MYASTHENIA GRVIS

Dr. M. SOFI MD; FRCP (London); FRCPEdin;

FRCSEdin

MYASTHENIA GRAVIS OVERVIEWHistorical Background

NMJ PhysiologyPathogenesisClinical ManifestationsDiagnosisTreatmentAssociated ConditionsRelated Disorders

Sir Thomas Willisa woman who

spoke freely and readily enough for a while, but after a long period of speech was not able to speak a word for one or two hours”

This has been interpreted as being the first written description of myasthenia gravis.

History of MG

Thomas Willis (1621–1675)

Chief Opechancanough"The excessive fatigues

he encountered wrecked his constitution.………………his eyelids were too heavy that he could not see unless they were lifted up by his attendants.“While in Jamestown, Chief Opechancanough was able to rest and he then could raise himself up to a standing position.

History of MG

Opchanacanough was a tribal chief of the Powhatan Confederacy of what is now Virginia in the United States, and its leader from sometime after 1618 until his death in 1646.

Most common disorder of NMJ transmission

Annual incidence of 10-20 new cases per million

Prevalence: 14.2:100000 (US) but on rise due to ↓ mortality, longer survival

The M:F ratio of MG in children and adults is 2:3.

Onset of MG at a young age is slightly more common in Asians than in other races

Age of onset has a bimodal distribution Second and third

decades (female predominance)

Sixth to eighth decade (male predominance)

Epidemiology: Myasthenia Gravis

0

20

40

60

80

100

120

140

1st 2nd 3rd 4th 5th 6th 7th 8th

womenmen

n=868

Generalized Myasthenia (Grob et al. ‘81)

0

5

10

15

20

25

30

35

1st 2nd 3rd 4th 5th 6th 7th 8th

womenmen

n=168

Ocular Myasthenia (Grob et al. ‘81)

M-Muscle cell.

T-synaptic terminal Axon

Pathophysiology To understand MG, familiarity

with normal anatomy and functioning of NMJ is necessary.

The nerve terminal of the motor nerve enlarges at its end, which is called the bouton terminale (terminal bulb). It lies within a groove or indentation along the muscle fiber.

The presynaptic membrane (nerve membrane), postsynaptic membrane (muscle membrane), and synaptic cleft (space between the 2 membranes) constitute the NMJ.

Synaptic cleft and postsynaptic membrane with multiple folds and embedded with several acetylcholine receptors.

Chemical synapses Illustration of the major

elements in chemical synaptic transmission.

An electrochemical wave called an action potential travels along the axon of a neuron.

When the wave reaches a synapse, it provokes release of neurotransmitter molecules, which bind to chemical receptor molecules located in the membrane of another neuron, on the opposite side of the synapse.

NMJ Transmission

MG autoimmune channelopathy: antibodies directed against the body's own proteins

Autoantibodies [IgG] develop against ACh nicotinic postsynaptic receptors.

Slight genetic predisposition: HLA types B8 & DR3 predispose for MG. DR1 more specific for ocular myasthenia.

The antibodies are produced by plasma cells, derived from B-cells converted into plasma cells by T-helper cell stimulation.

Cholinergic nerve conduction to striated muscle is impaired and postsynaptic receptor are destroyed.

The cholinergic receptors of smooth and cardiac muscle are not affected by the disease.

Patients become symptomatic once the number of ACh receptors is reduced to about 30% of normal.

Serum IgG from MG patients increases degradation of AChR.

Pathophysiology

NORMAL NMJ

ABNORMAL NMJ

ROLE OF THYMUS IN MG Thymomas were first noticed in MG patients in 1899 C. Weigert Frankfurt. Drs Jacques Miller (London) and Bob Good (USA) in 1960s showed that the thymus was a key ‘immune organ’. It generates ‘T cells’, the control freaks that help to switch on other immune cells to make antibodies and/or destroy germs.1973 physiologists realized that the ACh, the ignition keys, must somehow latch into specialized Ach receptors (AChRs) – the ignition locks. Basic scientists were using snake venoms to purify AChR (from electric fish) It was soon shown that most MG patients had similar antibodies – so giving us a valuable diagnostic test, which is now in routine use around the world

