The neuromuscular junction disorders including myasthenia gravis

THE NEUROMUSCULAR

JUNCTION DISORDERS

part 1

Dr Sudhakar Marella

PARTS OF NMJ

The anatomy of NMJ consist of following parts:

1. Pre-synaptic membrane

2. Synaptic cleft

3. Post-Synaptic membrane

4. Contractile apparatus

• The nerve is separated from the surface of the

muscle by a gap of about 20nm called junctional

cleft.

• Presynaptic membrane contains prejunctional

acetylcholine receptors and active zone.

Synaptic cleft: Lies Between the muscle endplate

and nerve terminal which are held in tight alignment by

basal lamina.

Post synaptic membrane – acetylcholine

receptors: At the post synaptic membrane the area

overlying the nerve terminal is called muscle end plate.

The membrane here is thrown into primary and

secondary clefts.

• At the shoulder of these clefts numerous acetylcholine

receptors are present.

The acetylcholine receptors are nicotinic and are of

following types

a. Junctional or mature

b. Extra junctional or immature

• Nicotinic receptors are broadly classified into two

subtypes based on their primary sites of expression:

1. muscle-type nicotinic receptors and

2. neuronal-type nicotinic receptors.

• In the muscle-type receptors, found at the neuromuscular

junction, receptors are either the embryonic form,

composed of α1, β1, δ, and γ subunits in a 2:1:1:1 ratio,

or the adult form composed of α1, β1, δ, and ε subunits

in a 2:1:1:1 ratio

• The neuronal subtypes are various homomeric or

heteromeric combinations of twelve different nicotinic

receptor subunits: α2 through α10 and β2 through β4

Acetyl choline receptors/Post junctional receptors:

• Present in the post junctional membrane of the motor

end plate & are of nicotinic type. These receptors exist

in pairs.

• It consists of protein made up of 1000 amino acids,

made up of 5 protein subunits designated as alpha, beta,

delta and epsilon joined to form a channel that

penetrates through and projects on each side of the

membrane.

• An average human end plate contains about 15 to 40

million acetylcholine receptors

• Each receptor has central funnel shaped core which is

an ion channel, 4 nm in diameter at entrance narrowing

to less than 0.7nm within the membrane.

• The receptor is 11 nm in length and extends 2nm into

the cytoplasm of the muscle cell.

Aetylcholine receptor. Note 5 subunits, each with 4 membrane-

spanning domains forming a rosette with a central opening. The

central opening acts as an ion channel

When acetylcholine receptors bind to the pentamericcomplex, they induce a conformational change in the proteins of the alpha subunits which opens the channel and occurs only if it binds to both the alpha binding sites.

For ions to pass through the channel both the gates should be open.

Cations flow through the open channel, sodium and calcium in and potassium out, thus generating end plate potential.

Na ions are attracted to the inside of the cell which induces depolarisation.

PREJUNCTIONAL RECEPTORS

• These are nicotinic receptors that control ion channel

specific for calcium which is essential for synthesis and

mobilization of acetylcholine.

• They contain protein subunits that are blocked by non

depolarising muscle relaxants resulting in fade and

exhaustion.

• They are also blocked by aminoglycosides and

polymyxin antibiotics

EXTRAJUNCTIONAL RECEPTOR

• These tend to be concentrated around the end plate,

where they mix with post junctional receptors but may be

found anywhere on the muscle membrane. In them, the

adult epsilon subunit is replaced by the fetal gamma

subunit.

• They are not found in normal active muscle, but appear

very rapidly after injury or whenever muscle activity has

ended.

• They can appear within 18hrs of injury and an altered

response to neuromuscular blocking drugs can be

detected in 24hrs of the insult.

Ach (Synthesis, storage, release)

• Synthesized in the Presynaptic terminal from substrate

Choline and Acetyl CoA.

CHAT

CHOLINE + ACETYL CoA ACETYL CHOLINE

COMT

50% Carrier Facilitated Transport Release

CHOLINE + ACETYL CoA ACETYL CHOLINE

Synaptic Cleft

• Different pools of acetylcholine in the nerve terminal

have variable availability for release

a) The immediately releasable stores, VP2:

Responsible for the maintainance of transmitter release

under conditions of low nerve activity. 1% of vesicles

b) The reserve pool, VP1: Released in response to nerve

impulses. 80% of vesicles

c) The stationary store: The remainder of the vesicles.

• Each vesicle contains approx 12,000 molecules of

acetylcholine, which are loaded into the vesicles by an

active transport process in the vesicle membrane

involving a magnesium dependent H+ pump ATPase.

• Contents of a single vesicle constitute a quantum of

acetylcholine.

• Release of acetylcholine may be

a) Spontaneous or

b) In response to a nerve impulse.

• When a nerve impulse invades the nerve terminal,

calcium channels in the nerve terminal membrane are

opened up.

• Calcium enters the nerve terminal and there is calcium

dependant synchronous release of the contents from 50-

100 vesicles.

• The number of quanta released by each nerve impulse is

very sensitive to extracellular ionized calcium

concentrations.

• Increased calcium concentration results in increased

quanta released.

• If calcium is not present, depolarization of the nerve,

even by electrical stimulation, will not produce release

of transmitter.

• Doubling the extracellular calcium results in a 16-fold

increase in the quantal content of an end plate potential.

• The calcium current persists until the membrane

potential is returned to normal by outward fluxes of

potassium from inside the nerve cell.

• Thus, the calcium current can be prolonged by

potassium channel blockers (e.g., 4-aminopyridine, and

tetraethylammonium), which slow or prevent potassium

efflux out the nerve

• Once the contents have been discharged, they are

rapidly refilled from the reserve stores.

