Myasthenia : epidemiologic features (I)

incidence per year : 2 to 20 / 106

Prevalence : 118-200 / 106 USA : 200 / 106

Increasing frequency in last decades

Onset at any age (from 6 month to more than 80 year-old)

but 60 % before 40 year-old *

Female : 65% *

F/H before 40 year-old : 2.75,

After 40 year-old 1.10 *
*(Goulon et al, 1987)

In Asia : 50% childhood MG mainly ocular ( 10 –15% in Europe and USA)

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 Myasthenia : (II)

Initial manifestations (1st month)

ocular 40%,

oculo-bulbar or bulbar 15 %,

limbs 10%,

Generalised 35 % *

Course

Relapse

Spontaeous worsening in the 3 first years

ocular ---> generalized (40 to 66 %*), most in 12 months

If pure ocular during 2 years : Ocular Myasthenia (14%*)
maximum in 3 first years *
* (Grob et al, 1987, 1487 patients)

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 Myasthenia : (III)

Very variable severity

Swallowing, respiratory 25% mild, 25%
severe (ICU), 50 % intermediate

transitory neonatal myasthenia

Associations

thymus
thymoma 20% and hyperplasia,young female ),

Other autoimmune diseases

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 Case L

21 years-old : long walks  diplopia and left
ptosis quasi total, few hours. Later same
symptomes at noon + speech and swallowing
difficulties
 7 month later. Swallowing problem increse (-
6kg), « nasal speech »
Total ophtalmoplegia
 Mestinon : favourable effect
 15 month : recurence : thymectomy
 1 month later : respiratoiry distress and
increassing swallowing difficulties, weakness
of limbs  intensive care unit
 55 mg cortancyl : positive effect
 Corticodependent 30 mg  Imuran 150 mg/d

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 Myasthenia diagnosis(I)
Clinical clues to diagnosis

Ocular symptoms (diplopia, ptosis), without pupillary

abnormalities

Bulbar» symptoms : swallowing difficulties, nasal speech,

Masticatory and /or lingual problems

Painless muscular fatigability ---> weakness (fall)

Falling neck

Purely muscular involvement (no sensory, no CNS symptoms)

Characteristic combination : ex ptosis and swallowing
problems

worsening with fatigue

chronology : variability
regular day time, menses
relapses

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 Typical of Myasthenia

Combination of facial (orbicularis) and ophthalmoplegia

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 Jaw opening + orbicularis

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 Short term variability for ptosis

T:O T : 5 mn
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 Long term variability for ptosis

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 D Milea

Variability :
Worsening with
effort

Increased ptosis
with sustained upper gaze

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 Limbs fatigability
Mingazzini

T0 T 50 s
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normal > 75 s Dr Eymard
 T 0
Short term variability
Rest beneficial effect

T2
T1
(eyelid closure :
30s)

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 Diagnosis (II)

Electromyography :
Stimulation : 3c/s,
decrement > 10%

Pharmacological test detection of a thymoma
Edrophonium IV, (thoracic CT scan)
Neostigmine IM

If ptosis : ice test

Specific antibodies
Anti-AChR ab

80% of generalized myasthenia

Often negatif in ocular myasthenia
Anti-MuSK

5%, always generalized

All tests may be negative : clinical survey ++++

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 Ice test

application
2 mn

before

Immediately after

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 Prostigmin test 250 mg
subcutaneous injection

Before After
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 Electrophysiological studies

F Fiber EMG
Single
if decrement negative
2 to 3 Hz : several proximal and distal nerve- Increased jitter
muscle to be tested Sensibility >> Specificity
Decrement Dr Christophe Vial
May miss even if weakness
Pr Emmanuel Fournier, Pitié-Salpêtrière

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 Associated diseases

Thymoma : 10 à 15% , mainly after 40 years

Autoimmunes diseases

dysthyroidis (3 to 18%) : Basedow, Hashimoto

Rhumatoid polyarthritis , lupus, sclerodermia

Biermer, hemolytic anemia , cytopenia

vitiligo, pemphigus, Raynaud

Inflammatory myopathies (severe, giant cells,
myocarditis, thymoma), Lambert-Eaton

mastitis .....

patient and familly

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 Myasthenia and Basedow ophtalmopathy

Mme G, born 60

80 : left ptosis, dysphonia, limb
fatigability, swallowing troubles
81 : thymectomia : very favorable
effect. minor symptomes (voice,
ptosis).

