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Definitie - Miastenia gravis este o maladie autoimuna care se manifesta prin slabiciune musculara si

fatigabilitate pronuntata. Miastenia a fost descrisa pentru prima data de catre Thomas Willis n 1972.
Miastenia are la baza sinteza de anticorpi ndreptati contra receptorului de acetilcolina situat pe
membrana fibrei musculare striate si care participa la contractia musculara.

Cuprins

Generalitati

Patogenia

Etiologie

Tabloul clinic

Diagnostic

Diagnostic diferential

Tratament

Generalitati
Miastenia gravis este o maladie relativ rara si poate debuta la orice vrsta. Femeile sunt afectate
putin mai frecvent dect barbatii cu un raport de 6:4. Incidenta mai mare a miasteniei la femei se
observa n jurul vrstei de 30 de ani, n timp ce incidenta maxima la barbati este atinsa la vrsta de
50-60 de ani.

Patogenia
Pentru a ntelege patogenia miasteniei gravis este necesar de a cunoaste mecanismul de generare
a contractiei musculare. Fibra musculara striata si primeste inervatia prin intermediul jonctiunii
neuromusculare. Aceasta jonctiune este alcatuita din membrana presinaptica care este butonul
terminal al axonului neuronului motor periferic, membrana postsinaptica care este membrana fibrei
musculara si fanta sinaptica. Pe membrana presinaptica se situeaza veziculele cu acetilcolina, iar pe
membrana postsinaptica receptorii acetilcolinei (ACh). La propagarea unui impuls spre membrana
presinaptica are loc eliberarea veziculelor n fanta presinaptica si acetilcolina difuzeaza spre
receptorii ACh provocnd deschiderea canalelor ionice si generarea potentialului de actiune
muscular. Dupa realizarea actiunii sale, acetilcolina este hidrolizata de catre acetilcolinesteraza.
n miastenie, sistemul imun devine ostil fata de receptorii ACh si ncepe sa sintetizeze anticorpi antiAChR. Ca rezultat are loc reducerea numarului de receptori ACh si respectiv actiunea acetilcolinei
este prejudiciata. Anticorpii ACh sunt prezenti n aproximativ 80-90% din cazuri de miastenie gravis.
Pacientii cu miastenie nsa fara anticorpi anti-AChR sunt recunoscuti ca fiind seronegativi (miastenia
gravis seronegativa). La o buna parte din acesti pacienti nsa se depisteaza alti anticorpi cum ar fi
anticorpii anti-MuSK.
Natura autoimuna a miasteniei este confirmata si prin observatiile unei asocieri frecvente dintre
miastenie si alte maladii autoimune (tiroidita autoimuna, lupusul eritematos de sistem, artrita
reumatoida, vitiligo s.a.)

Etiologia
Cauza miasteniei gravis este necunoscuta. Penicilamina este cunoscuta a declansa diferite tulburari
autoimune, printre care si miastenia gravis. Sunt cunoscute o serie de medicamente care pot
precipita si agrava miastenia gravis si care trebuie evitate la acesti pacienti:

Antibioticele (aminoglicozidele, ciprofloxacina, eritromicina, ampicilina)

Beta-adrenoblocantele (propanolol, ocprenolol)

Litiul

Procainamida

Verapamil

Quinidina

Clorochina

Prednisolonul

Timolol (beta-blocant utilizat pentru tratamentul glaucomului)

Anticolinergicele (trihexifenidil)

Tabloul clinic
Principala manifestare a miasteniei gravis este slabiciunea musculara. Slabiciunea poate afecta
toate grupurile musculare si n acest caz vom vorbi despre miastenia gravis generalizata. n cazul
formei oculare a miasteniei, slabiciunea este limitata doar la musculatura oculara extrinseca.
Musculatura bulbara este afectata n special n formele seronegative ale miasteniei. Slabiciunea n
membre are un caracter idiopatic, fiind mai pronuntata n segmentele proximale.
Variabilitatea slabiciunii este trasatura a miasteniei. Cunoasterea acesteia este obligatorie pentru o
evaluare corecta a pacientilor. Astfel, slabiciunea musculara n miastenie este mai pronuntata seara
si poate lipsi n orele diminetii. Acest fapt poate cauza erori de diagnostic.
Slabiciunea musculaturii faciale este prezenta practic n toate cazurile si determina o expresie
faciala de masca. Implicarea muschilor extraoculari va determina ptoza si diplopie. Frecvent
pacientul si ncreteste fruntea pentru a compensa ptoza palpebrala. Slabiciunea musculaturii
palatului moale va determina un aspect nazonat al vocii ct si un risc de regurgitatii si aspiratii
pulmonare. Procesul de masticatie deasemenea poate fi ngreunat, uneori pacientii fiind nevoiti sa-si
sprijine mandibula cu maina.
Ca regula progresia maladiei are loc la interval de saptamni sau luni. Daca maladia se prezinta
initial cu simptome oculare, slabiciune progreseaza ulterior distal, implicnd musculatura faciala,
bulbara, tronculara si a membrelor inferioare. Mai rar slabiciunea se poate limita la musculatura
oculara pentru perioade de luni sau ani de zile.
De o importanta majora n miastenie este afectarea musculaturii respiratorii care poate fi letala n
caz de exacerbari. Criza miastenica poate fi precipitat de infectii intercurente sau de un sir de
medicamente care au fost mentionate mai sus. n caz de dezvoltare a crizei miastenice cu
insuficienta respiratorie se recurge imediat la intubare oro-traheala.
Remisiile spontane ca regula sunt rare. Cele mai multe remisii sub actiunea tratamentului survin n
primii 3 ani ai maladiei.

Diagnostic
Pentru diagnosticul miasteniei gravis se utilizeaza o serie de analize imunologice, metode imagistice
ct si examenul electrofiziologic.

