MYASTHENIA
GRAVIS (MG)
Prototypic autoimmune disease in
which antibodies are directed against acetylcholine receptors (AChR) which
impair neuromuscular transmission and produce weakness.
Epidemiology
- prevalence approx.1/10,000
- may occur at any age but there are
2 peak ages of onset:
- 20-30s, female > male
- 60-80s, mostly males
Classification
/ Subgroups
- may classify by pattern of
weakness: ocular, bulbar, generalized
- most begin with ocular involvement
- 10-15% limited to ocular
involvement after 3 years
- may also classify by age of onset
Autoimmune
Neonatal - Transplacental
passage of AChR antibodies or other antibodies (e.g. MUSK)
Juvenile - < 18 yo, more
common in Orientals and often ocular and seronegative
Early onset - 18-50 yo
Late onset - >50 yo,
increased incidence of thymoma (30%)
Seronegative - No AchR
antibodies
Non-autoimmune
Congenital
myasthenic syndromes - Defects in proteins at the NMJ. Can be pre-synaptic,
synaptic or post-synaptic
Grading
System
(MG Foundation
of
Class I
Any ocular
muscle weakness
May have
weakness of eye closure
All other
muscle strength is normal
Class II
Mild weakness
affecting other than ocular muscles. May also have ocular muscle weakness of
any severity.
IIa - Predominantly affecting limb, axial
muscles, or both. May also have lesser
involvement of oropharyngeal muscles.
IIb - Predominantly affecting oropharyngeal
respiratory muscles, or both. May also
have lesser or equal involvement of limb, axial muscles, or both
Class III
Moderate
weakness affecting other than ocular muscles. May also have ocular muscle
weakness of any severity.
IIIa - Predominantly affecting limb, axial
muscles, or both. May also have lesser involvement of oropharyngeal
muscles.
IIIb - Predominantly affecting oropharyngeal,
respiratory muscles, or both. May also
have lesser or equal involvement of limb, axial muscles, or both.
Class IV
Severe
weakness affecting other than ocular muscles. May also have ocular muscle
weakness of any severity.
IVa - Predominantly affecting limb and/or axial
muscles. May also have lesser
involvement of oropharyngeal muscles.
IVb - Predominantly affecting oropharyngeal,
respiratory muscles, or both. May also
have lesser or equal involvement of limb, axial muscles, or both.
Class V
Defined by
intubation, with or without mechanical ventilation, except when employed during
routine postoperative management. The use of a feeding tube without intubation
places the patient in class IVb.
AChR
antibodies
- predominantly IgG
- detectable in
- 75-94% of patients wih
generalized MG
- 29-79% of patients with
ocular MG
- titres “generally” correlate with
disease severity in an individual, but not across a population
- 3 pathogenic mechanisms:
1. AChR antibodies bind to
acetylcholine binding site and block the receptor
2. AChR antibodies cross-link
receptors leading to their internalization and breakdown
3. AChR antibodies bind
complement leading to destruction of the muscle endplate (most common mechanism)
- seronegative patients (lack of detectable AChR antibodies in serum)
- 21-71% of patients with
ocular MG
- 6-25% of patients with
generalized MG
- may have antibodies directed
against other components of the NMJ e.g. MuSK (muscle specific kinase, protein
in postsynaptic membrane required for clustering of AChR at NMJ; anti-MUSK
found in approximatetly 1/3 of seronegative generalized, so 5% overall –
clinical phenotype remains to be determined)
Pathology
- decreased number of AChR at the
neuromuscular junctions (NMJ) of skeletal muscle
- in some cases NMJ has “flattened”
appearance (decreased folding of postsynaptic membrane) as a result of
complement-mediated damage to NMJ.
- type 2 muscle fibre atrophy
(non-specific)
Clinical
Presentation
- most commonly presents with
weakness of extraocular muscles
- ptosis and/or diplopia, +/-
photophobia
- can mimic any pattern of
ophthalmoplegia including pupil sparing IIIrd nerve palsy, internuclear
ophthalmoplegia (INO) or sixth nerve palsy
- Bulbar involvement common
eventually
- dysphagia, dysarthria, dysphonia
(hypernasal or hoarse)
- reduced facial expression, jaw
fatigue
- generally progresses over time so
that within 2 years of onset of ocular MG, 90% have bulbar and proximal
symmetric limb weakness
- muscle weakness is:
- painless
- fluctuates and progressively worsens over course of day
- worsens with prolonged use of
affected muscles (i.e. fatiguable)
- variable distribution and severity,
occasionally very asymmetric
- distal weakness less common and
leg weakness often later (rule out steroid myopathy in treated patient).
