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 Thelper 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 upgaze, (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 antiAChR 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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