinala, miopatie inflamatorie

EMGStimularea supramaximala (+ 10-25%) repetata a nervului periferic determina activarea maximala a tuturor fibrelor musculare -> PCUM - Anormal: progresiv raspund mai putine fibre => decrement + jittermuschi proximali si faciali: trapez, deltoid, anconeu, biceps, em tenara / hipotenara, orbiculari, platisma / culegere cu ac: variatia A PCUM sugereaza blocajul transmiterii / miopatie Stimulare:3-5 Hz -> 10 Hz = decrement PA2 -> PA5 (10-50 Hz => decrement 50% la m N)tehnici de favorizare a decrementului: stimulare 4-5 min; stimulare periferica + ischemie (garou pana la TAS)posttetanizare (20-50 Hz / contractie voluntara max 10 s) =>facilitare = creste nr fb activate -> apoi stimulare 3-5 Hz imediat si la fiecare 1 min -> 5-10 min = epuizare postfacilitarepseudofacilitare = creste A PCUM prin cresterea A fiecarui PA, dar aria ramane aceeasiMasurare: A PCUM: vf-vf / unda negativaD(ecrement) = (A4/5 A1) : A1 x 100 = N < 8%

Tratament MGImunosupresorCorticosteroidAzatioprinaCiclosporinaCiclofosfamidaInhibitor de acetilcolinesterazapiridostigminaPlasmafereza/IVIGTimectomie 10-55 ani

Algoritm de tratament

Patologia musculara

BASIC PATHOLOGICAL CHANGES

Muscle has a limited repertoire of reactions to injurywhich consists basically

of atrophy and myonecrosis.

Myonecrosis is segmental.

Necrotic fibers are invaded

by macrophages which remove the debris.

Myonuclei from adjacent intact segments proliferate and initiate regeneration.

Regenerating fibers are slender, basophilic, and have central rows of large nuclei.

Necrosis and regeneration go hand in hand but eventually one or the other prevails, depending on the disease

Myonecrosis occuring over a long period, as in the muscular dystrophies, results in loss of muscle.

Remaining myofibers are often hypertrophic and have structural abnormalities such as --internal nuclei,-- internal splits, and an ---irregular orientation of their myofilaments. Lost muscle is replaced by adipose tissue and collagen.

To the pathologist, myopathy is a muscle disease with myonecrosis and structural abnormalities.

Inflammatory myopathies are characterized by myofiber necrosis and inflammation.

Myopathy (primary disease of muscle) to a clinician means a condition with ---proximal weakness, ---elevated CK---myopathic EMG changes.

The latter consist of low voltage and short motor unit potentials caused by depletion of myofibers of the motor unit.

This broad group includes

1.the muscular dystrophies

2. inflammatory myopathies.

Facioscapulohumeral and scapuloperoneal dystrophy

Oculopharyngeal muscular dystrophy

Distal myopathies

Dermatomyositis affects children and adults. It causes a purple (heliotrope) discolorarion of the upper eyelids, edema around the eyes and mouth, skin rash on the face and over extensor surfaces of the extremities, muscle pain, weakness and stiffness of muscles. Contractures, subcutaneous calcification, intestinal ulceration, and other extramuscular manifestations are frequent in children.

Miopatii metaboliceAfectare metabolism glucidic:Glicogenoze (tip 1-5)

Afectare metabolism lipidic

Afectare mitocondriala:Asociata si cu alte afectari in special SNC

Miopatii congenitale Afectare

Proteine structurale

Aparat contractil al celulei musculare

Sindroame neurologice paraneoplazice:Definitie: grup de boli, de etiologie necunoscuta ce se petrec exclusiv, cu o frecventa inalta in asociere cu debutul unui cancer.Pot afecta orice structuta a SNC si SNP.Sd paraneoplazice reprezinta sub 1% din complicatiile neurologice ale unui cancer.De obicei asociate unor anumite tipuri de cancer, antedatand diagnosticul de cancer.Anumiti Ac au fost descrisi in sange si LCR (ipoteza autoimuna)---respectiv sd paraneoplazic este raspunsul imunologic impotriva antigenelor tumorale, ce sunt gresit directionate catre antigene similare din SN( ! model ce a fost dovedit pt sd Lambert Eaton).Ac: ---marker diag. in anumite sd paraneo,---identifica anumiti pacienti cu aspect clinic necaracteristic pt un anumit pt un anumit sd paraneo,--- suport teoretic pt terapie imunosupresoare.

Sdr. paraneoplazice ale SNC:Encefalomielita,Encefalita limbica,Encefalita bulbara,Mielita,Degenerarea cerebeloasa,Retinopatie,Opsoclonus-mioclonus,Sd de persoana intepenita,Mielopatia necrotizanta.

Sdr. paraneoplazice ale SNP:Neuropatia subacuta motorie,

Neuropatie subacuta senzitiva,

Neuropatie senzitivo-motorie,

Multineurita si vasculita,

Neuropatii autonome,

Neuromiotonia.

Sd paraneoplazice ale jonctiunii neuromusculare si ale muschilor:

Sd miastenic Eaton Lambert,

Dermatomiozita,

Miopatia acuta necrotizanta.

Sdr.Eaton Lambert (LEMS)Slabiciune musculara proximalaDisautonomieAreflexieNeuropatie distala senzitiva50-60% asociate SCLCAc anti VGCC 90-95%Rar afectare oculara/bulbara

Tratamentul sdr. paraneoplazice:

Evolutia clinica nu este uniforma,

Ameliorare spontana: la cativa pacienti cu sd paraneoplazic , ex cei cu: encefalomielita/ neuropatie senzitiva subacuta (cancer Pl cu cel mici), in sd mioclonus-opsoclonus asociat meduloblastomului , in degenerescenta cerebelara din Boala Hodgkin, in cazul neuropatiilor senzitivo-motorii acute sau subacute.

Tratamentul cancerului: greu de apreciat eficienta asupra sd paraneoplazic.

Trat imunosupresiv: CS, plasmafereza, doze crecute de Ig G iv.