- most commonly affected muscle
groups: jaw closure, neck flexors, deltoids, triceps
- may involve respiratory muscles
- bowel and bladder function
preserved
Causes
of exacerbations
- reduction in medications in
treated patient
- systemic illness/infection
- increased body temperature/fever
- thyroid dysfunction (hypo or
hyper)
- pregnancy and menstrual cycle (see
below)
- emotional or physical stress
- drugs that affect neuromuscular
transmission (see below)
Physical
Examination
- pupils UNAFFECTED
- ptosis often worsens after 60-90
seconds of sustained upgaze
- relieved by cooling (put ice over
eye for 2 minutes and reassess)
- look for contraction of frontalis
muscle, as a compensation for ptosis (produces “worried” or “surprised“ look)
- manual elevation of severely
ptotic eyelid may elicit more subtle ptosis on opposite side
- Cogan’s lid twitch sign is a brief excess elevation (“twitch”) of
the eyelid when patient returns to primary position from downgaze after a
sustained upgaze
- diplopia with ophthalmoparesis
- any pattern: vertical, horizontal
or oblique
- worsens with sustained gaze
- common to observe asymmetric
extraocular muscle weakness
- often difficult to ‘map out’
- facial weakness suggested by
inability to bury eyelashes and drooping of corners of mouth
- attempt to smile may produce the
appearance of a “snarl”
- to demonstrate muscle fatigue,
test muscle strength five consecutive times against a constant resistance
- preserved deep tendon reflexes
- no sensory findings
Differential Diagnosis
Brain stem / Spinal cord
mass,
demyelination, stroke
Anterior horn cell
Motor
neuron disease / ALS
Nerve root / Peripheral nerve
GBS / Miller-Fischer variant
CIDP
Lyme,
Diphteria
NMJ
Lambert-Eaton Myasthenic
Syndrome (LEMS; DTRs reduced or absent,
usually leg symptoms and signs predominate, ocular and bulbar involvement less
common and later in course)
Congenital myasthenic
syndromes
Neurotoxins (botulism, venoms)
Drug-induced myasthenia
(penicillamine, curare, quinines, procainamide)
Muscle
Progressive
external ophthalmoplegia (mitochondrial cytopathy)
Inflammatory
or metabolic myopathies
Steroid
myopathy
Hyperthyroidism
/
Muscular
dystrophies e.g Oculopharyngeal
Disorders
associated with MG
- Disorders of thymus, hyperplasia
or thymoma (see below)
- Other autoimmune conditions:
thyroiditis,
- Often a family history of
autoimmune disease (15% vs 1-2% in general population)
Thymus
- abnormalities found in 80% of
patients with MG
- ? site of exposure of autoreactive
B and T cells to AChR
- may be a site of considerable
production of AChR antibodies
- 65% of patients with early onset generalized MG have thymic hyperplasia (not seen on CT scan
– hyperplastic thymus looks normal on CT, seen microscopically)
- 30% of late-onset MG have a thymoma
- less common in early onset and
ocular MG
- rarely (if ever) found if
seronegative
- presence of thymoma worsens
prognosis
Investigations
AChR antibodies (see
above)
-
Highly specific, positive test rules in diagnosis
-
Sensitive for generalized MG, poor sensitivity in ocular MG (75-94%
generalized, 29-79% ocular)
-
Long delay in obtaining results and expensive
Edrophonium / Tensilon test
-
Edrophonium is an injectable short acting acetylcholinesterase inhibitor.
Injection transiently increases acetylcholine levels, improving weakness
secondary to impaired neuromuscular transmission
-
Must have an objective clinical measure e.g. stable ptosis (85-90% sensitive)
-
Less useful for dysarthria, dysphagia, limb weakness
-
Avoid test in presence of asthma, COPD with reactive airways, bradyarrythmias,
significant cardiac disease
-
Procedure: Inject 2 mg IV, wait several minutes for a response. Inject 3 mg,
wait for a response. Inject 5 mg, wait for a response. Maximum dose 10 mg.