Analizele imunologice
Depistarea anticorpilor n serul pacientilor cu miastenie gravis este o metoda de diagnostic
valoroasa, dat fiind prezenta acestor anticopri la 80-90% din pacienti.
Anticorpii contra receptorului de acetilcolina (anti-AChR) - testul este pozitiv la 74% din pacienti.
Anti-AChR sunt mai frecvent depistati la pacientii cu miastenie generalizata (80%) si doar la 50% din
pacientii cu forma oculara pura. Rezultatele fals pozitive pot fi obtinute n ca de sindrom LambertEaton, timom fara miastenie, cancer pulmonar cu celule mici, artrita reumatoida tratata cu
penicilamina ct si la 1-3% din populatia de peste 70 de ani.
Anticorpii contra fibrei striate - sunt prezenti la 84% din pacientii cu timoma mai tineri de 40 de ani si
mai rar la pacientii fara timoma.
Anticorpii contra tirozin kinazei musculare - Aproximativ jumatate din pacientii seronegativi (fara antiAChR) sunt pozitivi pentru anti-MuSK. Acesti pacienti pot reprezenta un grup distinct al miasteniei,
demonstrnd unele particularitati clinice. Pacientii cu anti-MuSK pozitivi tind a avea simmptome
bulbare mai severe asociata cu atrofie faciala si a limbii. n plus, ei nu beneficiaza de pe urma
inhibitorilor colinesterazei, aceste preparate putndu-le chiar agrava situatia.
Investigatiile imagistice
Tomografia computerizata a mediastinului este mandatorie pentru identificarea timomului, n special
la batrni, la care radiografia simpla poate fi negativa. RMN cerebrala si orbitala nu este
recomandata spre a fi efectuata de rutina, ea fiind necesara doar n cazurile neclare pentru
excluderea unor formatiuni de volum orbitare sau tronculare sau a sclerozei multiple.
Examenul electrofiziologic
Electromiografia poate detecta defectul de transmitere la nivelul jonctiunii musculare prin intermediul
pe doua: prin stimularea nervoasa repetitiva si prin electromiografia de fibra unica. Electromiografia
de fibra unica se considera a fi mai sensibila n diagnosticul miasteniei gravis dect stimularea
nervoasa repetitiva.
Testul cu edrofoniu (Tensilon)
Edrofoniul (Tensilon) este un inhibitor al acetilcolinesterazei cu actiune scurta care amelioreaza forta
musculara la pacientii cu miastenie gravis. Acesta este motivul pentru care se utilizeaza ca metoda
de diagnostic n miastenie. Pentru realizarea testului este necesar de a aprecia forta musculara
(ptoza sau strngerea minii) nainte si dupa administrarea edrofoniului. Dat fiind riscul de
bradicardie sinusala, se cere a avea la dispozitie o ampula cu atropina. Pentru test se utilizeaza 1 ml
solutie de edrofoniu de 10 mg/ml. Initial se administreaza 0,1 ml din doza. Daca nu survin careva
reactii adverse se administreaza restul de 0,9 ml.
n evaluarea testului este necesar de avut n consideratie ca aceste preparate pot ameliora forta
musculara si n caz de alte maladii asa ca scleroza laterala amiotrofica, polimiozita si unele forme de
polineuroneuropatii.

Diagnostic diferential
Diagnosticul diferential al miasteniei gravis se realizeaza cu urmatoarele maladii:

Scleroza laterala amiotrofica (SLA)

Sindromul miastenic Lambert-Eaton

Glioamele de trunchi cerebral

Scleroza multipla

Patologia tiroidiana

Dermatomiozita/polimiozita

Tromboza arterei bazilare

Sindromul Tolosa-Hunt

Tratamentul
Inhibitorii acetilcolinesterazei si terapia imunomodulatoare reprezinta pilonii tratamentului miasteniei
gravis. n formele moderate inhibitorii AChE pot reprezenta terapia de baza, n timp ce n formele
mai severe poate fi necesara asocierea preparatelor imunosupresoare.
Preparatele din grupul inhibitorilor AChE utilizate n miastenia gravis sunt piridostigmina (Mestinon,
Kalimin) si neostigmina (Prostigmina). Prednisolonul, azatioprina, imunoglobulina intravenoasa,
ciclosporina, ciclofosfamida, micofenolat, rituximab sunt preparatele care pot fi utilizate atunci cnd
este necesara terapia imunomodulatoare.
O alternativa la tratamentul medicamentos este plasmafereza, care actioneaza prin eliminarea
anticorpilor si complexelor imune din serul bolnavilor. Plasmafereza se utilizeaza n special n
perioada pre- si postoperatorie la pacientii cu miastenie gravis sau n tratamentul exacerbarilor.
Daca miastenia nu raspunde la alte tratamente, plasmafereza poate fi utilizata saptamnal ca
tratament de baza.
Tratamentul chirurgical al miasteniei se utilizeaza la pacientii cu timom sau hiperplazie a timusului.
Timectomia trebuie realizata la toti pacientii cu timom si la cei fara timom nsa cu vrste ntre 10-55
ani si cu miastenie generalizata. Remisiile induse de timectomie sunt mai frecvente la pacientii tineri
tratati chirurgical. Rata de remisie creste odata cu timpul atingnd 40-60% la 7-10 ani dupa
interventie. Mai amanuntit despre timectomie vedeti (Timectomia).

Ce este Miastenia Gravis?


Boala "invizibila", miastenia gravis este o boala cronica neuromusculara care se manifesta prin
oboseala severa la repetarea unei anumite miscari si slabiciunea muschilor voluntari ai corpului,
insusi termenul de miastenia gravis" se traduce prin "slabiciune musculara severa".
Ce inseamna boala neuro-musculara? Este vorba de un defect in transmiterea impulsului nervos de
la nerv la fibra musculara, ceea ce face ca muschii sa-si piarda tonusul si forta pana la
imposibilitatea de a efectua miscari.
Cauza miasteniei = boala autoimuna. Ce inseamna asta?
Bolile numite autoimune, din care face parte si MG, sunt caracterizate prin faptul ca organismul
produce anticorpi "anormali" sau care o iau razna" si ataca structuri normale ale corpului care nu
mai sunt recunoscute ca fiind proprii; in cazul miasteniei gravis, anticorpi anormali sunt produsi
contra unor proteine de la nivelul jonctiunii intre nerv si muschi - numite receptori, care astfel sunt
blocati. Impulsul nervos nu se mai transmite la muschi si acestia nu se mai contracta.
Cine se poate imbolnavi de miastenie?
Mg este considerata o boala rara, frecventa cazurilor este de 1 la 10000 persoane, mai frecvent
femeile intre 15 si 30 ani, barbatii sunt atinsi mai frecvent dupa varsta de 50 de ani, dar practic
oricine poate face boala, chiar si copiii mici.
Care sunt simptomele principale ale acestei boli "ciudate" ?
Caracteristica miasteniei gravis este slabiciunea progresiva a muschilor voluntari si afecteaza diferiti
muschi, in grade diferite, pe rand, sau mai multi deodata, de unde si marea variabilitate a
simptomelor de la caz la caz dar si pentru aceeasi persoana de la un moment la altul.
Slabiciunea se agraveaza la repetarea miscarilor si se amelioreaza la repaus.

