Aunali Khaku

Clinical Practice Essay

Mentor: Dr. Emma Ciafaloni, University of Rochester Medical Center, Neurology

Myasthenia Gravis

A 28 year-old woman presents with a six-week history of fluctuating eye droopiness and
intermittent double vision. For the past 2 weeks she has been experiencing difficulty
swallowing and her speech has become slurred in several occasions. She also reports
fatigue in her arms and legs and some shortness of breath but denies any numbness or
pain. Physical examination reveals right fatigable ptosis, diplopia on left lateral gaze,
nasal dysarthria, a flat smile and weakness of neck flexion and bilateral deltoids, biceps,
finger extensors, hip flexion and foot dorsiflexion. . How should her case be managed?

The Clinical Problem

Myasthenia Gravis (MG) is a disease of neuro-muscular junction. It is a

prototype autoimmune disorder characterized by the presence of antibodies against the

Acetylcholine receptor (AChR). It usually presents with pathological fatigable muscle

weakness. Symptoms usually begin in one of three muscles groups: eyes (ptosis and

ophthalmoplegia/double vision); bulbar muscles (dysarthria, dysphagia, facial weakness);

limb and trunk musculature (weakness). Respiratory muscles can be involved.

Symptoms are usually more pronounced in the evening. {{2 Drachman,D B. 1994; }}

Epidemiology

Numerous studies have looked at the incidence and prevalence of MG over the

decades. In 2000, Poulas showed a prevalence of 3 in 100,000 persons, {{4 Poulas,K.

2000; }} whereas an earlier study showed a higher prevalence at about 14 per 100,000

persons.{{5 Phillips,L.H.,2nd 1996; }} Most recently, Philips showed that there are

around 60,000 MG patients in the US. {{3 Phillips,L.H. 2004; }} There seems to be an
increase in incidence, probably due to increasing efficiency of diagnosis. There is a

female preponderance for cases with onset before age 40, consistent with many

autoimmune disorders. After age 40 however, the occurrence equalizes between the

sexes.

Etiology/Pathophysiology

MG is an autoimmune neurologic disorder. The defect in humoral immunity is

manifested most commonly by the presence of antibodies against the AChR. {{6 Ricny,J.

2002; }} {{28 Vincent,A. 2003; }} A substantial amount of evidence indicates that these

immunoglobulins play a central role in the pathogenesis of MG. Studies have shown that

MG can be passively transferred to mammals with serum from affected patients {{7

Toyka,K.V. 1975; }} Studies have also shown that plasmapheresis, which reduces the

number of circulating anti-AChR antibodies is beneficial. {{9 Pinching,A.J. 1976; }}

While some of the symptoms can be explained by the passive blocking of the

AChR {{10 Bufler,J. 1998; }} there is actually a more complicated cascade. The

observation that MG patients have lower numbers of muscle AChR suggests that there is

destruction of the motor end plates. Current molecular understanding of MG indicates

that most of the damage comes from the activation of complement and subsequent

destruction of the end plates by endocytosis and proteolysis. {{31 Drachman,D.B.

1982; }}

Humoral immunity however, does not account for all the pathophysiology and

defects in cell mediated immunity have also been shown. The chief observation that

suggests that defective cell mediated immunity plays a role MG is the observation of

thymic abnormalities (thymic hyperplasia and thymoma) in MG patients. {{27

Vernino,S. 2004; }} It is now believed that the primary defect is in antigen specific T-

helper cells which subsequently activate auto-reactive B cells that produce antibodies

directed against the AChR. {{32 Yi,Q. 1993; }} This is buttressed by the fact that there is

an association with the MHC II locus and a correlation with other autoimmune diseases.