-
A response occurs within 2-5 minutes and lasts for 5-10 minutes.
-
Cardiac monitoring is recommended. Atropine must be available in case of
significant bradycardia
-
Not specific, false positives occur especially with ‘softer’ endpoints
Repetitive nerve stimulation (RNS)
-
Repetitive stimulation of a nerve at 3 Hz (supramaximal nerve stimulation)
-
Positive response: Progressive decrement in amplitude of motor response,
>10% decrement is abnormal (Click HERE to
see diagram)
-
RNS of proximal muscles more sensitive (90%) than distal
-
Insensitive for ocular MG (60%)
-
Not specific, false positives especially with decrement of 10-20%, decrement
> 20% much more specific for MG
Single
fiber EMG (SFEMG)
-
Highly sensitive, not specific
-
Abnormalities include:
Jitter - difference in
timing of muscle fiber activation between muscle fibers in a single motor unit (Click
HERE to see diagram)
Block - failure of
neuromuscular transmission at one muscle fiber in a pair (Click
HERE to see diagram)
Ancillary tests:
-
CT chest (rule out thymoma)
-
Pulmonary function tests and bedside spirometry
-
Speech therapy swallowing assessment and Modified Barium Swallow
-
TSH/free T4 (autoimmune thyroid disease)
-
Vit B12 levels (pernicious anemia)
Treatment
Cholinesterase
inhibitors
-
inhibits acetylcholinesterase increasing the amount of acetycholine available
to bind to AChR, thereby improving neuromuscular transmission and weakess in MG
-
does NOT affect course of disease
-
Pyridostigmine / Mestinon
-
Start at 30 mg
-
Dose must be titrated to clinical effect and optimum dose varies in each
individual
-
Onset 30-45 min, peak effect 1-2 h, duration 3-6h (longer in some)
-
Give 30-60 minutes prior to meals to improve bulbar weakness / dysphagia
-
Neostigmine
-
Useful in ICU setting, not used as outpatient
-
Use IV at 1/30 to 1/60 of the
-
Renal excretion, dose reduction in renal failure
-
Side effects: increased sweating, salivation, lacrimation, abdominal cramps,
diarrhea, bronchoconstriction, bronchorrhea, bradycardia (rarely except with
high doses or im/iv use), cholinergic crisis.
-
To ameliorate symptoms, can try giving concurrent medication that blocks
muscarinic but not nicotinic AChR i.e. glycopyrrolate, scopolamine, loperamide,
ipratropium, atropine
Corticosteroids
-
Generally use lower doses initially since high doses carry increased risk of
adverse effects and may paradoxically worsen myasthenic symptoms (~40% of
patients) and in 10% result in the need for respiratory support – onset on
average 4 days after starting (1-14 days) and lasts 4 days (1-21 days).
-
Prednisone
-
Start at 10-20 mg daily and increase every few days by a similar amount to
effect
-
Same dose given on alternate days (e.g. 100 mg every other day instead of 50 mg
per day) may reduce some adverse effects. Some patients can’t tolerate
secondary to fluctuation in weakness with worsening on ‘off’ day
-
Maximum dose 1 mg/kg/d
-
Onset of effect 3-6 months
-
After improvement, taper SLOWLY at rate of 5 mg per month after 2-3 month of
stabilization in symptoms
-
Monitor for adverse effects, in particular osteoporosis (routine use of
bisphosphonate suggested if steroid likely to be used > 6 months), hypertension,
infections, worsening of diabetic control, avascular necrosis of hip, peptic
ulcers, psychosis etc.
Azathioprine
/ Imuran
-
Suppresses both humoral and cellular immune response
-
Concurrent use with steroids may lead to more rapid and successful taper of
steroid
-
Start at 25-50 mg daily, increase q 1-2 weeks until therapeutic dose achieved
(max 2-3.5 mg/kg/day)
-
Allopurinol inhibits breakdown of imuran and therefore need to reduce dose of
imuran if used concurrently (0.5-1 mg/kg/d)
-
Side effects: myelosuppression (may be increased by concurrent use of ACE
inhibitors), infections, hepatotoxicity, rash, alopecia, pancreatitis
-
Follow CBC, LFTs qweekly x 8weeks then monthly
Mycophenolate
/ Cellcept
-
Less experience. In theory more attractive – B cell specific, less toxic
-
Start at 500 mg po bid, increase in 1-3 months to 750 bid, and then to 1000 mg
po bid, up to total of 2500-3000 mg/day.