Trebuie sa intelegem ca muschii nu inseamna numai cei care misca bratele si picioarele, cei cu care
mergem, alergam, urcam scari sau caram greutati, ci tot muschi sunt si cei care ne ajuta sa vorbim,
sa mestecam si sa inghitim mancarea, sa tinem ochii deschisi, sa vedem o singura imagine cu ambii
ochi, cei care ne coordoneaza mimica fetei ca si cei care ne coordoneaza respiratia. Bolnavii de
miastenie pot avea probleme cu toti acesti muschi, simultan sau pe rand.
Ciudat, nu? Nu seamana cu nicio boala "obisnuita".
Cum descriu bolnavii de miastenie ceea ce simt?
De cele mai multe ori si pentru bolnav e greu sa realizeze si sa descrie ce simte, mai ales cand
simptomele sunt discrete si apar si dispar aparent fara explicatie. Activitati simple pentru cei mai
multi oameni devin dificile sau imposibile pentru miastenic, cum ar fi mancatul, vorbitul sau rasul
...cand am ochii obositi, pleoapele imi sunt grele si se lasa peste ochi, incat nu-i mai pot deschide,
pe amandoi sau uneori doar pe unul din ei.
cand ma uit lateral sau in sus, vad dublu, uneori sunt doua obiecte in loc de unul sau imaginile
capata un al doilea contur
vorbesc cu voce tare si la un moment dat nu mai pot pronunta clar, vocea devine nazonata si nu
se mai intelege ce spun
uneori am o fata "lunga", parca fara expresie, colturile gurii imi sunt lasate, nu mai pot sa rad cu
toata gura ci doar schitez o grimasa
alteori nu mai pot sa tin gura inchisa, simt ca mandibula cade si trebuie sa o mentin cu mana
cand mananc ceva tare, un covrig sau biscuit, la un moment dat obosesc sa mestec si mancarea imi
ramane in obraji, ca la hamsteri...
ma inec cand inghit alimente solide, trebuie sa beau mereu apa in timpul mesei
ma inec si cu apa, tusesc si imi dreg mereu vocea, uneori apa imi iese pe nas...
scap obiectele din mana, nu mai pot sa tin nici pixul pe hartie, nu pot ridica bratele in sus sa ma
pieptan...
urc greu treptele, ma opresc des, nu mai pot sa ma ridic de pe scaun, din pat
cand merg, mi se moaie dintr-o data genunchii si chiar am cazut brusc pe strada sau pe scari, lumea
m-a etichetat drept betiv(a) sau drogat(a)....
am avut toate aceste simptome....
am ajuns in criza, nu am mai putut inghiti nici saliva si nici respira bine si m-au dus la spital unde
imediat m-au conectat la un aparat de respiratie artificiala......
Sunt povestile celor ca noi.

Tratamentul miastenia Gravis

inShare

Astzi, pot fi controlate MG. Exist mai multe terapii disponibile pentru a ajuta la reducerea
slbiciune muscular. Cele mai multe persoane cu MG au rezultate bune la tratament. La
unele persoane MG, ca multe alte boli autoimune, poate merge n remisie (o perioad de
timp fr simptome) i slbiciune muscular pot disprea complet.
Remiterea sau mbuntirea pot aprea fr tratament, n unele cazuri. n conformitate cu
distrofie muscular de asociere, pn la 20 la sut din persoan cu MG poate avea
remiterea complet a simptomelor fr nici un tratament, i un alt 20 la sut pot mbunti
fr tratament. Aceste mbuntiri spontane sunt mult mai probabil s apar n timpul
stadii incipiente de MG.
Tratamentul MG pot include:

Medicamente. Medicamente folosite includ colinesterazic inhibitori


precumneostigmin i pyridostigmine. Aceste medicamente ajuta la mbuntirea
semnalelor nervoase muchii i crete rezistentei
musculare. Immunosuppressivedroguri precum prednison, ciclosporin,
i azathioprine , de asemenea, pot fi utilizate pentru a suprima producerea
anticorpilor anormale. Aceste certificate trebuie utilizate cu urmrire atent medicale
pentru c ei pot fi asociate cu principalele efecte secundare.

Thymectomy, ndeprtarea chirurgical timus (care este anormale n cele mai multe
persoane cu MG). Aceasta operatie este adoptat pentru persoanele cu MG care au
tumori, precum i pentru persoanele fr tumori. Aceasta mbuntete simptome n
mai mult de jumtate din persoanelor fr tumori. Acesta poate vindeca unii oameni
cu MG, eventual prin re-balancing sistemul imunitar.

Alte terapii uneori utilizat pentru a trata MG perioadele mai ales dificil de slbiciune includ:

Schimb plasmapheresis sau plasm. Aceasta este o procedur care elimin anticorpi
anormale din snge.

High-doz globulina intravenoas imun. Acest tratament temporar interfereaz cu


capacitatea sistemului imunitar de a deteriora confluena nervoase muscular.
Opiuni de tratament pentru o persoan cu MG depinde de severitatea slbiciune,
muchii care sunt afectate, i vrsta persoanei i alte probleme medicale.

n cteva cazuri, MG poate provoca grave slbiciune soldate cu insuficien respiratorie


acut. Dar cei mai muli oameni se pot atepta s conduc viaa normal sau aproape
normal.

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MYASTHENIA GRAVIS: DIAGNOSTIC TESTS

Antibodies
Anti-AChR
MuSK
Striational
Other
General principles
Other diagnostic tests
Repetitive nerve stimulation
Single fiber EMG
Tensilon testing

Decremental response to RNS in Myasthenia


Gravis

General Principles of Diagnostic Testing for MG

Rationale
o As thymectomy or long term immunotherapy may be
necessary to treat MG, it is essential to establish a firm
diagnosis
o A firm diagnosis avoids inappropriate treatments, and
their side effects, in patients who do not have the
disease.

The mainstays of diagnostic testing have traditionally been


o Pharmacological
o Serological
o Electrodiagnostic

Strategy of diagnostic testing


o As a general rule, a firm diagnosis is based upon
A characteristic history and physical examination,
and
Two positive diagnostic tests,
preferably serological and electrodiagnostic.
o Diagnostic investigations of MG should usually include
both
Testing for serum anti-AChR antibodies
Repetitive nerve stimulation studies

Tensilon tests
o May be readily performed at the bedside

o Are not as sensitive, or specific, as the serological and


electrophysiological studies

Single fiber EMG: Reserved for selected patients in whom other


tests have been negative or equivocal.
Other diagnostic tests: Generally not required or indicated in
majority of MG cases
o Motor point muscle biopsies
Count AChRs at neuromuscular junctions
Evaluate neuromuscular transmission by in vitro
electrophysiologic methods
Immunocytochemical staining of muscle endplates
for immunoglobulin and complement
o Tests of ocular movement
o Genetic evaluation for defects in AChR subunits

Cogan

Tensilon test: Before (left); After (right)