{{11 Castleman,B. 1966; }}

Although the exact mechanism of how and why aberrant T cells get activated

remains unknown, a prominent theory suggests that a viral infection of the myoid cells in

the thymus is the initiating event. The CD8 Tc cells then attack these myoid cells which

subsequently puts the skeletal muscles AChR in jeopardy of autoimmune attack. {{1

Kao,I. 1977; }} {{33 Kirchner,T. 1988; }}

While the pathogenesis of MG is fairly well characterized, some gaps exist. For

instance, symptoms of MG do not always correlate with antibody levels, and seronegative

cases have also been documented (although recent evidence suggests that a proportion of

seronegative cases have the anti-musk antibodies present). {{28 Vincent,A. 2003; }}

Nonetheless, the autoimmune attack on the AChR’s then produces the symptoms

characteristic of MG. In normal muscles there are more ACh receptors than needed

which provides a safety factor for muscle contraction. The destruction of ACh receptors

removes this safety factor. More ACh release is now required for normal contraction.

Repeated stimulation diminishes this supply producing weakness. (This is visualized

electro-diagnostically by the observation of decreased amplitude of CMAP to repetitive

stimulation.

Strategies and Evidence:

History and Physical

 While the history and physical is fairly accurate in diagnosing MG, {{26

Meriggioli,M.N. 2004; }} formal diagnosis (characteristic electrophysiologic

abnormalities, response to anti-cholinesterases, and demonstration of circulating

antibodies) is often warranted to rule out mimics.

The natural history of MG is characterized by variable weakness, remissions and

exacerbations. A myasthenic crisis occurs when an exacerbation involves weakness in

the respiratory muscles that endangers ventilation or dysphagia that compromises

nutrition. This is an emergency requiring intubation or parenteral nutrition as the case

may be. {{13 Mayer,S.A. 1998; }}{{14 Thomas,C.E. 1997; }}

A clue to the accurate diagnosis of MG is its characteristic distribution of

weakness. The first symptom in many individuals is either diplopia (double vision due to

ophthalmoplegia) or ptosis. MG without ocular involvement is rare and other conditions

should be excluded before making this diagnosis. {{30 Grob,D. 1987; }} A careful

neurological exam should objectively demonstrate ophthalmoplegia of multiple

extraocular muscles. Other parts of the history and physical may help to rule out MS,

stroke, and focal INO lesions.

The pupillary light reflex is generally intact ruling out a focal CN III palsy.

Ophthalmoplegia is usually fluctuating and not definitively localized to the III, IV, and VI

cranial nerves. Fatigable ptosis, elicited by asking the patient to maintain sustained up-

gaze, (curtain sign) is perhaps one of the most useful features on exam.

A second group of muscles characteristically involved are muscles innervated by

cranial nerve motor nuclei originating in the medulla (face and oropharynx). This

presents with dysarthria, dysphagia, and facial weakness.

 The third muscle group affected by MG is limb and neck muscles. It is

uncommon for MG to present solely with limb and neck musculature involvement

without cranial musculature weakness. Involvement of respiratory muscles predisposes

to exacerbations or crisis. Often a superseding stressor decompensates a patient into a

crisis. Respiratory infections, systemic illnesses, surgeries (including thymectomy),

emotional stresses, medications and pregnancy are all possible triggers. Nonetheless,

spontaneous exacerbations and crisis can occur without evident stressors as well. A

complication to watch out for with respiratory muscle involvement is aspiration.

A minority of patients with severe dysphagia are at risk for malnutrition. These

patients often also have muscular atrophy. The atrophy however, is not a manifestation of

lower motor neuron disease but more a marker of malnutrition as verified by the diffuse

nature of the atrophy and the absence fasciculations. Occasionally some patients may

have fasciculations secondary to cholinergic drugs use.

A minority of MG patients have symptoms restricted to ocular muscles. This

subset is termed purely ocular myasthenia and such patients have lower titers of anti-

AChR and a better prognosis.