-
Serum levels can be done to guide dose.
-
Very expensive.
-
Risk of infections increased.
Cyclosporine
-
Use when above treatments have failed since expensive and has significant side
effects
-
Neoral
-
Start at 2-5 mg/kg (lean body weight) divided q12h and adjust to maintain serum
trough of 100-150 ng/ml
-
Metabolised by P450 pathway
-
Monitor for hepatotoxicity, nephrotoxicity, hypertension, gingival hyperplasia,
hirsutism, neuropathy, tremor. Risk of infections increased.
IVIg
-
Useful for acute decline or myasthenic crisis
-
> 2/3 of patients will improve with treatment
-
onset of improvement 7-10 days after starting IVIg therapy, lasts weeks (range
days to months)
-
2 g/kg IV given over 2-5 days, as per protocol
-
Half-life ~ 21 (12-45) days
-
Monitor for side effects: volume overload, rash, fever and flu-like symptoms,
headaches, chest and abdominal pain, anaphylaxis, renal failure, transaminitis,
aseptic meningitis
Plasma
Exchange (PLEX)
-
Useful for acute decline or myasthenic crisis
-
> 2/3 of patients will improve with treatment
-
Equally efficacious as IVIg but may have more adverse effects
-
Reduces AChR titers by 50-70%
-
3-5 exchanges of 5% of body weight (50ml/kg) each over 3-10 days
-
Duration of benefit 2-8 weeks
-
Also effective in seronegative MG
Thymectomy
-
Most accepted indications: seropositive early-onset generalized MG or for
removal of thymoma
-
Removal of thymoma may not improve MG
-
Controversial, at best it may take months to a year or more for the patient to
improve. Retrospective meta-analysis suggests 2X increase in likelihood of
‘remission’ (20% to 40% after thymectomy)
-
34-46% of patients with early-onset MG and thymic hyperplasia will be in
complete remission within 2-5 years of thymectomy and 33-40% significantly
improved
-
Elective procedure, stabilize / optimize patient first
-
Consider pre-op IVIg or PLEX
Drugs
and MG
- A number of drugs have the potential to impair neuromuscular
transmission and worsen MG
- None of these drugs are absolutely
contraindicated but must monitor patient more closely
- Antibiotics: aminoglycosides > macrolides, fluroquinolones
- Antiarrythmics: beta-blockers,
calcium channel blockers, quinidine, procainamide
- Antirheumatic: chloroquine,
penicillamine
- Anesthetic agents:
Non-depolarizing agents (vecuronium, pancuronium, atracurium), succinylcholine
- Magnesium (high levels inhibits
presynaptic voltage-gated calcium channel)
- Dilantin
- ACE inhibitors and allopurinol if
on azathioprine
- see references below for more
complete list
Pregnancy
- 1/3 stable, 1/3 worsen, 1/3
improve in pregnancy
- higher risk of relapse in
post-partum period
- In 1/8 pregnancies, neonatal MG
will occur secondary to transplacental passage of AchR antibodies
- Cholinesterase inhibitors,
steroids, and IVIg are safe in pregnancy. Azathioprine also appears to be safe.
PLEX can be done but care must be taken to avoid volume shifts.
- Magnesium sulfate for treatment of
ecclampsia may worsen MG
- C-section not routinely planned
but should be considered in severe disease
References:
Nicolle, M. The Neurologist
8:2-21, 2002
Vincent, Palace and Hilton-Jones.
Lancet 357:2122, 2001
Continuum, Myasthenia Gravis, 5(3),
1999
Drachman, DB. NEJM 330:1797, 1994
Last
update:
Reviewed
by: Dr. M. Nicolle
Neurological Medicine Pocketbook
©
2003-2004 UWO Neurology Residents
http://www.uwo.ca/cns/resident
All
Rights Reserved