Edrophonium (Tensilon) Testing

General
Drug properties
o Action

Inhibits acetylcholinesterase
Prolongs presence of neurotransmitter,
acetylcholine, in the NMJ
Results in enhanced muscle strength
o Duration: Lasts for a few minutes
o Response
In patients with NMJ dysfunction
Not specific for MG
o Time course: Minutes; Rapid-onset; Short-acting
Method
Initially
o Dosing: 2 mg of edrophonium is administered
intravenously as a test dose
o Monitoring heart rate: Bradycardia or ventricular
fibrillation may develop
Follow-up
o After observing for about 2 minutes, if no clear response
develops
o Up to 8 additional mg of edrophonium is injected
A double-blind protocol with a saline injection as placebo has
been advocated
Testing should be performed with patient free of all
cholinesterase-inhibitor medications
Cholinergic side effects of edrophonium
o May include increased salivation and lacrimation, mild
sweating, flushing, urgency & perioral fasciculations.

o Atropine should be readily available to reverse effects of


edrophonium in case of hemodynamic instability
o Extra precautions are especially important in elderly
patients
Positive test
Most myasthenic muscles respond in 30 to 45 seconds after
injection
Improvement in strength that may persist for up to 5 minutes
Requires objective improvement in muscle strength.
Subjective or minor responses, such as reduction of a sense of
fatigue, should not be over interpreted
Utility of Tensilon test
Only useful in patients with objective, preferably measurable,
findings on physical examination
Rarely helpful in the diagnostic evaluation of equivocal cases of
MG
Sensitivity for MG is relatively low (60%) compared to other
diagnostic tests
Tensilon testing should not be used to determine adjustments
in the dose of pyridostigmine
False positive results
o Can occur in patients with LES, ALS or even localized,
intracranial mass lesions
o Positive testing does not necessarily predict respose to a
longer-acting anti-AChE drug

Muscle AChR
(Adult)
Serum antibodies vs Acetylcholine Receptors

General testing method


o Measurement using immunoprecipitation methodology
o Method: Human nicotinic AChRs from skeletal muscle
labeled with 125I--Bungarotoxin
Antibody (IgG) targets in MG: Nicotinic AChRs
o 1-subunit of AChR
Typical myasthenia gravis
Epitope location: Main immunogenic region on
extracellular tip of 1-subunit
Main immunogenic region (MIR) features
o Cluster of overlapping epitopes
o Conformation dependent
o Also commonly a target of anti-AChR
antibodies in Experimental autoimmune MG
(EAMG)
o Cross-linking
Single bivalent antibody cannot bind to
both MIRs on same AChR
Antibodies can cross-link adjacent AChRs
o Clinical correlation
o -subunit
Acquired slow channel syndrome

Binding to Adult AChRs (containing -subunit)1


o 13% of serums with no IgG binding to fetal
AChRs
o Increases finding (sensitivity) of anti-AChR
antibodies in MG by ~ 3%
o Occur in patients with either ocular or
generalized MG syndromes
o -subunit: Neonatal MG (Transient); Recurrent
arthrogryposis
Measurement of serum IgG & IgM antibodies that bind
to AChRs
o Antigenic target
AChRs from human skeletal muscle: Mixed
innervated & denervated, or
Myogenic cell line expressing both adult & fetal
AChRs
o Relatively specific and sensitive test for MG
o Anti-AChR antibodies occur in
Adults with generalized MG: 85 to 90%
Childhood MG: 50%
Ocular MG: 50% to 70%
o Lower titers
o Bind best to adult AChRs with subunit
MG and thymoma: Nearly 100%
Some patients taking penicillamine with or without
MG
"False" positives

o Thymoma without MG
o Immune liver disorders
o Lambert-Eaton syndrome (13%)
o Primary lung cancer: 3%
o Older patients (> 70 years): 1% to 3%
o Neuromyotonia
Antibody effects on AChRs
o Modulation
Mechanism
o Anti-AChR antibodies cross-link AChRs on the
post-synaptic membrane
o Endocytosis & degradation of AChRs are
accelerated
Test results
o May occur in a rare patient when anti-AChR
antibody binding is negative.
o MG: Usual loss = 20% to 90% of AChRs
(Normal < 20%)
o MG with thymoma: > 90% loss
o False positives: Hemolysis; Muscle relaxant
drugs; Serum heating
o Blocking binding site for ACh on AChR (positive = 26% to
100% blocking).
Prevalence: Repeated arthrogryposis; 52% of
generalized MG; 30% of ocular
1% of patients with no binding or blocking
antibodies
o Complement binding

Damage to postsynaptic membrane: Simplification


of postsynaptic folds
Widening of synaptic cleft
Clinical correlations of MG & anti-AChR antibodies
o Absolute titer of AChR binding antibodies
Among patients: No relation with severity of MG
In individual patient: Improvement often seen with
reduction in titer of > 50%
o Titer of antibody binding to main immunogenic
region (MIR) of AChRs 2
Correlates with disease severity: Ocular vs
Generalized
MIR location: Extracellular end of 2 subunits of
pentameric AChR
> 50% of MG AChR Abs bind to MIR
o Antibody blocking & modulation of AChRs
Some correlation with disease severity
Not diagnostically specific
o Neonatal MG: Transient
High anti-fetal/anti-adult muscle anti-AChR antibody
ratio
o Recurrent arthrogryposis
IgG vs subunit of fetal AChR: Blocks AChR function
o Slow channel syndrome: Acquired
IgG vs adult AChR
o IgG vs Clustered AChRs
Present in

o "Sero-Negative" ocular or generalized MG


patients: 50%
o AChR Ab+ patients: Many
Complement fixing
Antibody subclass: IgG1
Associated with thymic pathology: Lymphocytic
infiltrates; Germinal centers
o Neuronal AChR: 3 subunit
Autonomic PN (42%)
Isaacs (25%)
LEMS (12%)
o Also see: AChR disorders
Patients with MG but no anti-AChR antibodies
o Rule out hereditary MG
o Low frequency of thymic pathology & thymoma
o May have antibodies to other neuromuscular junction
antigens