The rest of the neurological exam should be normal. Since the sensory system is

unaffected, both protopathic and epicritic sensations should be intact. Generally reflexes

are preserved, even in the weak muscles, although with long standing untreated MG there

might be some reflex changes. (Jozefovicz RF, Logigian E; Ciafaloni E: Disorders of

Neuromuscular Junction Transmission. Year Two case Seminars. Block 2-The Weak

patient. 2007)

Laboratory/chemical and Electro-diagnostic Studies

 The test that is currently regarded as virtually essential to make the diagnosis of

MG is the Tensilon (Edrophonium) test. {{24 Daroff,R.B. 1986; }} Injection of this short

acting acetylcholine-esterase inhibitor IV inhibits breakdown of ACh at the NMJ

transiently reversing symptoms. While the test is fairly sensitive it is difficult to

objectively characterize the response, particularly in ocular myasthenia. Moreover the

test is not without hazard. Since ACh is also utilized by the parasympathetic system,

some patients may develop bradyarrythmias (treated with Atropine). As this is more

likely in older people, EKG’s are recommended in this group. It is better to avoid this

test in asthmatics and people prone to arrhythmias. An alternative to the tensilon test is

the ice-pack test. {{25 Golnik,K.C. 1999; }}

There are 2 major electro-diagnostic studies employed in the diagnosis of MG. In

the repetitive nerve stimulation study, a nerve innervating a weak muscle is stimulated at

3 Hz. A positive MG tests will show more than 10% decrement in the compound muscle

action potential (CMAP) amplitude. This study has a relatively high sensitivity when

multiple muscles are used though other diseases such as myotonic myopathy, periodic

paralysis also show a similar pattern. {{26 Meriggioli,M.N. 2004; }}

The second study is single fiber EMG. In MG, the characteristic findings include

and increase in jitter and blocking. While this is the most sensitive test, it is also

expensive and time consuming and hence rarely performed. The test is also positive in

disorders of acetylcholine release. {{41 Oh,S.J. 1992; }}

Lab studies including hematologic, CSF, urinalysis are usually normal. Detection

of antibodies against the acetylcholine receptor (anti-AChR) is very specific for the

disease. Other auto-antibodies detected include anti-MuSK, modulating anti-AChR

antibody, blocking AChR antibody anti-titin etc {{19 Mihovilovic,M. 2003; }} Patients

with a thymoma usually have elevated anti-striated muscle antibodies. It is important to

realize however that antibody titers do not always correlate with clinical symptoms.

Imaging

Since there is an increased preponderance of patients with thymic hyperplasia or

thymoma imaging with MRI or CT to rule out a thymoma and to stratify patients for

management is the norm.

Differential Diagnosis

After ruling out stroke, MS, INO, toxins (organophosphates, cholinergics), and

thyroid abnormalities, the differential for myasthenia is fairly limited. The most common

disease that masquerades as MG is the Lambert-Eaton myasthenic syndrome (LEMS).

Unlike MG however the weakness associated with LEMS improves with exercise.

LEMS has an increased prevalence in older males, and is frequently associated with

malignancy. EMG studies will rule out myopathies and neuropathies. Bulbar ALS can

also mimic myasthenia as it can present with fatigable dysarthria worse at the end of the

day. Moreover there have also been cases in the literature of ALS with ophthalmoplegia.

{{43 Palmowski,A. 1995; }} Since ALS is a serious life threatening diagnosis this has to

be excluded from the differential.

Treatment

Treatment for MG can be broadly divided into symptomatic treatment, and

treatment to limit disease progression. The most frequent symptomatic treatment is the

use of long acting anticholinesterase medications. Other symptomatic modalities include

the use of eye patches for diplopia, and prisms. IVIG and plasmapheresis are

predominantly acute treatments, targeting the immune system. The treatment modalities

classically defined as disease modifying are corticosteroids, immunosuppressives, and

thymectomy. {{34 Schwendimann,R.N. 2005; }}

Long acting Anticholinestarases

Neostigmine and pyridostigmine are frequently employed. Oral and parenteral

preparations exist. As with edrophonium, these drugs can have muscarinic side effects

such as abdominal cramps, diarrhea and increased salivation. Regimens can be designed

to achieve peak concentrations to coincide with the activity that the patient is most

restricted in. Studies comparing efficacies of the various drugs in this class are lacking.