• The reserve vesicles are anchored to actin fibrils in the

cytoskeleton, by vesicular proteins called synapsins

• Some calcium that enters the axoplasm, on the arrival of

the nerve impulse binds to calmodulin, which activates

protein kinase-2 which phosphorylates synapsins, which,

in turn dissociates the vesicle from the actin fibrils

allowing it to move forward to the release site.

• Docking of the vesicle and subsequent discharge of

acetylcholine by exocytosis, involves several other

proteins.

• Membrane protein called SNAREs ( Soluble N-

ethylmatrimide sensitive attachment proteins) are

involved in fusion, docking, and release of acetylcholine

at the active zone.

• SNARE includes – synaptic vesicle protein

synaptobrevin, synataxin and SNAP-25.

Small synaptic vesicle cycle in presynaptic nerve terminals. Vesicles bud off the

early endosome and then fill with neurotransmitter (NT; top left). They then move to the

plasma membrane, dock, and become primed. Upon arrival of an action potential at the

ending, Ca2+ influx triggers fusion and exocytosis of the granule contents to the synaptic

cleft. The vesicle wall is then coated with clathrin and taken up by endocytosis. In the

cytoplasm, it fuses with the early endosome, and the cycle is ready to repeat

• The released acetylcholine diffuses to the muscle type

nicotinic acetylcholine receptors which are concentrated

at the tops of junctional folds of membrane of the motor

end plate.

• Binding of acetylcholine to these receptors increases Na

and K conductance of membrane and resultant influx of

Na produces a depolarising potential, end plate potential.

• The current created by the local potential depolarise the

adjacent muscle membrane to firing level.

• Acetylcholine is then removed by acetylcholinesterase

from synaptic cleft, which is present in high

concentration at NMJ.

• Action potential generated on either side of end plate

and are conducted away from end plate in both

directions along muscle fiber.

• The muscle action potential in turn initiates muscle

contraction

STRUCTURE OF NA CHANNEL

• This Na channel is cylindrical

• Has membrane protein

• Its two ends act as gates

• Both should be open to allow passage of ions.

• Voltage dependent gate is closed in resting state and

opens only on application of a depolarising voltage,

remains open as long as the voltage persists

• The time dependent gate is normally open at rest closing

a few milliseconds after the voltage gate opens and

remains closed as long as the voltage gate is open

• It reopens after the voltage gate closes.

• The channel is patent, allowing sodium ions only when

the gates are open.

POSSIBLE CONFIGURATION OF Na

CHANNELS• Resting state: Voltage gate closed

Time gate open

Channel closed

• Depolarization: Voltage gate open

Time gate open

Channel open

• With in a few milliseconds: Voltage gate open

Time gate closed

Channel closed

• End of depolarization: Voltage gate closed

Time gate open

Channel closed

Major Events in Neuromuscular

Transmission

• Motor neuron depolarization causes action potential to travel down

the nerve fiber to the NMJ

• Depolarization of the axon terminal causes an influx of Ca2+ which

triggers fusion of the synaptic vesicles and release of

neurotransmitter (ACh)

• ACh diffuses across the synaptic cleft and binds to post-synaptic

ACh receptor (AChR) located on the muscle fiber at the motor

end-plate

• Binding of ACh to AChRs opens the channels causing an influx of

Na, depolarization of the sarcolemma that travels down the t-

tubules and ultimately causes the release of Ca2+ from the

sarcoplasmic reticulum - CONTRACTION.

• Unbound ACh in synaptic cleft defuses away or is hydrolyzed

(inactivated) by AChE

Major disorders of the

neuromuscular junction

1. Acquired Myasthenic Syndromes

2. Hereditary and Congenital Myasthenic

Syndromes

Acquired Myasthenic Syndromes

Presynaptic• Botulism

• Lambert-Eaton myasthenic syndrome

Synaptic• Insecticides

Postsynaptic• Myasthenia gravis

• Snake venom toxins

Hereditary and Congenital

Myasthenic Syndromes

Presynaptic

• Episodic apnea

• Paucity of synaptic vesicles

Synaptic

• AChE deficiency

Postsynaptic

• Slow channel syndrome

• Fast channel syndrome

• Primary AChR deficiency

• Rapsyn deficiency

• Plectin deficiency

Myasthenia Gravis

• Myasthenia gravis was first recognised as a distinct clinical entity by Thomas Willis, a 17th century Oxford physician,

• The first modern description was made in 1877 by Samuel Wilks, a London physician.

• The first reasonably complete accounts were those of Wilhelm Erb (1878), who characterized the disease as a bulbar palsy without an anatomic lesion, and of Samuel Goldflam (1893); for many years thereafter, the disorder was referred to as the Erb-Goldflam syndrome.

• Jolly (1895) was the first to use the name myasthenia gravis, to which he added the term pseudoparalytica to indicate the lack of structural changes at autopsy.

• In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane.

• In addition, the postsynaptic folds are flattened, or "simplified."

• These changes result in decreased efficiency of neuromuscular transmission.

• Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials.

• Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction.

• The amount of ACh released per impulse normally

declines on repeated activity (termed presynaptic

rundown).

• In the myasthenic patient, the decreased efficiency of

neuromuscular transmission combined with the normal

rundown results in the activation of fewer and fewer

muscle fibers by successive nerve impulses and hence

increasing weakness, or myasthenic fatigue.

• This mechanism also accounts for the decremental

response to repetitive nerve stimulation seen on

electrodiagnostic testing

Pathophysiology

• Binding of AChR antibodies to AChR results in impairment of neuromuscular transmission in several ways, including the following:

I. Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus accelerating internalization and degradation of AChRmolecules

II. Causing complement-mediated destruction of junctionalfolds of the postsynaptic membrane

III. Blocking the binding of ACh to AChR

IV. Decreasing the number of AChRs at the NMJ by damaging the junctional folds on the postsynaptic membrane, thereby reducing the surface area available for insertion of newly synthesized AChRs

• Patients without anti-AChR antibodies are recognized

as having seronegative MG (SNMG).