C. Weigert

Jacques Miller

Signs and SymptomsPresenting symptoms of myasthenia gravis and the major considerations in the differential diagnosisPresenting symptoms Other disorders to consider

Ocular (50 percent)

Brainstem and cranial nerve lesions (including Horner's syndrome), thyroid ophthalmopathy, oculopharyngeal muscular dystrophy, chronic external ophthalmoplegia (mitochondrial disease)

Bulbar (15 percent)Brainstem and multiple cranial nerve lesions, motor neuron disease, obstructive or malignant lesion of the nasal and oropharynx

Limb weakness (<5 percent)

Motor neuron disease, chronic inflammatory demyelinating polyneuropathy (CIDP) and other motor neuropathies, multiple radiculopathies, Lambert-Eaton myasthenic syndrome, myopathies

Isolated neck (uncommon)

Motor neuron disease, inflammatory myopathy, paraspinous myopathy

Isolated respiratory (rare)

Motor neuron disease, acid maltase deficiency, polymyositis

Distal limb (rare) Motor neuron disease, CIDP and other motor neuropathies, distal myopathies

Ophthalmic symptoms 75% initially

complain of ptosis and diplopia.

90% of patients with MG develop ocular symptoms.

50% of patients will present solely with ocular symptoms, and about 50-60% of these patients will progress to develop generalized disease.

Ptosis may be unilateral or bilateral, and it may shift from eye to eye.

Non-ophthalmic symptoms 15% present with

bulbar symptoms. 85% with bulbar

weakness develop generalized weakness.

10% present with limb and trunk weakness.

85% of patients with generalized weakness will have limb muscles.

MG can lead to respiratory failure. Can be the first presentation of the disease.

Signs and Symptoms

Ice pack test MG who has ptosis,

placing ice over an eyelid will lead to cooling of the lid, which leads to improvement of the ptosis.

Lightly placing ice that is in a surgical glove or that is wrapped in a towel over the eyelid will cool it within 2 minutes.

Positive test is clear resolution of the ptosis.

This test has a pooled sensitivity and specificity of 82% and 96%, respectively.

Patients with respiratory distress should have an evaluation of pulmonary function.

This evaluation includes pulse oximetry, a measure of pulmonary function ( PEFR, [FEV1]), and ABG sampling to determine PCO2 level.

Evidence of hypoxemia, poor respiratory effort, or CO2 retention is an indication for intubation and mechanical ventilation.

Additional Tests for MG Diagnosis

Anti–acetylcholine receptor antibody

(AChR) antibody (Ab) test is reliable for autoimmune (MG).

Highly specific (100%). Positive in 90% generalized

MG. 50-70% ocular MGFalse-positive anti-AChR Ab test

results occur in: Thymoma without MG L-Eaton myasthenic

syndrome R A treated with

penicillamine, 1-3% of the population

older than 70 years.

Anti-MuSK– antibodies About 1/2 Seronegative MG may

have positive (Anti-MuSK antib) Anti-MuSK (Muscle specific

tyrosine kinase) positive individuals may have more pronounced Bulbar weakness Tongue and facial atrophy. Neck, shoulder and

respiratory involvement without ocular weakness.

Anti–striated muscle antibody The anti–striated muscle (anti-SM)

Ab test is also important in MG. Anti-SM Ab is present in about

84% of patients with thymoma who are younger than 40 years

In individuals older than 40 years, anti-SM Ab can be present without thymoma.

MYASTHENIA GRAVIS DIAGNOSTIC BLOOD TESTS

Generalized myasthenia percent positive

Ocular myasthenia percent positive

AChR antibodies 80 to 90 40 to 55

MuSK antibodies (in AChR Ab negative patients)

40 to 50 <10

Repetitive nerve stimulation 75 <50

Single fiber electromyography 92 to 99 80 to 95

MG: myasthenia gravis; AChR: acetylcholine receptor; MuSK: muscle-specific kinase.

