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Miastenia Gravis

Fiziologia transmiterii sinaptice


Sinapsa neuromusculara:

butonul sinaptic: vezicule cu cuante de Acy

fanta sinaptica: parcursa de Acy -> fixare


pe R sarcolemei -> descompusa de Acyesteraza in acetat + colina -> recaptata de
axon

membrana postsinaptica (sarcolema):


fixarea Acy de R specifici -> depolarizare
locala = potential de placa motorie (PPM),
daca e suficient de mare -> contractie = PA

Fiziologia transmiterii sinaptice


PA -- depinde de A-PPM -- nr. de cuante de Acy:
- scade la primele stimulari peste 0,1 Hz, apoi N
- creste 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 sinapsei
factor de siguranta variabil (PPM +/- -> PA) = jitter
neuromuscular

Fiziologia transmiterii sinaptice


Factorul de siguranta depinde de:
eliberarea cuantelor de Acy
activitatea Acy-esterazei
functionalitatea si densitatea R-Acy
densitatea canalelor Na si arhitectura mb
postsinaptice

Fiziopatologia transmiterii sinaptice


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

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

Patogenia MG
Ac anti R-Acy (90%)

Ac anti MusK = kinaza musculara - in


vitro corelat cu agregarea R
Nu corelatie: niv. Ac - severitatea bolii

Patogenia MG
Ac - Ig G - 3 mecanisme:
mediat de complement - corelat cu grd de
distructie a mb postsinaptice
cresc rata de distructie a R
blocheaza R( deschiderea canalului de Na) deficit sever

Clinic
Osserman
I - 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 - axial
b - orofaringian +
respirator
III - medie: a, b
IV - severa: a, b
V - protezata respirator si
alimentar

Diagnostic
Neostigmina : 1 mg IV 45 ; 3mg i.m 5min
(+): ameliorare in 1 mm (! SLA, SdrMi)
Testul cu gheata (hT incetineste degradarea Acy):
gheata pe pleoapa 5min ridicare > 50%
Testul de somn: 30 min ridicarea pleoapei
Dozare serica Ac :
anti R-Acy + 90%
anti-striationali (anti-timici) + intre 20-50 ani
CT / RMN timus
EMG

Diagnostic diferential
ocular
bulbar

patologie nucleara si de TC (incl Horner),


distrofie oculofaringiana, miastenie
congenitala, Graves
patologie nucleara si de TC, boala neuronului
motor, lez ORL

deficit
lateralizat al
membrelor
extremitate
distala

central, radicular, periferic

tulburare
respiratorie
izolata
deficit
cervical

boala neuronului motor, Smi, polimiozita,


distrofie miotonica, deficit acid-maltaza

miopatii distale, radiculopatii, neuropatii

boala neuronului motor, miopatie paraspinala,


miopatie inflamatorie

EMG
Stimularea supramaximala (+ 10-25%)
repetata a nervului periferic determina
activarea maximala a tuturor fibrelor
musculare -> PCUM - Anormal: progresiv
raspund mai putine fibre => decrement +
jitter
muschi proximali si faciali: trapez, deltoid,
anconeu, biceps, em tenara / hipotenara,
orbiculari, platisma / culegere cu ac:
variatia A PCUM sugereaza blocajul
transmiterii / miopatie

Tehnica EMG
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
postfacilitare
- pseudofacilitare = creste A PCUM prin cresterea A fiecarui
PA, dar aria ramane aceeasi
Masurare: A PCUM: vf-vf / unda negativa
- D(ecrement) = (A4/5 A1) : A1 x 100 = N < 8%

Tratament MG
Profilaxie
Etiologic- absent
Patogenic- imunosupresive
corticosteroizi
azatioprina

Simptomatic- anticolinesterazice

Algoritm de tratament

Patologia musculara

Histochemical staining of frozen muscle using


myofibrillar ATPase and oxidative enzyme
stains shows two fiber types, type 1 (slow-red)
and type 2 (fast-white). These fibers have
distinct myosin isoforms. Type 1 fibers are rich
in oxidative enzymes, mitochondria, myoglobin
(an oxygen carrier), and lipid. They are capable
of protracted slow action and clonic activity.
Type 2 fibers are rich in glycogen and
glycolytic enzymes. They are capable of fast,
powerful, tonic contraction. By varying the pH
of the ATPase preincubation, type 2 fibers can
be further subdivided into 2a and 2b. Fiber
types are segregated in birds (red and white
meat). In mammals, type 1, 2a, and 2b fibers
are present in all muscles, mixed like a
checkerboard. Their proportion varies in
different muscles.