• Many patients with SNMG have antibodies against

muscle-specific kinase (MuSK).

• MuSK plays a critical role in postsynaptic differentiation

and clustering of AChRs

Role of the thymus • The role of the thymus in the pathogenesis of MG is not entirely

clear, but 75% of patients with MG have some degree of thymus abnormality (eg, hyperplasia or thymoma).

• Histopathologic studies have shown prominent germinal centers.

• Epithelial myoid cells normally present in the thymus do resemble skeletal muscle cells and possess AChRs on their surface membrane. These cells may become antigenic and unleash an autoimmune attack on the muscular endplate AChRs by molecular mimicry

• Of patients with MG, 75% have thymic disease, 85% have thymichyperplasia, and 10-15% have thymoma.

• Extrathymic tumors may include small cell lung cancer and Hodgkin disease.

• Hyperthyroidism is present in 3-8% of patients with MG and has a particular association with ocular MG

• prevalence of 2–7 in 10,000.

• It affects individuals in all age groups, but peaks of

incidence occur in women in their twenties and

thirties and in men in their fifties and sixties.

• Overall, women are affected more frequently than

men, in a ratio of 3:2.

• The cardinal features are weakness and fatigability of

muscles

• The special vulnerability of certain muscles gives myasthenia

a characteristic stamp.

• Usually the eyelids and the muscles of the eyes—and

somewhat less often of the face, jaws, throat, and neck—are

the first to be affected.

• Infrequently the initial complaint is referable to the limbs.

• More specifically, the weakness of the levator palpebrae or

extraocular muscles is the initial manifestation of the disease

in about half the cases, and these muscles are involved

eventually in more than 90 percent

• Muscles of facial expression, mastication, swallowing,

and speech are affected in 80 percent of patients at

some time in the illness, and in 5 to 10 percent these

are the first or only muscles to be involved.

• Less frequent is an initial or early involvement of the

flexors and extensors of the neck, muscles of the

shoulder girdle, and flexors of the hips

• Of the trunk muscles, the erector spinae are the most frequently affected.

• In the most advanced cases, all muscles are weakened, including the diaphragmatic, abdominal, and intercostal muscles and even the external sphincters of the bladder and bowel.

• The involvement of any group of muscles closely parallels their degree of weakness early in the disease.

• The clinical rule holds that the proximal muscles are far more vulnerable than distal ones, as they are in almost all other forms of myopathy

• As the disease advances, it often spreads from the

cranial to the limb and axial muscles.

• The onset of weakness is usually insidious

• The disease remains exclusively ocular in only 16% of

patients.

• About 87% of patients have generalized disease

within 13 months after onset.

• In patients with generalized disease, the interval from

onset to maximal weakness is less than 36 months in

83% of patients.

• The other characteristic feature of myasthenic

weakness is its tendency to increase as the day wears

on or with repeated use of an affected muscle group,

but patients seldom volunteer this information.

• A few patients report being paradoxically worse on

awakening, especially if they have not received

medication during the night.

• Smooth and cardiac muscles are not involved and

other neural functions are preserved.

• The tendon reflexes are unaffected

• Exposure to bright sunlight, surgery, immunization,

emotional stress, menstruation, and physical factors

might trigger or worsen exacerbations.

• Intercurrent illness (eg, viral infection) or medication can

exacerbate weakness, quickly precipitating a myasthenic

crisis and rapid respiratory compromise.

• Spontaneous remissions are rare.

• Long and complete remissions are even less common.

• Most remissions with treatment occur during the first 3

years of disease

MGFA Clinical Classification

Class I MG :Any ocular muscle weakness

May have weakness of eye closure

All other muscle strength is normal

Class II MG :Mild weakness affecting other than ocular muscles

May also have ocular muscle weakness of any severity

Class IIa:

Predominantly affecting limb, axial muscles, or both

May also have lesser involvement of oropharyngeal muscles

Class IIb:

Predominantly affecting oropharyngeal, respiratory muscles, or both

May also have lesser or equal involvement of limb, axial muscles, or both

Class III MG :Moderate weakness affecting other than ocular muscles

May also have ocular muscle weakness of any severity

Class IIIa MG :

Predominantly affecting limb, axial muscles, or both

May also have lesser involvement of oropharyngeal muscles

Class IIIb :

Predominantly affecting oropharyngeal, respiratory muscles, or both

May also have lesser or equal involvement of limb, axial muscles, or both

Class IV MG :Severe weakness affecting other than ocular muscles

May also have ocular muscle weakness of any severity

Class IVa :

Predominantly affecting limb, axial muscles, or both

May also have lesser involvement of oropharyngeal muscles

Class IVb :

Predominantly affecting oropharyngeal, respiratory muscles, or both

May also have lesser or equal involvement of limb, axial muscles,

or both

Class V MG :

Defined by intubation, with or without mechanical ventilation, except

when used during routine postoperative management

Use of a feeding tube without intubation places the patient in class

IVb

Diagnosis of Myasthenia Gravis

History • Diplopia, ptosis, weakness

• Weakness in characteristic distribution

• Fluctuation and fatigue: worse with repeated activity, improved by rest

• Effects of previous treatments

Physical examination • Ptosis, diplopia

• Motor power survey: quantitative testing of muscle strength

• Forward arm abduction time (5 min)

• Vital capacity

• Absence of other neurologic signs

Laboratory testing

• Anti-AChR radioimmunoassay: 85% positive in generalized MG; 50% in ocular MG

• 40% of AChR antibody–negative patients with generalized MG have anti-MuSK antibodies.