Approximate sensitivity of the confirmatory tests for myasthenia gravis

Osserman Class Mean Antibody Titer (x 10-9 M)

Percent Positive

R (Remission) 0.79 24

I (Ocular only)

2.17 55

IIA (Mild Generalized)

49.8 80

IIB (Moderate Generalized)

57.9 100

III (Acute Severe)

78.5 100

IV (Chronic) 205.3 89

Anti-acetylcholine receptor antibody Positive in 74% of patients. (80% of patients with generalized myasthenia and in 50% of those with pure ocular myasthenia). False-positive anti-AChR occur in: a) Thymoma without Myasthenia

b) Lambert-Eaton Syndrome

c) Small cell lung cancer

d) R A treated with Penicllamine

e) 1-3% population older than 70 years

Laboratory Studies MG

• Plain chest radiographs may identify a thymoma as an anterior mediastinal mass

• Chest computed tomography is important to identify or rule out thymoma or thymic enlargement in all cases of MG

• In strictly ocular MG, magnetic resonance imaging of the brain and orbit is helpful to evaluate for mass lesions compressing the cranial nerves or a brainstem lesion that may masquerade as ocular MG

Other studies (Imaging)

Thymoma

Stage IVa thymoma in a 50-year-old man. Contrast-enhanced chest CT scan shows a primary mass (M) and a pleural drop metastasis (arrow)

THYMOMA ASSOCIATED WITH MG

CT showing Thymoma marked with blue arrow

Muscle fatigability can be tested for many muscles.

A thorough investigation includes:

looking upward and sideward for 30 seconds: ptosis and diplopia

looking at the feet while lying on the back for 60 seconds

keeping the arms stretched forward for 60 seconds

Ten deep knee bends Walking 30 steps on

both the toes and the heels

Five sit-ups, lying down and sitting up completely

"Peek sign": after complete initial apposition of the lid margins, they quickly (within 30 seconds) start to separate and the sclera starts to show

PYSICAL EXAMINATION FOR MG

ALS Basilar artery thrombosis Brain stem gliomas Cavernous sinus

thrombosis Dermatositis/Polymyositis LEMS Multiple sclerosis Sarcoidosis & neuropathy Thyroid disease Tolosa-Hunt Syndrome

Myasthenic syndromes Mitochondrial cytopathies Mitochondrial myopathies

± external ophthalmoplegia

Neurasthenia Oculopharyngeal muscular

dystrophy Botulism Brainstem syndromes Compressive lesions of

cranial nerves Congenital myasthenic

syndromes

MG: DIFFFERENTIAL DIAGNOSIS

CONDITIONS THAT MIMIC OCULAR MYASTHENIA —

 They include the following conditions:

• Thyroid ophthalmopathy• Chronic progressive external

ophthalmoplegia• Myotonic dystrophy and

oculopharyngeal dystrophy• Brainstem and motor cranial

nerve pathologyCONDITIONS THAT MIMIC

GENERALIZED MYASTHENIA • Generalized fatigue — Although

fatigable weakness may be a major aspect of MG, it is important to differentiate this from complaints of generalized fatigue or tiredness.

• Statins and myasthenia — Statin treatment may be associated with a myasthenic syndrome or exacerbation of myasthenia symptoms

• Motor neuron disease —(ALS) can involve the bulbar muscles, leading to facial weakness, dysarthria, or dysphagia. However, ptosis or diplopia as typically seen with MG are NOT features of ALS

• Lambert-Eaton myasthenic syndrome — shares with MG the involvement of the neuromuscular junction, and it has a similar pathophysiology (an autoimmune disease often associated with malignancy).

• Penicillamine-induced myasthenia — Approximately 1 percent of patients treated with penicillamine, usually for rheumatoid arthritis or Wilson's disease, develop an autoimmune myasthenia gravis that shares many of the characteristics of primary MG

CONDITIONS THAT MIMIC MYASTHENIA GRAVIS

Tensilon Test Edrophonium is an AChE inhibitor. Rapid onset (30s) and short

duration of action (about 5 minutes).

Focus on a weak muscle group and evaluate for change.

Initial dose of 2mg given IV. If no change give additional 8mg IV.