86 : exacerbation : swallowing
troubles , diplopia, limb fatigability
95 : Basedow. Exophthalmia,
treatment by neomercazole

Simultaneously : diplopia ,
fluctuating and alternating ptosis ,
bulbar symptoms, limb fatigability

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 Multiple associations

Myasthenia
+
Sclerodermia
Biliairy cirrhosis
Vitiligo
Gougerot-Sjogren

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 Familial form of autoimmune myasthenia

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 Myasthenia Gravis Crisis

Myasthenic crisis to be suspected

if rapid worsening of weakness,
severe swallowing impairment
dyspnoea, orthopnoea, poor coughing
important and short time variability of
symptoms

Cholinergic crisis
If excessive bronchic secretions, fasciculations,
cramping, stiffness and weakness

Both types of crises often intermingled

Care unit survey +++
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MuSK positive MG
female

Generalized , severe

Oculo-Bulbar, scapular, respiratory

Onset mean 35-40 y

Female /Male : 9/10

Atrophy tongue, face, masseters

Poor response to AChE inhibitors

EMG : often negative

Thymectomy : no benefit

Immunosuppressants
involuted
no thymoma

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 MuSK positive Myasthenia gravis

Triple furrow

Severe bulbar involvement

Paralysis and atrophy of Difficult diagnosis , EMG-, poor
tongue response anticholinesterase

Mild form possible infantile form ,discussion with

Neonatal muyasthenia congenital myasthenic syndrome
rare but possible
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 Low affinity AChR Ab
50% of sero- MG

Generalized and ocular

Clinical features and thymus

Response to thymectomy

Similar to AChR positive

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 Ocular myasthenia

10 to 15 % patients

Isolated ocular weakness after 2 years (some exceptions)

Beginning later than generalised MG; about 40 years

Male : 60%

Thymoma is rare

Anti-AChR antibody low or negative (40 à 70%) with
radioprecipitation assay. Low affinity + Multiple
innervation

Anti-MuSK ab negative endplates

Special physiopathology : antibodies specifically directed against

ocular AChR ?, NMJ special vulnerability to anti-AChR ab, multi-
innervated endplates …..

Ocular “plus” recurrent minimal bulbar syndrome
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 Isolated limb and/or axial involvement
No oculo bulbar signs
Misdiagnosis : polymyositis
EMG : may be myopathic
If CPK level nl ->
look for decrement
Anti-ACh R ab
AChE inhibitors

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 distal MG

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 Old patient

Rather frequent

General picture same as in young
patients

Presentation, (oc-bulbar), course

Diagnosis test

Responsive to therapies

Particularities

Mis / Underdiagnosed: stroke

Multiple therapies may be
dangerous : (allopurinol + Imuran)

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 Neonatal Myasthenia Gravis

10 à 15 % of babies born to mothers with

autoimmune myasthenia gravis present NMG

Transitory myasthenic syndrome

Duration from several days to 3 months, then

total recovery

High probability of recurrence in classical

for the next pregnancies

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 fœtal or
adult
AChR
fœtal onset Myasthenia gravis expressed
in oocyte

Much rarer than common NMG

Arthrogryposis,
Hydramnios
Severe and recurrent
Very long lasting
Mother mildly affected
may be unaffected
High proportion of recurrence
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Maternal Fœtal ab
inhibit electively
Fœtal (γ) AChR function
A Vincent
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 Benign Fetal myasthenia

Recenly recognized :

No fetal signs at birth

No fetal signs
severe neonatal Myasthenia
till 6 months
laryngomalacy
Till now : 5y
nasal voice, facial involvement
High Fetal AChR ab titer in mother (γ TE671 cells)

Next pregnancy : mother treated by thymectomy,

and during pregnancy by steroids,
IvIg  50% decrease
unaffected child
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 Myasthenia : diagnosis pitfall (I)
Objectives signs discrete and fluctuating

Missed MG diagnosis :
Blurred vision, little difficulties for swallowing,
fatigability; wrong diagnosis : « psychogenic »;
keep in mind the diagnosis of myasthenia

Excessive MG diagnosis :
« functional » patients : contrast between rich
symptoms but no objective signs during a long
standing observation  test with placebo

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 Differential diagnosis of myasthenia :
isolated, rapid onset unilateral ophthalmoparesis
exclude tumor of cavernous sinus /aneurysm

D Milea In case of isolated ophtalmoplegia :

Cerebral imaging mandatory
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 Ocular myopathy I mitochondriopathy

Progressive non fluctuating evolution

Ophthalmoplegia « plus »

Retinitis pigmentosa

Perception deafness

Heart bloc

Neuropathy

Cerebellar syndrome

But purely OM forms

Ragged red fiber
Muscular biopsy : RRF ,Cox fibers-
Mitochondrial DNA deletion (single, multiple

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 Ocular myopathy II
Oculopharynx myopathy

Late onset after 40 years

Dominant autosomal transmission

Ptosis and swallowing problems

Long lasting disease

Diagnosis :

GCG triplet expansion (PABP) > 7

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Other myasthenic syndromes

Penicillamine (PR, Wilson), if persistance

after medication interruption : true autoimmune MG

Botulism (mydriasis, bowel, dysautonomia, intoxication)

Lambert-Eaton syndrome (dysautonomia, prominent lower

limb weakness, anaplastic cancer in 50% , reduction of motor
potential, potentiation, anti-calcium channel antibody)

Congenital Myasthenic Syndromes : neonatal onset, family history,

myopathic features, double response after single simulation
molecular genetic)

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 Therapy

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 Score
activité
Quotidienne Speech