• Repetitive nerve stimulation: decrement of >10% at 3 Hz: highly probable

• Single-fiber electromyography: blocking and jitter, with normal fiber density; confirmatory, but not specific

• Edrophonium chloride (Tensilon) 2 mg + 8 mg IV; highly probable diagnosis if unequivocally positive

• For ocular or cranial MG: exclude intracranial lesions by CT or MRI

Antibodies to Achr or Musk

• Anti-AChR antibodies are detectable in the serum of 85% of all myasthenic patients but in only about 50% of patients with weakness confined to the ocular muscles.

• The presence of anti-AChR antibodies is virtually diagnostic of MG, but a negative test does not exclude the disease.

• The measured level of anti-AChR antibody does not correspond well with the severity of MG

• In an individual patient, a treatment-induced fall in the antibody level often correlates with clinical improvement, while a rise in the level may occur with exacerbations.

Prevalence and Titers of Antibody to

Acetylcholine Receptor in Patients with MG

Osserman MG Class* Mean Anti-AChR Titer (×

10–9 M)

Positive Results, %

R 0.79 24

I 2.17 55

IIA 49.8 80

IIB 57.9 100

III 78.5 100

IV 205.3 89

• Antibodies to MuSK have been found to be present in

40% of AChR antibody–negative patients with

generalized MG, and their presence is a useful

diagnostic test in these patients.

• MuSK antibodies are rarely present in AChR

antibody–positive patients or in patients with MG

limited to ocular muscles.

• These antibodies may interfere with clustering of

AChRs at neuromuscular junctions, as MuSK is

known to do during early development

• Anti-MuSK–positive individuals tend to have more

pronounced bulbar weakness and may have tongue

and facial atrophy.

• They may have neck, shoulder and respiratory

involvement without ocular weakness.

• They are also less likely to respond to acetylcholine

esterase (AChE) inhibitors, and their symptoms may

actually worsen with these medications

Anti–striated muscle antibody

• The anti–striated muscle (anti-SM) Ab test is also

important in patients with MG.

• Anti-SM Ab is present in about 84% of patients with

thymoma who are younger than 40 years and less often

in those without thymoma.

• Thus, a positive test result should prompt a search for

thymoma in patients younger than 40 years.

• In individuals older than 40 years, anti-SM Ab can be

present without thymoma

Antistriational antibody

• Serum from some patients with MG possesses antibodies that bind in a cross-striational pattern to skeletal and heart muscle tissue sections. These antibodies react with epitopes on the muscle protein titin and ryanodine receptors (RyR).

• Almost all patients with thymoma and MG, as well as half of the late-onset MG patients (onset at 50 years or later), manifest a broad striational antibody response.

• Striational antibodies are rarely found in anti-AChR–negative patients.

• They can be used as prognostic determinants in MG; as in all subgroups of MG, higher antibody titers are associated with more severe disease

• Because of a frequent association with thymoma, the presence of titin/RyR antibodies should arouse a strong suspicion of thymoma in a young patient with MG

Electrophysiologic Testing

The following 2 studies are commonly performed:

• Repetitive stimulation of a muscle at 2-3 Hz, also known as repetitive nerve stimulation (RNS)

• Single-fiber electromyography (SFEMG), aimed at evaluating neuromuscular block, jitter, and fiber density

• SFEMG is more sensitive than RNS in assessing MG.

• However, SFEMG is technically more difficult and much more dependent on the experience and skill of the testing physician.

• Consequently, RNS is the most frequently performed neurophysiologic test of neuromuscular transmission

Repetitive nerve stimulation

• During low-frequency (1-5 Hz) RNS, the locally available acetylcholine (ACh) becomes depleted at all neuromuscular junctions (NMJs), and less is therefore available for immediate release. This results in smaller excitatory postsynaptic potentials (EPSPs).

• In patients without MG, all EPSPs exceed the threshold to generate an action potential (ie, there is a safety factor). No change in the summated compound muscle action potential (CMAP) is noted.

• In patients with MG, the number of AChRs is reduced, lowering the safety factor. During RNS, some EPSPs may not reach threshold, which means that no action potential is generated. This results in the decrement in the amplitude of the CMAP

• In patients with myasthenia gravis, this decremental

response usually has a maximum decrement at the

fourth or fifth response, followed by a tendency toward

repair

• A stimulation rate of 1-5 per second should result in a

10% or more decrease in amplitude by the fourth or

fifth action potential; any decrement over 10% is

considered abnormal.

• The most common employed stimulation rate is 3 Hz.

• Patients with MG rarely have a decreased response in

a clinically normal muscle.

• Thus, testing a proximal weak muscle gives a better

yield than testing a unaffected distal muscle, even if

the latter is technically easier.

• Testing a facial muscle (eg, the orbicularis oculi) is

useful because most patients suffer from eyelid

weakness or ptosis.

• RNS results are less likely to be positive in patients

with ocular MG

Factors affecting results

• Lower temperatures increase the amplitude of the

CMAPs.

• Patients with MG may report clinically significant

improvement in cold temp, and they typically report

worsening of ptosis in bright sunlight or on a warm day.

• Therefore, maintaining a constant and perhaps higher-

than-ambient temperature during RNS testing is

important to bring out abnormalities of NMJ function.

• The temperature of the skin overlying the tested muscle

should be at least 34°C.

• Administration of AChE inhibitors before testing may

mask the abnormality and consequently should be

avoided for at least 1 day beforehand

Single-fiber electromyography

• SFEMG is capable of determining jitter (ie, variability of

the time interval between the action potentials of 2

single muscle fibers in the same motor unit) and fiber

density (ie, number of single-fiber action potentials

within recording radius of the needle).