Repetitive Nerve Stimulation (RNS): 2 to 3 Hz

RNS: General

Repetitive Nerve Stimulation

From: M Al-Lozi

Most frequently used electrodiagnostic test for MG


Nerve to be studied is electrically stimulated six to ten times at
2 or 3 Hertz
Compound muscle action potential (CMAP) is recorded with
surface electrodes over muscle
Nerves tested
o At least one proximal & one distal motor nerve
o Innervation of weak muscles
If decrement present
o Repeat RNS: To ensure decrement is reproducible

o Test for: Post-exercise facilitation (Repair of decrement)


o Perform EMG
Rule out: Denervating disorder producing decrement
Look for: Small-short or Unstable motor unit action
potentials supportive of NMJ disorder
If NO decrement at baseline
o Look for post exercise exhaustion: Appearance of
decrement after exercise
o Perform: Single fiber EMG
RNS in Myasthenia Gravis
Normal muscles: No change in CMAP amplitude with repetitive
nerve stimulation
Myasthenia gravis
o Progressive decline in CMAP amplitudes with the first 4 to
5 stimuli.
o Positive RNS test features
Decrement in CMAP amplitude
o Size: More than 10% in reduction in CMAP
amplitude
Measure from 1st to 4th or 5th potential
in train
o Smallest CMAP is often 2nd or 3rd potential in
train
Post-tetanic potentiation (Post-exercise facilitation)
o Definition: Reduction in (Repair of) decrement
after exercise
o Stimulus: Isometric exercise, brief (10 to 15
sec)

o Time course
Onset: Immediate
Duration: ~2 minutes
o Degree of repair: Partial or Complete
Post-exercise exhaustion
o Definition: Post exercise appearance, or
exacerbation, of decremental response
o Protocol
Stimulus: Muscle exercise for 1 minute
Repeat RNS after 1, 2, 3 and 4 minutes
o Time course
Onset: Maximal 3 to 5 minutes after
exercise
Disappears by: 10 minutes after exercise
o RNS is positive in about 75% of patients with generalized
MG, if:
Proximal & Clinically involved muscles are tested
Muscle is warm: Cooling reduces size of decrement
More than one muscle is tested: Strong muscles
often have less decrement
o Diagnostic issues
Sensitivity of RNS for MG: Greatly reduced when
distal muscles are tested
RNS is positive in only 50% of patients with ocular
MG.
Diagnostic specificity

o A decremental response to RNS is not


specific for MG
o Decrements may also be seen in
Presynaptic disorders: Such as LEMS
Motor neuron diseases: Including ALS

Normal SFEMG

Increased jitter: MG patient


From: M Al-Lozi

Myopathies: McArdle's; Myotonia


Also see: Rapid RNS

Single fiber electromyography (SFEMG)

Principle: Muscle fibers innervated by a single axon


o Normal: Activated with consistent latencies
o NMJ disorders
Increased variability of latencies among muscle
fibers in single motor unit
Muscle fiber potential may be blocked if
transmission at its NMJ fails completely.
SFEMG

o Simultaneously records potentials of two muscle fibers


innervated by an individual axon
o Measures this variability = "Jitter"
o SFEMG is the most sensitive test for MG
Sensitivity: > 95% positive in generalized & ocular
MG
o When the test site includes facial muscles
o Abnormal jitter is not specific for MG
May occur in other neuromuscular disorders,
including ALS, polymyositis or LEMS
More specific for MG if large degree of jitter occurs
with mild or no other changes on EMG
o MuSK MG: Jitter may be present in absence of RNS
decrement

Myasthenia Gravis: A Review of Available Treatment


Approaches
Nils Erik Gilhus,1,2 Jone F. Owe,1,2 Jana Midelfart Hoff,1,2 Fredrik
Romi,1,2 Geir Olve Skeie,1,2 and Johan A. Aarli1,2
Department of Clinical Medicine, University of Bergen, 5020 Bergen,
Norway
2
Department of Neurology, Haukeland University Hospital, 5021
Bergen, Norway
1

Received 14 April 2011; Accepted 11 August 2011


Academic Editor: Renato Mantegazza
Copyright 2011 Nils Erik Gilhus et al. This is an open access article
distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

Abstract
Patients with autoimmune myasthenia gravis (MG) should be further
classified before initiating therapy, as treatment response varies for

ocular versus generalised, early onset versus late onset, and


acetylcholine receptor antibody positive versus MuSK antibody positive
disease. Most patients need immunosuppression in addition to
symptomatic therapy. Prednisolone and azathioprine represent first
choice drugs, whereas several second choice options are
recommended and should be considered. Thymectomy should be
undertaken in MG with thymoma and in generalised, early-onset MG.
For MG crises and other acute exacerbations, intravenous
immunoglobulin (IvIg) and plasma exchange are equally effective and
safe treatments. Children and females in child bearing age need
special
attention
regarding
potential
side
effects
of
immunosuppressive therapy. MG pathogenesis is known in detail, but
the immune therapy is still surprisingly unspecific, without a pinpointed attack on the defined disease-inducing antigen-antibody
reaction being available.

1. Introduction
Myasthenia gravis (MG) has a prevalence of 150 per million, with
nearly one million MG patients worldwide. The yearly incidence is 10
15 per million per year [1]. Before any treatment was available the
prognosis was severe, with an expected 50% 10-years mortality. With
modern treatment facilities such as immunotherapy, thymectomy, and
intensive care facilities available, population-based studies show that
MG and non-MG individuals have the same life expectancy [2], but still
often with reduced physical abilities, reduced quality of life, and risk of
complications.
There are three key aspects of MG which define the therapeutic
opportunities.(i)MG is a well-defined autoimmune disease and thus
responds to immunoactive treatment.(ii)MG is caused by impaired
acetylcholine receptor (AChR) stimulation in the postsynaptic skeletal
muscle membrane and thus responds to an increase in AChR activity.
(iii)MG has muscle weakness as the only symptom, and consequently
should respond to measures that increase muscle function and
counteract muscle weakness.
MG treatment is firmly established as the domain of neurologists.
Neurologists should be in charge even if the target organ is skeletal
muscle, disease mechanisms are systemic, thymus is a target organ
for diagnostic, therapeutic and scientific approach, hypoventilation is a
life-threatening symptom, and diplopia often the most troublesome
symptom. Ten percent of MG patients have another autoimmune
disorder in addition, further supporting the need for complementary
medical competence. Close cooperation with other fields of medicine
provides knowledge regarding new immunoactive drugs, thus
expanding the therapeutic opportunities for MG.

For complicated and rare disorders such as MG, the establishment of


medical centres supervising the treatment of the majority of MG
patients and of all complicated patients is important to improve
treatment quality. Increased treatment experience will optimize
present therapy and facilitate the introduction of new and better
treatment procedures. Centres with special competence and
qualifications in MG treating the majority of patients will further
enhance research, including well-controlled and prospective treatment
studies.
Ideally treatment recommendations should be based on scientific
evidence of high quality, preferentially more than one blinded and
controlled prospective study with a sufficient number of well-defined
MG patients. There are disappointingly few such studies for MG.
Recommendations therefore, rely on studies of lower quality and even
sometimes only on case reports, clinical experience, and knowledge
from non-MG treatment. It is important for patients as well as doctors
to know which treatment is supported by high-quality evidence and
which is more tentative and based on clinical experience and
circumstantial evidence.