Beware cholinergic effects (nausea, diarrhea, salivation, fasciculations, bradycardia).

Have atropine at bedside.

• The ice pack test can be used in patients with ptosis, particularly those in whom the edrophonium test is considered too risky.

• It is not helpful for those with extraocular muscle weakness.

• Since it is based on the physiologic principle of improving neuromuscular transmission at lower muscle temperatures, the eyelid muscles are the most easily cooled by the application of ice.

• In the ice pack test, a bag (or surgical glove) is filled with ice and placed on the closed lid for two minutes. The ice is then removed and the extent of ptosis is immediately assessed.

• The sensitivity appears to be about 80 percent in those with prominent ptosis.

• The predictive value of the test has not yet been established.

Ice pack test 

Repititve nerve stimulation

Anti-AChE inhibitors stopped 6-24 hrs prior to testing.

2-3 electric shocks/second delivered, action potentials recorded.

In normal individual, amplitude of evoked muscle action potential dose not change.

In MG, rapid reduction in the amplitude of the evoked response of more than 10-15%

Single Fiber EMGThe most sensitive test for MG Electrode measures action

potentials of two muscle fibers innervated by the

same motor axon. Variability in time of the 2nd action potential relative

to the 1st is called “jitter”. MG causes increased “jitter”.

ALS Basilar artery thrombosis Brain stem gliomas Cavernous sinus

thrombosis Dermatositis/Polymyositis LEMS Multiple sclerosis Sarcoidosis & neuropathy Thyroid disease Tolosa-Hunt Syndrome

Myasthenic syndromes Mitochondrial cytopathies Mitochondrial myopathies

± external ophthalmoplegia

Neurasthenia Oculopharyngeal muscular

dystrophy Botulism Brainstem syndromes Compressive lesions of

cranial nerves Congenital

MG: DIFFFERENTIAL DIAGNOSIS

Disorders of the thymus Thymoma Hyperplasia of

thymus Autoimmune

disorders Thyroiditis Autoimmune

thyroid disease (3-8%)

RA SLE

Lymphoid Hyperplasia

Rebound Hyperplasia secondary to

Chemotherapy Radiotherapy Corticosteroid

Therapy Thermal Burns Systemic Stress

MG can be exacerbated by hyper/hypothyroidism, occult infection or drugs.

Associated Conditions

Pyridostigmine (Mestinon) is the most commonly used AChE inhibitor.

Peak serum concentrations reach in 90 to 120 minutes and has a similar half-life.

60 to 120 mg every 3 to 4 hours are most effective.

Patients may modify their dose to match their level of activity and to reduce the common adverse side effects of cramping and diarrhea.

It is rare for pyridostigmine alone to improve transmission to a satisfactory level, and therefore most patients require more definitive therapy.

MG TREATMENT OPTIONSAche inhibitors

Sir Henry Dale English physiologist-pharmacologist

Showed that "the actions of acetylcholine are both muscarinic and nicotinic, and at different synapses exert different effects which can be differently antagonized”.

Another application came in the recognition of physostigmine, drug that block the enzymatic destruction of acetylcholine, and so allow this substance to accumulate in cases of deficiency, as in myasthenia gravis.

Dale shared Nobel Prize in 1936 for developing the theory of

neurohumoral transmission.

Sir Henry Dale(1875-

1968)

MG PHAMACOLOGICAL AND PYSIOLOGICAL ADVANCES

Curare– Calabar Bean--

Sir TR Fraser (1860) and his team in Edinburgh found that the Calabar bean poison protects against curare, and they then purified physostigmine from it.

Claude Bernard (1850) French Physiologist showed that the arrow poison Curare works by blocking NMJ. (It is now used to relax muscles during surgery).

February, 1841- January, 1920

July 12, 1813-February 10, 1878

Anti-cholinesterase Inhibitor (AChEI) inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.

Acetylcholinesterase inhibitors: Occur naturally as venoms and poisons. Are used as weapons in the form of

nerve agents. Are used medically:

In myasthenia gravis, to prevent enzymatic breakdown of ACh to increase neuromuscular transmission.