• Increased jitter (with or without impulse blocking) and

normal fiber density are suggestive of a neuromuscular

fiber transmission defect

• SFEMG of the extensor digiti communis (EDC) yields

abnormal results in 87% of patients with generalized

MG.

• Examination of a second muscle raises the sensitivity

to 99%.

• In ocular MG, examination of the frontalis is more

useful than examination of the EDC.

• Frontalis findings are abnormal in almost 100% of

patients, but only about 60% of EDC findings are

abnormal

• Treatment with AChR inhibitors does not normalize

SFEMG results.

• SFEMG findings are abnormal in almost 100% of

patients, whereas RNS findings are abnormal in only 44-

65%.

• SFEMG is a good substitute for RNS in patients with

ocular MG

Anticholinesterase Test

• Edrophonium is used most commonly for diagnostic testing because of the rapid onset (30 s) and short duration (5 min) of its effect

• This test evaluates weakness (eg, ptosis, partial or complete ophthalmoplegia, and forced hand grip) in an involved group of muscles before and after intravenous (IV) administration of edrophonium

• 1 mg (0.1 mL) of edrophonium is given intravenously; if this dose is tolerated and no definite improvement in strength occurs after 45 s, another 3 to 6 mg is injected. If there is no response after another 45 s, an additional 3 to 5 mg may be given over approximately 1 min.

• A total dose of 10 mg is rarely necessary.

• Most patients who respond do so after 3 to 5 mg have been administered

• The use of neostigmine is sometimes preferable to edrophonium because the longer duration of its effect allows more deliberate and repeated testing of muscle function.

• Neostigmine methylsulfate is injected intramuscularly in a dose of 1.5 mg

• After intramuscular injection, objective and subjective improvement occurs within 10 to 15 min, reaches its peak at 20 min, and lasts up to 1 h, allowing for careful verification of the neurologic improvement

• the anticholinesterase-inhibiting drugs carry a rare risk of ventricular fibrillation and cardiac arrest, so that testing should be carried out preferably where emergency support is accessible.

• This test may give both false-negative results and false-

positive results.

• It has a low sensitivity in ocular MG; 50% of patients

presenting with eye symptoms will be missed.

• On the other hand, diseases other than MG, such as ALS

and cavernous sinus lesions can score positive on the test

• This test has been combined with EMG and ocular

tonography to increase its sensitivity in ocular MG;

however, it still produces false-negative and false-positive

results.

• The combination of edrophonium with electronystagmo-

graphic analysis of optokinetic nystagmus, seems

promising for the diagnosis of ocular MG

Ice Pack Test

• The ice pack test (ie, placing ice over the lid) has

gained interest among ophthalmologists for assessing

improvement in ptosis and diplopia in ocular MG.

• The rationale behind this test is that cooling might

improve neuromuscular transmission

Radiography

• On plain anteroposterior and lateral views, radiography

may identify a thymoma as an anterior mediastinal mass.

• A negative chest radiograph does not rule out a smaller

thymoma, in which case a chest computed tomography

(CT) scan is required.

• Chest CT scan is mandatory to identify or rule out

thymoma or thymic enlargement in all cases of MG

• It is essential to rule out mass lesions compressing the

cranial nerves in strictly ocular MG.

• CT or magnetic resonance imaging (MRI) of the brain and

orbit is indicated

• MRI can evaluate for intraorbital or intracranial lesions,

basal meningeal pathology, or multiple sclerosis.

Treatment

• Anticholinesterase Medications

• Immunosuppression

• Thymectomy

Anticholinesterase Drugs

• The usual dose of pyridostigmine is 30 to 90 mg given

every 6 h

• The maximum useful dose of pyridostigmine rarely

exceeds 120 mg every 4–6 h during daytime

• The oral dose of neostigmine ranges from 7.5 to 45 mg

given every 2 to 6 h.

• Neostigmine is poorly absorbed from the GI tract and

should be used only if pyridostigmine is unavailable

• For mild cases without thymic tumor, for patients in

partial remission after thymectomy, and for purely ocular

myasthenia, the use of anticholinesterase drugs may be

the only form of therapy necessary for some period of

time

Corticosteroids

• For the patient with myasthenia with moderate to severe

generalized weakness who is responding inadequately to

anticholinesterase drugs, the long-term administration of

corticosteroids is the most consistently effective form of

treatment

• The usual form of corticosteroid therapy is prednisone (or

corresponding doses of prednisolone), beginning with 15

to 20 mg/ day and increasing the dose gradually until a

satisfactory clinical response is obtained, or until a daily

dose of 50 to 60 mg is reached

• With higher doses or more rapid elevations of the doses,

worsening in the first week is common

• Once the maximal effect from prednisone has been

attained, the dosage can be reduced gradually over

months to the lowest point at which it is still

effective.

• The usual practice has been to then institute an

alternate-day schedule, which diminishes the side

effects

• At the outset of steroid therapy, anticholinesterase

drugs are given simultaneously; as the patient

improves, the dosage of the latter may be adjusted

downward

Immunosuppression

• Immunosuppression using glucocorticoids, azathioprine,

and other drugs is effective in nearly all patients with MG.

• The choice of drugs or other immunomodulatory

treatments should be guided by the relative benefits and

risks for the individual patient and the urgency of

treatment.

• It is helpful to develop a treatment plan based on short-

term, intermediate-term, and long-term objectives.

• If immediate improvement is essential either because of

the severity of weakness or because of the patient's need

to return to activity as soon as possible, IVIg should be

administered or plasmapheresis should be undertaken

• For the intermediate term, glucocorticoids and

cyclosporine or tacrolimus generally produce clinical

improvement within a period of 1–3 months.