2. MG Classification
The various subgroups of autoimmune MG respond differently to
treatment. Thus, before deciding any treatment, all individual MG
patients should be defined according to subgroups. Classification
aspects reflect the investigations of each patient that are necessary to
undertake [3]:(1)early-onset MG: age at onset <50 years. Thymic
hyperplasia;(2)late-onset MG: age at onset >50 years. Thymic atrophy;
(3)thymoma-associated MG;(4)MG with anti-MuSK antibodies;(5)ocular
MG: symptoms only from periocular muscles;(6)MG with no detectable
AChR and MuSK antibodies;
The MG group with no detectable antibodies is heterogeneous. Some of
these patients have low-affinity AChR antibodies that are not
detectable by the routine assays and sometimes also thymic
hyperplasia [4]. Some may similarly have undetectable MuSK
antibodies, and some most probably have autoantibodies against other
antigen(s) in the postsynaptic membrane. There are not yet any
commercial tests available for the low-affinity AChR antibodies [5]. MG
patients with a thymoma have nearly always detectable AChR
antibodies in serum. Necessary investigations include tests for AChR
and MuSK autoantibodies and CT/MR of the anterior mediastinum. Titin
and ryanodine receptor antibodies may be helpful for classification. For
patients with no AChR and MuSK antibodies, it is necessary with
thorough examinations to exclude other causes for their muscle
weakness,
including
nonautoimmune
myasthenic
syndromes.
Neurophysiological examinations with repetitive nerve stimulation and

jitter measurements are important to establish the initial diagnosis,


especially in patients without detectable antibodies.
MG should be classified according to severity [6]. This is important
when deciding specific treatment in the individual patient. It is also
important in the followup to evaluate effects of various interventions.
An accurate MG severity evaluation is crucial for controlled therapeutic
studies. MG represents a challenge for such evaluation due to variation
among muscle groups and variation during the day.
MG in early childhood poses special treatment challenges linked to
growth and development in general and of the immune system [7]. The
same is true for treatment of MG women in childbearing age, mainly
due to potential effects of the disease and the therapies on the
developing child in utero [8]. Epidemiology differs between ethnic
populations and also regarding the frequency of the various MG
subgroups [9]. However, MG patients are classified in the same way
universally. Nonautoimmune myasthenic syndromes (genetic, toxic)
and non-MG autoimmune syndromes (LEMS, neuromyotonia) are not
included in this review.

3. Treatment of Acute Exacerbations


Acute exacerbations of MG need effective and urgent life-saving
treatment. Life-threatening hypoventilation is the utmost threat.
Plasma exchange and intravenous immunoglobulin (IvIg) are both
effective for acute MG [10]. Their beneficial and symptom-relieving
effect is regarded as well proven from several studies and from
widespread clinical use [11]. In contrast to most other treatment
options, the clinical response is rapid, occurring already after 2-3 days
and often with a dramatic effect. This treatment should be given for
severe exacerbations and is mandatory for MG crisis or threatening
crisis. Plasma exchange or IvIg can also be used for less severe
exacerbations, before surgery or together with initiation of
immunosuppressive therapy with a slower effect [12]. Severe MG
exacerbations with impaired respiratory function need hospitalization
and often intensive care treatment.
Plasma exchange and IvIg have a similar clinical effect, and a similar
responder rate. The only controlled and randomised study did not show
any difference for these two treatment options [13]. Also
nonrandomised evidence favours an equal effect, although the clinical
impression may be a somewhat faster and more extensive effect for
plasma exchange. IvIg has less side effects and less severe side
effects. Optimal technique and high experience reduce the
complication rate, especially for plasma exchange. Both treatment
options are expensive, but IvIg represents a simpler procedure and
may be superior from a total economic perspective [11]. Patients

responding to plasma exchange and IvIg are not necessarily the same.
Thus, if one treatment fails, the other may well be tried. It should be
more convenient to add IvIg after plasma exchange than doing the
procedure the other way around, this is to avoid washing away all
therapeutic immunoglobulin just given to treat the patient.
For severe MG and in an acute situation, high-dose parenteral
corticosteroids can be given and also in addition to plasma exchange
or IvIg [10]. An early exacerbation can be seen after initiation of
corticosteroids, but with pharmacological doses, a therapeutic effect
often appears very early.

4. Drug Treatment
4.1. General
Patients with the diagnosis of MG should always be considered for
symptomatic as well as immunoactive drug treatment. Nearly all
patients need some treatment, at least in periods where the disease
shows clinical activity with permanent or intermittent muscle
weakness. Symptomatic drugs have a short-lasting activity both
regarding effect and side effects. Dosage can be rapidly changed and
the treatment is flexible. Immunoactive drugs have an effect linked to
pathogenesis, and the effect usually needs some time before it
becomes manifest. Side effects are relevant and should be considered
in a long-term perspective. Immunoactive drugs need special attention
in children and MG women of childbearing age [6]. Thus, the
considerations for patient and doctor are different for symptomatic and
immunoactive drug treatment.
4.2. Symptomatic Drugs
Acetylcholine esterase inhibition at the neuromuscular junction has a
symptomatic effect in myasthenia and especially in autoimmune MG
[3, 10, 1416]. Optimal dosage is adjusted according to effect and side
effects. Side effects appear from the nonneuromuscular cholinergic
synapses in the autonomic system, which are overstimulated.
Alternative ways to increase the amount of acetylcholine at the
neuromuscular end plate have been tried, but with less effect than
inhibiting the degradation. Acetylcholine esterase inhibitors have a
stable and predictable effect, apparently unchanged over years. No
scientific comparisons have been undertaken between the various
esterase inhibitors. The most commonly used is pyridostigmine and
also the faster acting neostigmine. Ambenonium is used in some
countries. Some MG patients with anti-MuSK antibodies are
hypersensitive to an increase in acetylcholine concentration.