Despite their relative success, anticholinesterase drugs are not a panacea. Almost

universally, some symptoms persist, side effects occur, underlying pathogenesis continues

and not all patients respond. {{2 Drachman,D B. 1994; }}

Thymectomy

The abundance of evidence suggesting that thymic abnormalities play a major

role in the pathophysiology of MG, provide a rationale for thymectomy. {{21

Sempowski,G. 2001; }} Thymectomy has been one of the greatest successes in the

treatment of MG, and observational studies suggest an efficacy of around 80% in patients

without thymoma. Because of this, thymectomy is routinely recommended for most

patients with generalized MG. The beneficial effects of thymectomy are delayed and

only become clinically evident after months. The two main surgical methods for

performing a thymectomy are transcervical and transthoracic. The removal of the entire
gland is associated with a better outcome. Pre and post-operative plasmapheresis, IVIG

and corticosteroids are routinely used to prophylax against crisis. {{35 Gronseth,G.S.

2000; }}

Plasmapheresis/Plasma exchange

This therapeutic regimen works by removing the humoral autoimmune factors

present in MG. It is primarily used for treating exacerbations and providing rapid relief

in instances such as prior to thymectomy or when initiating corticosteroids.

Plasmapheresis is occasionally used chronically to manage refractory patients. {{36

Dau,P.C. 1977; }} {{39 Illa,I. 2005; }}

IVIG therapy

An alternative to plasmapheresis is the infusion of pooled human IgG. While the

exact mechanism for the therapeutic effect seen by IVIG remains uncertain, numerous

hypotheses have been suggested. The mechanism which enjoys the most popular support

is the supposition that amongst the pooled IgG are some anti-idiotypic antibodies which

react with and remove from the circulation the autoimmune humoral components

responsible for the symptoms of MG. Other mechanisms proposed include the

hypothesis that the pooled IgG inhibits complement mediated lysis and that it modulates

the immune response. IVIG however is not entirely benign. Side effects include

headache, aseptic meningitis, muscle pains, rashes, etc. plasmapheresis and IVIG are

swift, ephemeral, and costly. {{38 Dalakas,M.C. 2004; }} {{39 Illa,I. 2005; }}

Corticosteroids
 Like in other autoimmune disorders, corticosteroids are generally required to halt

disease progression. Apart from immune suppression, corticosteroids may also have an

independent effect on NMJ transmission. Prednisone is generally used. Since initiation

of prednisone has been correlated with a transient worsening of symptoms, a low dose is

used initially and then gradually increased to around 1mg/kg. Therapeutic effects are

usually rapid. Because of the side effects of corticosteroids (osteoporosis, increased risk

of infection, etc) gradual tapers have to be instituted. Alternate day regimens along with

H2 blockers, Vitamin D, biphosphonates, and close monitoring are important. {{42

Schneider-Gold,C. 2005; }}

Other Immunosuppresives

These medications are usually reserved for people who do not show a response to

corticosteroids, thymectomy, and anticholinesterases and as steroid sparing agents for

long-term treatment. Commonly used immunosuppressives include azathioprine (AZA),

cyclophosphamide, cyclosporine, and mycophenolate. {{15 Ciafaloni,E. 2005; }}

Other Issues:

For the most part, a crisis is managed by maintaining vital functions. After

tracheal intubation, cholinergic drugs are usually stopped due to the potential for

increasing pulmonary secretions. {{13 Mayer,S.A. 1998; }}

Drugs to be avoided in MG include the aminoglycoside antibiotics, tetracycline,

bacitracin, clindamycin, quinine, quinidine, procainamide, propranolol, phenytoin,

CCB’s, penicillamine, succinylcholine, magnesium and curare. {{36 Dau,P.C. 1977; }}

 Since MG frequently occurs in women of child bearing age, issues related to

pregnancy are paramount. While it is possible to have a normal pregnancy, frequently