• The beneficial effects of azathioprine and mycophenolate

mofetil usually begin after many months (as long as a

year), but these drugs have advantages for the long-term

treatment of patients with MG.

• For the pts refractory to optimal treatment with

conventional immunosuppressive agents, a course of

high-dose cyclophosphamide may induce long-lasting

benefit by "rebooting" the immune system

Mycophenolate mofetil

• One of the most widely used drugs in the treatment of

MG because of its effectiveness and relative lack of side

effects.

• A dose of 1–1.5 g bid is recommended.

• Its mechanism of action involves inhibition of purine

synthesis by the de novo pathway.

• Since lymphocytes lack the alternative salvage pathway

that is present in all other cells, mycophenolate inhibits

proliferation of lymphocytes but not proliferation of other

cells.

• It does not kill or eliminate preexisting autoreactive

lymphocytes, and therefore clinical improvement may be

delayed for many months to a year, until the preexisting

autoreactive lymphocytes die spontaneously

• The advantage of mycophenolate lies in its relative lack

of adverse side effects, with only occasional production

of GI symptoms, rare development of leukopenia, and

very small risks of malignancy or PML inherent in all

immunosuppressive treatments

Azathioprine

• Until recently, it has been the m.c. used immuno-

suppressive agent for MG because of its relative safety in

most patients and long track record.

• Its therapeutic effect may add to that of glucocorticoids

and/or allow the glucocorticoid dose to be reduced.

• However, up to 10% of patients are unable to tolerate

azathioprine because of idiosyncratic reactions consisting

of flulike symptoms of fever and malaise, bone marrow

suppression, or abnormalities of liver function.

• An initial dose of 50 mg/d should be used for several

days to test for these side effects.

• If this dose is tolerated, it is increased gradually to

about 2–3 mg/kg of total body weight, or until the

white blood count falls to 3000 to 4000/L.

• The beneficial effect of azathioprine takes 3–6

months to begin and even longer to peak.

Calcineurin inhibitors

• Cyclosporine and tacrolimus (FK506) are approximately as

effective as azathioprine and are being used increasingly in

the management of MG.

• Their beneficial effect appears more rapidly than that of

azathioprine.

• Either drug may be used alone, but they are usually used

as an adjunct to glucocorticoids to permit reduction of the

glucocorticoid dose.

• The usual dose of cyclosporine is 4–5 mg/kg per d, and the

average dose of tacrolimus is 0.07–0.1 mg/kg per d, given

in two equally divided doses (to minimize side effects).

• Side effects of these drugs include hypertension and

nephrotoxicity, which must be closely monitored.

Rituximab

• Rituximab, a monoclonal antibody that depletes

CD20 B cells, has been used with variable—

sometimes dramatic—success in the treatment of

MG, especially in patients with anti-MuSK antibody.

Plasma Exchange and

Intravenous Immune Globulin

• For severe myasthenia that is refractory to treatment

with AChE drugs and prednisone, or during an acute

worsening

• This form of treatment may be lifesaving during a

myasthenic crisis

• To improve the patient's condition prior to surgery

(e.g., thymectomy)

Plasmapheresis

• It has been used therapeutically in MG.

• Plasma, which contains the pathogenic antibodies, is

mechanically separated from the blood cells, which are

returned to the patient.

• A course of five exchanges (3–4 L per exchange) is

generally administered over a 10- to 14-day period

• A 2-L exchange will remove 80 percent of circulating

antibodies

• Improvement is noted in a couple of days, but it does not

last for more than 2 months.

• In a crisis requiring plasma exchanges and mechanical

ventilation, anticholinesterase drugs should be

discontinued and resume them as the patient is being

weaned from the ventilator

• Complications are primarily limited to complications of

intravenous (IV) access (eg, central line placement) but

also may include hypotension and coagulation disorders

(though less commonly)

Intravenous immune globulin

• It is similarly useful in the short-term control of acutely

worsening myasthenia.

• The usual dose is 2 g/kg given in divided doses over 3

to 5 days

• The mechanism of action of IVIg is not known

• the treatment has no consistent effect on the

measurable amount of circulating AChR antibody

• Adverse reactions are headache, fluid overload, and

rarely aseptic meningitis or renal failure

Thymectomy

• Two separate issues should be distinguished: (1)

surgical removal of thymoma, and (2) thymectomy as a

treatment for MG.

• Surgical removal of a thymoma is necessary because

of the possibility of local tumor spread, although most

thymomas are histologically benign.

• In the absence of a tumor, the available evidence

suggests that up to 85% of patients experience

improvement after thymectomy; of these, 35% achieve

drug-free remission

• Complete removal of thymic tissue is widely considered

to be of the utmost importance, any small remnant

might lead to recurrence

• It is the consensus that thymectomy should be carried out

in all patients with generalized MG who are between the

ages of puberty and at least 55 years

• Remission occurs more frequently in young patients with a

short duration of disease, hyperplastic thymus, more

severe symptoms, and a high antibody titer

• There is also suggestive evidence that patients with MuSK

Ab–positive MG may respond less well to thymectomy

• In ocular MG, thymectomy should be delayed at least 2

years to allow for spontaneous remission or the

development of generalized MG

• The MGFA thymectomy classification is as follows:

T-1 transcervical thymectomy – Basic; extended

T-2 videoscopic thymectomy - Classic or VATS (video-

assisted thoracic surgery) thymectomy; VATET (video-

assisted thoracoscopic extended thymectomy)

T-3 transsternal thymectomy – Standard; extended

T-4 transcervical and transsternal thymectomy

Complications

• Systemically, myasthenic crisis is the most dreadful

complication.