4.3. Immunoactive Drugs


Prednisone/prednisolone remains a first-choice drug in MG [3, 1418].
It has a well-proven positive effect experienced through decades of
clinical practice in a high number of patients. However, there are no
formal trials and no scientific comparisons with other drugs. Side
effects occur in most patients, and they are usually of clinical
significance. Prednisone/prednisolone is regarded to be safe in
pregnancy. To reduce the amount of side effects, dosing the drug every
second morning is usually advocated. Most patients keep a sufficient
clinical effect on the MG symptoms with this regimen and with
markedly less side effects. Patients often continue to do well on a very
low every second day dose, but experience an exacerbation if taking
this low dose away. We recommend cautiousness regarding MG
patients doing well and being stable on prednisone/prednisolone in a
low dose; continued long-term treatment may be necessary.
Azathioprine is the other well-established first-choice immunoactive
drug used for MG [3, 1418]. This drug is often used in combination
with prednisone/prednisolone. Formal scientific evidence for its effect
in MG is lacking, but a controlled trial showing the superiority of the
combination prednisoloneazathioprine over prednisolone alone is
much cited [19]. Azathioprine is regarded as safe and with few side
effects, also during long-term treatment. It is listed among drugs that
should not be used in pregnancy, although formal evidence of
teratogenic effects in MG patients is lacking. During the first few
months of treatment, the numbers of leucocytes and leucocyte
subgroups have to be counted weekly. The clinical effect of
azathioprine is slow to appear. Improvement should not be expected to
appear until after 36 months, and full effect of the drug first occurs
after 1-2 years. This is a reason why azathioprine is usually combined
with other immunoactive treatments, such as prednisone/prednisolone,
and especially in the initial phase. Marked improvement on
azathioprine is reported in 7090% of MG patients in open series.
Mycophenolate mofetil is regarded as an alternative drug for mild MG
[3, 1418]. However, after promising results in open MG patient
treatment, randomized and controlled trials failed to confirm a positive
effect [20]. The drug has few and mild side effects and is easy to use
both for patients and doctors. Despite its limitations, mycophenolate
mofetil is still regarded as an alternative drug for mild MG, whereas
more severe MG is usually not treated by this drug because of the
negative controlled trials.
Methotrexate should
be
used
only
when
first-choice
immunosuppressive drugs do not have sufficient effect [3,1418].
Methotrexate has a good and proven effect for other autoimmune
disorders, but is not formally tested for MG. Still it should be tried in

selected MG patients with a marked functional deficit, partly because it


is usually well tolerated.
Cyclosporine A is an inhibitor of T cells and has well-documented
immunosuppressive effects after organ transplantation. A controlled
prospective study with a limited number of included patients proved
the effect of this drug for generalised MG [21]. Due to the danger of
side effects, cyclosporine is regarded as a second-choice immunoactive
drug for moderate to severe MG not responding to azathioprine and
prednisolone [3,1418].
Rituximab is a chimaeric monoclonal antibody that targets B
lymphocytes through its binding to the CD 20 molecule. MG is a
prototype of an antibody-mediated autoimmune disease, and so
rituximab and B-cell depletion are a very promising treatment
alternative. In a recent review by Benveniste and Hilton-Jones [22], the
effect of rituximab in 53MG patients was recorded, including patients
with both AChR and MuSK antibodies. The authors concluded that
markedly positive effects were observed with distinct improvement of
severe symptoms. Rituximab should be reserved for patients with
severe MG, where treatment with prednisolone and at least two other
standard immunosuppressive drugs has failed. For milder MG, the risk
of progressive multifocal leucoencephalopathy and other potential
long-term side effects probably outweigh its therapeutic potential. This
drug seems to be particularly useful for anti-MuSK MG.
Tacrolimus (FK506) is a calcineurin inhibitor just as cyclosporine. The
drug inhibits the proliferation of activated T lymphocytes, but also acts
on ryanodine receptor-mediated calcium release from sarcoplasmic
reticulum in muscle cells. The drug has shown a beneficial effect in MG,
and it represents an alternative second-choice drug for moderate to
severe MG [3, 1418], perhaps especially for MG patients with
ryanodine receptor autoantibodies [23].
Other drugs, such as cyclophosphamide and several new and selective
immunosuppressive drugs, have probably a positive effect on MG, as
they have on other autoimmune disorders. However, this effect has not
been documented so far or is less well documented than for the abovementioned drugs. Potential side effects are significant.

5. Thymectomy
Thymectomy should be undertaken in all the 1015% of MG patients
with a thymoma. MG improvement sometimes occurs in such patients,
but less consistently than in patients with a hyperplastic thymus. The
main reason for thymectomy in thymoma patients is to remove a
potentially infiltrating tumour [24]. In some patients with no or very
mild MG symptoms, a severe exacerbation of MG with an increase in

AChR autoantibodies has been reported after the removal of a


thymoma [25].
Thymectomy should always be considered as an early therapeutic
measure in early onset MG with generalised symptoms [3, 10]. Many
patients benefit considerably. Thymic hyperplasia with an enlarged
thymus and numerous germinal follicles is associated with
improvement after thymectomy. Although no blinded and fully
controlled studies have been undertaken, scientific evidence and
clinical experience undoubtedly confirm thymectomy as a therapeutic
option [26]. A transsternal approach and video-assisted thoracoscopy
appear equally effective [27]. Postoperative improvement occurs
gradually after 224 months. Age alone should not decide thymectomy
or not. Some of the MG patients that experience their first symptoms
after the age of 50 years have a hyperplastic thymus and also other
features in common with the early onset MG group. Such patients are
expected to respond to thymectomy.
Nonthymectomy
Late-onset MG patients should also be considered for thymectomy, but
thymectomy is undertaken only in a minority of them [3, 10, 26]. Early
debut age within this late-onset group (<60 years) and thymic
hyperplasia on MR/CT imaging favour thymectomy. Higher age,
symptoms for a longer time period, atrophic thymus, and presence of
non-AChR antibodies against titin and/or ryanodine receptor all count
against
thymectomy.
For MG with purely ocular symptoms, thymectomy is not
recommended. For MG patients with anti-MuSK antibodies, the majority
of evidence points to no therapeutic effect of thymectomy. Anti-MuSK
MG is probably not linked to thymic pathology.
Thymectomy
Some MG patients have no detectable muscle antibodies at repeated
testing and even with generalised myasthenic symptoms. As a
proportion of such seronegative MG patients have low-affinity AChR
antibodies, thymectomy should be an option also for patients in this
group. For patients with generalised MG, onset at relatively low age,
and with a hyperplastic thymus on imaging, thymectomy should in our
opinion
be
performed.
Thymectomy should always be undertaken in hospital units with
experience in this type of surgery. Neurologists should evaluate the
patients immediately before surgery and continuously in the
postoperative phase. The patients should be in a stable condition at
the time of surgery, and the threshold for treatment with plasma
exchange or IvIg preoperatively should be low. Such treatment will
secure a fast recovery and counteract postoperative complications,
most importantly from the respiratory system.

6. Accessory Treatment
During acute MG exacerbations, intensive care therapy with respiratory
support is life saving. Infections should be treated rigorously. The
marked reduction in MG mortality is for a large part due to modern
intensive care therapy [2], although also pharmacological treatment
and thymectomy represent cornerstones in MG therapy.
Physical training, weight control, and sensible life style modifications
should be discussed with all MG patients [10]. Seasonal flu vaccination
should be recommended. Symptomatic ophthalmological treatment
may be helpful for ocular MG with troublesome diplopia.