BASIC PATHOLOGICAL CHANGES

Muscle has a limited repertoire of


reactions to injury
which consists basically

of atrophy

and

myonecrosis.

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.

1.Distrofii musculare
2.Miopatii inflamatorii
3.Miopatii endocrine
4.Miopatii induse de medicamente si toxice alcool
5.Miopatii metabolice
6.Miopatii congenitale
7.Miopatii asociate paraliziilor periodice

Distrofia musculara (DM) este un grup de


afectiuni rare ereditare in care fibrele
musculare sunt neobisnuit de predispuse la
leziuni.
Muschii, si in special muschii scheletici
devin din ce in ce mai slabi. In stadiile
avansate de distrofie musculara, tesutul
conjunctiv inlocuieste fibrele musculare. In
unele forme de distrofie musculara sunt
afectati miocardul si alti muschi involuntari
(netezi) precum si alte organe.
Tipurile cele mai comune de distrofie
musculara par sa fie cauzate de deficienta
genetica a unei proteine numite distrofina.
Nu exista un tratament pentru distrofia
musculara; medicatia si terapiile avand
doar rolul de a incetini evolutia bolii.

PROGRESSIVE MUSCULAR DYSTROPHIES


Muscular dystrophies are genetically transmitted
diseases characterized pathologically by
degeneration and
loss of myofibers and clinically by
inexorably progressive weakness and,
many of them, by elevated CK. T
he pattern of weakness, tempo of evolution, and
mode of inheritance vary among different
dystrophies.
Over 30 genes causing muscular dystrophy are
known presently.
Muscular dystrophies are clinically classified into
the following groups

Facioscapulohumeral and scapuloperoneal dystrophy


Oculopharyngeal muscular dystrophy
Distal myopathies

INFLAMMATORY
MYOPATHIES
Inflammatory myopathies are characterized
pathologically
by myonecrosis and mononuclear
inflammatory infiltrates and clinically by
weakness and soreness of muscles and
elevated CK and erythrocyte sedimentation
rate.
The main inflammatory myopathies are
polymyositis, dermatomyositis, and inclusion
body myositis.

Polymyositis is a cell-mediated
autoimmune disorder in which
cytotoxic T-cells and macrophages
invade and destroy myofibers.

Polymyositis

Lymphocyte in
myofiber

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.

Perifascicular
Necrotic
Dermatomyositis atrophy
capillary
The key pathological change of
dermatomyositis is a vasculitis which
involves endomysial and perimysial
capillaries and arterioles. This vasculitis
begins with endothelial swelling and is
followed by endothelial necrosis and
capillary loss. The vasculitis is caused by
circulating anti-endothelial antibodies.

Inclusion body myositis

The pathological changes of IBM are


highly characteristic. Light
microscopy shows myofibers with
vacuoles or cracks some of which are
lined by basophilic granules. These
are best seen in cryostat sections
stained with modified Gomori

Dermatomyositis and polymyositis


(and less frequently inclusion body
myositis) are associated with
scleroderma, mixed connective tissue
disease, and cancer. Patients with
polymyositis and dermatomyositis may
have cardiac involvement leading to
arrhythmia and heart failure,
arthralgia, Raynaud phenomenon,
interstitial pneumonitis, and renal
involvement. Some of them have
circulating antibodies to a
macromolecular complex of tRNA
synthetases.

Miopatii metabolice
Afectare 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.
Sdr. 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 sdr. miastenic Eaton Lambert ).
Ac: ---marker diag. in anumite sdr. paraneo,
---identifica anumiti pacienti cu aspect clinic necaracteristic pt un anumit
sdr. 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.

Sdr. paraneoplazice ale jonctiunii


neuromusculare si ale muschilor

Sdr. miastenic Eaton Lambert,


Dermatomiozita,
Miopatia acuta necrotizanta.

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.