• Aspiration pneumonia also may occur as a

consequence of poor oropharyngeal muscle function.

• Cholinergic crisis may follow excessive treatment with

cholinesterase inhibitors.

• The most common severe complication of MG is

respiratory failure, which often presents with the rapid

deterioration of respiratory effort that ultimately results

in apnea

Myasthenic crisis

• It is a life-threatening condition, which is defined as

weakness from acquired myasthenia gravis (MG) that is

severe enough to necessitate intubation or to delay

extubation following surgery

• The respiratory failure is due to weakness of respiratory

muscles.

• Severe bulbar (oropharyngeal) muscle weakness often

accompanies the respiratory muscle weakness, or may

be the predominant feature in some patients.

• When this results in upper airway obstruction or severe

dysphagia with aspiration, intubation and mechanical

ventilation are necessary

• Myasthenic crisis may be precipitated by a variety of

factors, most often a concurrent infection or some drugs.

• It can also follow a surgical intervention, pregnancy,

childbirth, or tapering of immunosuppressive medications.

• In addition, myasthenic crisis can occur spontaneously as

part of the natural history of myasthenia gravis (MG) itself

• Management of the crisis entails timely and careful

intubation followed by mechanical ventilation in a critical

care unit

• Anticholinergic drugs, which exaggerate secretions, are

best withdrawn at the time of intubation.

• The use of plasma exchange appears to hasten

improvement and weaning from the ventilator.

• When weaning from the ventilator is anticipated,

anticholinesterase agents are reintroduced slowly, and

treatment with corticosteroids can be instituted if

necessary

• Myasthenic crisis frequently occurs within the first 2

years after disease onset, and about one-fifth of the

patients develop crisis episodes within the first year

• Most often myasthenic crisis develops in patients with

generalized myasthenia

• A third of the patients who survive the first crisis

experience a second crisis.

• Myasthenic crisis is more common in patients of

myasthenia gravis associated with thymoma

• Infections are the most common precipitating factors, 30-

40% of cases

Cholinergic Crisis

• Patients taking an excess of acetylcholinesterase

inhibitors may precipitate a cholinergic crisis

characterized by both muscarinic and nicotinic toxicity

• Symptoms may include an increase in perspiration,

lacrimation, salivation and pulmonary secretions,

nausea, vomiting, diarrhea, bradycardia, and

fasciculations

• Although cholinergic crisis is an important consideration

in the evaluation of the patient in myasthenic crisis, it is

uncommon.

• Regardless of whether myasthenic or cholinergic crisis

is suspected, acetylcholinesterase inhibitors should be

significantly lowered or discontinued to avoid excessive

pulmonary secretions in the setting of respiratory

distress.

Drugs with Interactions in MG

• Antibiotics

• Aminoglycosides: e.g., streptomycin, tobramycin,

kanamycin

• Quinolones: e.g., ciprofloxacin, levofloxacin, ofloxacin,

gatifloxacin

• Macrolides: e.g., erythromycin, azithromycin,

• Nondepolarizing muscle relaxants for surgery

• D-Tubocurarine (curare), pancuronium, vecuronium,

atracurium

• Beta-blocking agents

• Propranolol, atenolol, metoprolol

• Local anesthetics and related agents

• Procaine, Xylocaine in large amounts

• Procainamide (for arrhythmias)

• Botulinum toxin

• Botox exacerbates weakness

• Quinine derivatives

• Quinine, quinidine, chloroquine, mefloquine (Lariam)

• Magnesium

• Decreases ACh release

• Penicillamine

• May cause MG

Lambert-Eaton Myasthenic

Syndrome (LEMS)

• Rare presynaptic disorder of neuromuscular

transmission in which quantal release of acetylcholine

(ACh) is impaired

• An autoimmune attack directed against the voltage-

gated calcium channels (VGCCs) on the presynaptic

motor nerve terminal results in a loss of functional

VGCCs at the motor nerve terminals

• VGCC antibody levels do not correlate with disease

severity among patients with LEMS.

• However, antibody levels do fall in individual patients

if the disease improves after cancer therapy or

immunosuppression

• In patients with LEMS who have SCLC or other cancer,

cancer cells presumably contain antigens that mimic

VGCCs and induce production of VGCC antibodies.

• In patients with LEMS but no cancer, VGCC antibodies

are probably produced as part of a more general

autoimmune state.

• In patients who have LEMS without cancer, an antibody

response to domain IV of the 1A subunit of P/Q-type

VGCCs is more common than in patients who have

LEMS with cancer.

• Symptoms of LEMS usually begin insidiously and

progress slowly.

• Many patients have symptoms for months or years

before the diagnosis is made.

• Weakness is the major symptom.

• Proximal muscles are more affected than distal

muscles; lower extremity muscles are affected

predominantly

• LEMS patients never present initially with ocular

weakness; 5% present with bulbar weakness, and 95%

present with limb weakness.

• Increased temperatures from fever or the environment

may worsen the weakness.

• Patients may experience transient worsening after hot

baths and showers or during systemic illnesses.

• The oropharyngeal and ocular muscles are mildly

affected in about one quarter of cases of LEMS, with

symptoms that may include ptosis, diplopia, and

dysarthria, but they are usually not affected to the same

extent or severity as in myasthenia gravis

• Respiratory muscles are not usually affected. When

respiratory muscle function often is involved, the

involvement is usually not as severe as with MG

• Most patients have a dry mouth, which frequently

precedes other symptoms of LEMS. (Many do not mention

this unless specifically questioned.)

• Many patients report an unpleasant metallic taste.

• Some patients have other manifestations of autonomic

dysfunction, including impotence in males and postural

hypotension.