7. Treatment Principles
MG should be treated early and with vigour, after classification of
subtype and MG severity. Moderate or severe myasthenic weakness
represents an immediate and permanent challenge. Treatment at an
early stage with thymectomy and/or immunoactive drugs improve
long-term outcome. With a lack of initial response, it is not sufficient to
have tried only 2-3 alternative drug options. Drugs can be combined.
Longitudinal measurement of AChR antibodies can be helpful in
evaluating treatment effect and also in the differentiation between MG
and non-MG symptoms experienced by the patient [5]. The clinical
response and evaluation is most important, but there tends to be a
correlation between MG severity/activity and AChR antibody
concentration in the individual patient. There are no studies
systematically and prospectively examining the usefulness of repeated
antibody examinations in established MG. Non-MG drugs given to
patients with MG should always be checked for potential adverse
neuromuscular effects.
Most MG patients are in the need of long-term therapy. For patients in
a stable remission when on immunoactive drugs, a conservative policy
regarding full drug withdrawal is recommended. A low-dose
prednisolone, azathioprine, or other immunoactive drugs can in such
patients be sufficient to maintain the stable condition, but also
necessary to avoid new exacerbations. Younger patients in particular,
not least after thymectomy, can obtain a full clinical remission without
any need for continued drug treatment. Late-onset MG patients and
thymoma MG patients usually need life-long treatment.
In 10% of MG patients, the onset is before age 18 years [6]. The
disease is very rare in infancy. In Asian populations, up to 50% of cases
present in adolescence [9]. Most children with MG have AChR
antibodies. Those without antibodies should be thoroughly checked for
non-MG myasthenic syndromes. The response to thymectomy is
usually very favourable, and thymectomy should be done early.

Immunosuppressive drugs are used for moderate and severe cases in


the same way as for adults, but chronic administration of such drugs in
children usually leads to significant side effects. Children more often
obtain full remission after thymectomy, so that withdrawal of
immunosuppressive drugs should be tried after a couple of years,
especially if a marked reduction of AChR antibody titre has occurred.
Pregnancy and giving birth for MG women is usually uncomplicated,
although operative intervention during birth (Caesarean section,
forceps use) occurs more frequently than in controls, related to
prolonged labor [28]. Anticholinesterase drugs and prednisolone are
considered to be safe during pregnancy. Azathioprine and other
immunosuppressive drugs should be withdrawn before a planned
pregnancy and should be avoided in the fetal organ-developing period.
Arthrogryposis occurs with increased frequency in children of MG
mothers, caused by movement inhibition in utero due to transplacental
transfer of mothers AChR antibodies and thereby reduced function of
the fetal AChR [28, 29]. 1015% of the children of MG mothers
experience a transient neonatal MG, usually mild and lasting only a few
days. This risk is influenced by AChR antibody subclass and antigen
specificity [7]. Lactation is recommended by most neurologists
irrespective of mothers immunosuppressive MG drug treatment.
Previous thymectomy does not influence pregnancy and giving birth
negatively and could have a protective effect on neonatal MG [8].
Fathers MG is not known to have any influence on the child, apart from
the increased risk for MG and other autoimmune disease due to
genetic factors.
MuSK-antibody associated MG has a phenotype that differs from nonMuSK MG [14]. The patients tend to have more severe symptoms, and
the therapeutic response is more variable. Cholinesterase inhibitors
should be tried, but considered less beneficial for this subtype. Most
patient series report no confirmed effect of thymectomy.
Immunosuppressive drugs should be tried for the same indications as
in non-MuSK MG. Prednisolone/prednisone and azathioprine have lower
success rate in patients with MuSK antibody MG. As patients with this
MG subtype often have severe and progressive symptoms and from
bulbar and respiratory muscles, effective and intense therapy is
necessary. Most patients use corticosteroids. From many case reports,
rituximab and plasma exchange seem to be important alternatives
often used, and the same is probably true for IvIg [10, 11, 14, 22].

8. Future Treatment
It is a paradox that MG treatment is still so unspecific. MG is the best
characterised autoimmune disease with well-defined pathogenetic
antibodies that impair function through the destruction and inhibition
of muscle cell AChR. Still our therapeutic immunosuppression is aimed

at general mechanisms of the immune system. The external causes for


MG are totally unknown, apart from those 1015% of patients with a
paraneoplastic condition linked to thymic neoplasia.
The ultimate aim of eradicating MG by removing the cause of the
disease seems still far away.
Antigen-specific treatment of MG should be promising, and such
strategies work in animal models. Induction of specific immunological
tolerance to AChR or MuSK, shifting the immune response from harmful
to nonharmful is theoretically possible [3, 30, 31]. Strategies involving
antigen-presenting cells are considered for treatment of autoimmune
disorders, and manipulation of this process could be antigen-specific. Tcell receptor vaccination may be less promising, since T-cell receptor
usage is not very restricted in human MG [32]. A sensible approach
would be to remove the pathogenic autoantibodies specifically, or
remove the plasma cells and/or B lymphocytes producing these
antibodies [3]. So far such treatment has not been cost-effective. The
effect has not been superior to todays standard treatment, costs have
been higher, and procedures more complicated. Administering
nonpathogenic AChR (or MuSK) antibodies to MG patients and thereby
blocking the action of the patients own pathogenic antibodies would
be an alternative experimental approach.
MG is improved by the inhibition of acetylcholine esterase. Other nonAChR molecules could theoretically be influenced therapeutically to
improve the neuromuscular function. So far no such additional
treatment has been established as effective in the clinical situation.
New and more selective immunoactive drugs are marketed worldwide.
These drugs are established as first- or second-line treatment for an
increasing number of autoimmune and inflammatory disorders, due to
their proven superior clinical effect. For MG, these drugs have not been
evaluated in prospective and controlled trials. The present treatment
has reasonably good effect in the large majority of MG patients, so that
most patients have a high level of daily function and with few and
modest side effects of the treatment. However, there is a need for
better and more focused treatment. Such treatment should be
established through formal multicenter trials in MG networks, not by
random and individual off-label use of the drugs. As pathogenesis
differs in MG subgroups, the immunoactive treatment needs to be
individualised. Subgroups of MG will respond differently to various
treatment alternatives. In the future, the detailed evaluation of each
MG patient will hopefully have distinct therapeutic consequences, so
that the treatment regime is tailored according to the specific
autoimmune dysfunction.
http://www.hindawi.com/journals/ad/2011/847393/

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