MG will complicate the pregnancy. Many MG therapies are known teratogens, and drugs

and therapies have to be adjusted to minimize harm to the fetus and maximize efficacy

for the mother. It is highly recommended that a woman planning a pregnancy should

consult with her neurologist before the pregnancy. {{16 Ciafaloni,E. 2004;17

Ciafaloni,E. 2004; 15 Ciafaloni,E. 2005; }}

Areas of Uncertainty

Despite the tremendous strides made in the diagnosis and treatment of MG, there

remain many areas of uncertainty. Efforts are underway to better understand and

characterize the pathophysiology of the disease (specific cellular and molecular

immunologic mechanisms). This will aid in designing targeted therapeutic regimens. {{8

Steinman,L. 1990; }} There are an increasing number of trials looking at the role of

alternative immunosuppressives with fewer side effects in MG. One such drug that has

shown considerable promise is Mycophenolate mofetil (MMF). {{15 Ciafaloni,E.

2005; }} {{20 Ciafaloni,E. 2002; }}

Guidelines

Since MG can present in a wide variety of ways, and in a very diverse patient

population, it is difficult to have a standard recommendation for every patient. In a

majority of cases, diagnosis is easily ascertained with Tensilon testing and the history and

physical. Electrodiagnostic testing and AChR Ab titers confirm the diagnosis. Most of

the time treatment has to be individually tailored to suit the specific needs of individual
patients. Evidence based reviews for particular therapeutic regimens have been

conducted and are widely available. The evidence based review for thymectomy for

instance indicates that thymectomy is recommended for most people with generalized

myasthenia. {{21 Sempowski,G. 2001; }} In patients with a thymoma it is mandatory.

In older patients where the risks of surgery may outweigh the benefits, thymectomy

should not be performed. Thymectomy should never be done as an emergency as the

benefits are delayed and it can precipitate a crisis.

Summary and Recommendations

Ina all patients who present with such symptoms, a thorough history and physical

should be performed. In this particular patient, the history and physical strongly suggest

MG. Since she is young and has low risk factors for bradyarrhythmias, Tensilon testing

would be indicated. The diagnosis can be confirmed by testing for AChR Ab. If these

are negative, electro-diagnostic studies (RNS or SFEMG) may be performed. A chest CT

or MRI would also be warranted to look for thymic abnormalities.

Since she has moderate bulbar symptoms, a course of PLEX or IVIG would be

useful to stabilize her. This would also prepare her for chronic immunosuppression using

corticosteroids or other immunosuppressives. When initiating prednisone, a useful

protocol is to start with 20mg po qd and titrate upwards gradually till around 2mg/kg qod.

This dose is maintained for a few months then tapered. A long acting anticholinesterase

like Pyridostigmine (Mestinon) would be prescribed to provide symptomatic relief. This

should be continued as long as symptoms remain. Once the disease goes into remission

due to corticosteroids, Mestinon should be discontinued as it only increases side effects.

 Immunosupressives should also be considered. AZA for instance is a useful

adjunct with steroid sparing effects. Due to the potential for liver toxicity, blood counts

and liver enzymes need to be monitored. While not proven to be teratogenic, its use is

discouraged during pregnancy. Cyclophosphamide and cyclosporine are fairly toxic and

hence reserved for refractory patients. Once again due to the risk for spontaneous

abortion, the use of cyclosporine is discouraged in pregnancy. Anew drug showing great

promise is MMF. Since it is relatively new, its effects during pregnancy remain

uncertain. {{16 Ciafaloni,E. 2004; }}

Since this is a young woman, discussions about thymectomy would be important.

Nonetheless, thymectomy should be deferred till she is stabilized. Thymectomy should

not be performed when pregnant. Since pregnancy can exacerbate MG, a considerable

amount of counseling will need to be done to inform the patient of the risks to both the

fetus and the mother of both some of the therapies, and of untreated MG.

While managing an MG patient can be difficult, it s often touted as one of the great

successes in neuromuscular diseases as often the disease can be adequately controlled if

not put into remission.

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