• Exacerbation of weakness has been described after

administration of aminoglycoside or fluoroquinolone

antibiotics, magnesium, calcium channel blockers, and

iodinated intravenous contrast agents.

• Reflexes usually are reduced or absent in LEMS.

• They can frequently be provoked or increased by having

the patient actively contract the muscle group in

question for 10 seconds prior to reflex testing or by

repeatedly tapping the muscles.

• An increase in reflex activity after contraction is a

hallmark of LEMS

Voltage-gated calcium channel antibodies

• Antibodies to voltage-gated calcium channels (VGCCs)

have been reported in 75-100% of LEMS patients who

have small cell lung cancer (SCLC) and in 50-90% of

LEMS patients who do not have underlying cancer.

• They are also found in fewer than 5% of patients with

myasthenia gravis (MG), in up to 25% of patients with

lung cancer without LEMS, and in some patients who do

not have LEMS but have high levels of circulating

immunoglobulins (eg, those with systemic lupus

erythematosus or rheumatoid arthritis).

Acetylcholine receptor antibodies

• ACh receptor (AChR) antibodies are most commonly

associated with myasthenia gravis (MG) and are

occasionally found in low titers in LEMS.

• The only true methods of differentiating MG from LEMS

are the detection of AChR antibodies and the presence

of underlying malignancy.

• In all adult patients with LEMS, diagnostic imaging (eg,

computed tomography [CT] or magnetic resonance

imaging [MRI]) of the chest for cancer detection should

be performed

• If imaging findings are negative in a patient with a

substantial risk of having lung cancer, bronchoscopy

should be performed.

• If both imaging and bronchoscopy results are initially

negative and risk factors for lung cancer are present,

positron emission tomography (PET) scanning should

be considered

Repetitive Nerve Stimulation Studies

Characteristic responses to repetitive

nerve stimulation in patient with

Lambert-Eaton myasthenic syndrome.

(A) Responses elicited from hand

muscle by stimulation of nerve at 3 Hz.

Amplitude of initial response is less

than normal, and response is

decremental. (B) Responses as in A,

immediately after voluntary activation

of muscle for 10 seconds. Amplitude

has increased. (C) Responses in hand

muscle elicited by 20-Hz stimulation of

nerve for 10 seconds. Response

amplitude is less than normal initially,

falls further during first few stimuli, then

increases and ultimately becomes

more than twice initial value.

• RNS studies confirm the diagnosis of LEMS by

demonstrating characteristic findings

• Compound muscle action potentials (CMAPs) recorded

with surface electrodes are usually small, often less

than 10% of normal, and fall during 1- to 5-Hz RNS.

• During stimulation at 20-50 Hz, the CMAP increases in

size (ie, facilitation) and characteristically becomes at

least twice the size of the initial response.

• A similar increase in CMAP size is seen immediately

after the patient voluntarily contracts the muscle

maximally for several seconds

• Facilitation greater than 100% is seen in some but not all

muscles (or in all patients) with LEMS.

• Facilitation greater than 50% in any muscle suggests

LEMS.

• If facilitation is greater than 100% in most muscles tested

or greater than 400% in any muscle, the patient almost

certainly has LEMS.

• If facilitation is less than 50% in all muscles tested, the

patient still may have LEMS, especially if weakness has

been present for only a short time or the patient has been

partially treated.

• In LEMS, the CMAP amplitude is low in most muscles

tested

• When LEMS is mild, the electromyography (EMG)

findings may resemble those of MG, including normal

CMAP amplitudes, decremental response to RNS at low

rates, and little facilitation.

• One helpful feature is that in LEMS, the EMG findings

are usually more severe than the clinical findings would

suggest.

• The opposite is frequently true in MG

Single-fiber electromyography

• The jitter and blocking measured by single-fiber EMG is

increased markedly in LEMS, frequently out of

proportion to the severity of weakness.

• In many endplates, jitter and blocking decrease as the

firing rate increases. This pattern is not seen in all

endplates or in all patients with LEMS.

• Because jitter and blocking may also decrease at higher

firing rates in some endplates of patients with MG, this

pattern does not confirm an LEMS diagnosis unless it is

dramatic and seen in most muscles.

Management

• If an underlying neoplasm is present (eg, small cell lung

cancer [SCLC]), initial treatment should be aimed at the

neoplasm because weakness frequently improves with

effective cancer therapy.

• Typical treatments for patients with SCLC as the cause

of their LEMS would include combination therapy with

cisplatin and etoposide.

• Through both tumor modulation and its direct

immunosuppressive properties, chemotherapy does

seem to improve the symptoms of LEMS.

• In patients with LEMS who do not have cancer,

aggressive immunotherapy should be considered

• A Cochrane review identified only 4 controlled trials of

3,4-diaminopyridine (DAP) and a single cross-over study

that examined the use of IV immunoglobulin (IVIg) and

concluded that there was limited but moderate-to-high-

quality evidence to suggest improved muscle strength

with these interventions

• The initial pharmacotherapy for LEMS is with agents that

increase the transmission of acetylcholine (ACh) across

the neuromuscular junction, either by increasing the

release of ACh (eg,3,4 DAP) or by decreasing the action

of acetylcholinesterase (eg, pyridostigmine).

• If these treatments are not effective and the patient has

relatively mild weakness, aggressive immunotherapy may

be warranted. In such cases, plasma exchange (PEX) or

high-dose intravenous immunoglobulin (IVIg) may be

used initially to induce rapid, but transitory improvement.

• Prednisone and azathioprine, the most frequently used

immunosuppressants, can be used alone or in

combination.

• Cyclosporine may benefit patients with LEMS who are

candidates for immunosuppression but cannot take or do

not respond well to azathioprine