Sur la semaine Chewing

Max : 0 Swallowing

Day activity Breathing

Score Teeth brushing
The passed week Difficulties holding
a comb

Difficulty rising
from a chair

Diplopia

Ptosis
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 Myasthenia
Symptomatic treatments

Respect of contra-indications

AChE inhibitors

Pyridostigmin, long acting Pyridostigmin

Empiric posology

Beging low, all along day

Adverse effects : cramps, fasciculations, diarrhoea,



ICU

Gastric tube

Ventilation

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Telithromycin, Interferons,
 Treatment interferring with the
immune system: thymectomy

Thymoma. if locally invasive : focused irradiation

Absence of thymoma :

No randomised study

On retrospective studies and physiopathological
arguments

Young patient < 40 years

Generalized form, even mild

With anti-AChR ab, without anti-MuSK ab

Early, but not as an emergency treatment

Usually when corticosteroids are under 20 mg/d

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 Treatment interferring with the
immune system: corticotherapy

Prednisone : progressively 1mg/kg, 4 to 6 weeks, 0.5

mg/kg at the end of 4th month, 0.25 mg/kg at 9ème
month, then search for the minimum efficient dose

Worsening at the begining of treatment : 50%
mechanism ?

Positive effect : 60 à 80 % of cases, = imuran

Secondary effect : weight, diabetes, HTA, stomac,
osteoporosis, infections, insomnia, psychiatric
problems, cataract

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Treatment interferring with the immune
system: immunosuppressive drugs

Azathioprine (imuran)

2 to 3 mg/kg (2 à 3 pills/day), one year

2/3 dose, 2nd year, 1/3 dose, 3rd year

Delayed response (6 to 8 weeks)

remission / improvement : 60 to 80 % cases, = Prednisone

Secondary effect :

Potentiation by zyloric

At onset : immuno-allergic, 2% cas ;

fever, asthenia, eruption, diarrhea, liver and pancreas; treatment
discontinuation

chronical : neutro-lymphopenia, hepatitis (decrease doses),
pancreatis (may be very late), infections, spinocellular carcinomas
skin lymphoma

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Treatment interferring with the immune
system: plasma exchange and IGIV

Plasma exchange

2 or 3 / week CI infection (pulmonary)

IgGIV :

Classically : Only exacerbation

Always associated with corticosteroids/azathioprine

Before surgery (Thymectomy, others)

Efficiency and time of improvement identical

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 STRATEGY

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 Myasthenic score

Barré : max 2.30 : 15
Swallowing

Mingazzini : max 75 s : 15 normal :10

Neck anteflexion abnormal without chocking : 5

Without resistance : 5 chocking

With resistance : 10

Sit from decubitus
Closing lid

Without help : 10
total : 10

With help : 5 partial : 5

impossible : 0
none : 0

oculomotricity
Mastication

normal : 10
normal : 0

Isolated ptosis : 5
abnormal : 10

diplopia : 0
Phonation

Normal speech : 10

Nasal speech : 5

aphonia : 0
Max : 100
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 Myasthenia : therapy strategy

Parameters : thymoma, severity, age

Always : AChE, respect of drugs contra-indications

If thymoma : thymectomy + if extensive thymoma, radiotherapy

Generalized seropositive, until 40 years-old : thymectomy

Severe form (swallowing, respiratory, VC < 60)

Short term : ICU , IV immunoglobulins, plasma exchange

Steroids and/or azathioprine, (young : corticoids, old : imuran)

Severe, resistant ( azathioprine + steroids)

If unsufficient , Mycophenolate mofetyl
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 Myasthenia treatment : peculiar
cases I

Anti-MuSK : anticholinesterase often unsufficient or
badly tolerated may. No thymectomy.
Immunosuppressant, steroids, plasmapheresis > ivIg

Seronegative :

Diagnostic certainty

Same treatment, including thymectomy (long lasting and
exacerbation)

Old patient :

at risk patient,,

Azathioprine > steroids

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 Myasthenia treatment : peculiar
cases II
Ocular myasthenia

Diagnosis problems

AChE inhibitors drug poorly effective

Correction (prisms) but variability

If disabled : steroids: 1/2 mg/kg, 1 year minimally. The

patient’s choice

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Myasthenia treatment : peculiar cases III

Generalized myasthenia resistant to treatment:

Reappraise diagnosis

Is therapy correctly administered or taken ?

Psychological component

Other associated disease : thymoma, dysthyroïdis, other

3rd line :
IV Ig, plasmapheresis
Cyclosprin 2.5 mg/ per day, morning and
Rituximab (monoclonal anti B lymphocytes 1g day O,
day 15, 6 months) ++++ Delayed benefit, 75% of patients
Multifocal leuko-encephalopathy

Cyclophosphamide (bolus)
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 Complete stable remission and antibody specificity in myasthenia
gravis.Bagi et al, Neurology 2013

Complete Stable Remission 22.2% 3.6% 21.9%

Favorable pharm Rem + Minimal 47, 4 % 63.7% 41.9%

Unchanged 17.4 % 27.3% 23.8%d

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