In the treatment of Glaucoma. To treat Alzheimer's disease. To treat Lewy Body Dementia. As an antidote to anticholinergic

poisoning.

Acetylcholine

Acetylcholinesterase

Anti-cholinesterase Inhibitor

MG is one of the most treatable neurologic disorders.

These agents increase the amount of available ACh at the NMJ by inhibiting the degradation of ACh.

Most patients are able to titrate the dosage of their medication to control the symptoms of the disease, but severe exacerbations can occur in patients with previously well-controlled disease

Pyridostigmine is the most used AChE inhibitor.

Peak serum concentrations reach in 90 to 120 minutes and has a similar half-life.

60 to 120 mg every 3 to 4 hours are most effective.

Patients may modify their dose to their level of activity

It is rare for pyridostigmine alone to improve transmission to a satisfactory level, and therefore most patients require more definitive therapy.

Cholinesterase Inhibitors

• The corticosteroid regimen should be tailored according to the patient’s overall improvement.

• The lowest effective dose should be used on a long-term basis.

• Because of the delayed onset of effects, steroids are not recommended for routine use in the emergency department (ED).

• Other medications that are used to treat more difficult cases include – azathioprine,– mycophenolate mofetil,– cyclosporine,– cyclophosphamide

• However, the effectiveness of many of these medications is far from proved, and caution should be advised against using any of them lightly

Immune modulation:Most patients with generalized MG require additional immunomodulating therapy. Immunomodulation can be achieved by various medications, such as commonly used corticosteroids

Mary Broadfoot Walker (1888—1974) was a British physician who first demonstrated the effectiveness of physostigmine in the treatment of myasthenia gravis.

She had noted that the symptoms and signs of myasthenia were similar to those found in curare poisoning, and physostigmine was used as an antidote to curare poisoning at that time.

The first case of MG successfully treated with physostigmine was published in the Lancet in June 1934.

Mary Broadfoot Walker

MYASTHENIA GRAVIS TREATMENT

She was the first to recognize (1935) the association between the condition familial periodic paralysis and hypokalaemia.

Described the glucose challenge test used in diagnosing hypokalaemic periodic paralysis and the use of intravenous potassium in its treatment.

In1935 her research on myasthenia was incorporated into her MD thesis which was submitted via the University of Edinburgh and for which she received a Gold Medal.

Although she never became a Fellow of the Royal College of Physicians she was awarded the Jean Hunter Prize in 1962

Mary Broadfoot Walker

MYASTHENIA GRAVIS TREATMENT

Plasmapheresis The response occurs

over hours to days and is useful to treat or abort

myasthenic crisis preoperatively. Pathogenic antibodies

removed at NMJ. Usually a course of 5 exchanges over a 2

week period is useful for

relief of symptoms.

IVIG The recommended total monthly dose is 2 g/kg

in five daily doses slowly enough to avert rate related side effects.

Half-life of IVIg is about 4weeks, and monthly doses are reasonable, with the goal of slowly tapering the frequency of treatments based on the clinical status.

Clinical responses occur over 2 to 4 weeks.

Plasmapheresis and IVIG

THYMECTOMY Thymus has a central role in

pathogenesis - thymectomy is an important part of Rx.

Radiographic/CT evidence of an anterior mediastinal mass warrants thymectomy at any age because 10% of patients with MG will have thymoma.

In the absence of mediastinal mass, it seems appropriate to counsel the patient to undergo thymectomy to increase the probability of sustained remission. “Ernst Ferdinand

Sauerbruch”, German surgeon (1875-1951) performed thymectomy for the relief of myasthenia gravis.

Fifty-six board-certified neurologists with interest and expertise in myasthenia completed a survey of indications for thymectomy in myasthenia gravis.

Thymectomy was advocated for virtually all patients with thymoma.

Variable subset of patients with generalized myasthenia without thymoma.

Occasionally for selected patients with disabling ocular myasthenia.

EVIDENCE BASED EFFECTIVENESS OF THYMECTOMY IN MG

HEN MECKING

ROGER

SMITH

ARIS

ONASSIS

AMIT BAHCHAN

THANK YOUFOR YOURATTENTION