Background he following case reports are to be used as a teaching guide for optometry students and T residents and are relevant for all levels of training. can be a diagnostic challenge because it mimics any pupil-sparing ophthal- Ocular and Generalized moplegia. Neuromuscular anatomy and physiology are reviewed. Ocular and generalized findings for myasthenia gra- Myasthenia Gravis: vis are presented as well as the most cur- rent treatment options available. These A Teaching Case Series cases exemplify the importance of opto- metric in-office history skills, diagnos- Stephanie A. Klemencic, OD, FAAO tic testing and clinical decision-making necessary to effectively diagnose and co- Jessica Condie, OD, FAAO manage emergent and non-emergent cases of myasthenia gravis. David Mei, OD Student Discussion Guide Case Descriptions Abstract Case 1 Myasthenia gravis is an affecting receptors A 67-year-old white male presented in skeletal muscle. Ocular symptoms include variable , and/or to the urgent care optometry clinic re- blurred vision. Ocular manifestations may be the initial symptoms in undi- porting sudden onset right eye ptosis agnosed disease, prompting patients to seek eye care. Symptoms of shortness of and binocular, vertical, diplopia, worse at the end of the day, of one week dura- breath or difficulty swallowing may indicate myasthenic crisis, a life-threatening tion. (Table 1) The patient denied diffi- condition. We present two cases of myasthenia gravis, one with ocular and the culty swallowing, breathing, hoarseness other with generalized disease. These teaching cases exemplify the importance of or generalized weakness. His medical optometric in-office history skills, diagnostic testing and clinical decision-making history was positive for hypertension, necessary to effectively diagnose and manage emergent and non-emergent cases of atrial fibrillation and high cholesterol. myasthenia gravis. He reported good compliance and con- Key Words: diplopia, ptosis, ocular myasthenia gravis, generalized myasthenia trol of these conditions with atenolol, simvastatin, Niaspan, and coumadin. gravis, myasthenic crisis He was a non-smoker and had no drug allergies. He was oriented to person, place and time. Due to the variable and fatigable ptosis and diplopia, which improved with ice pack testing, and without symptoms of generalized involvement, the patient was diagnosed with presumed ocular myasthenia gravis. The following blood work was ordered: acetylcholine recep- tor antibody (AchR) test and thyroid function tests (T3, T4 and TSH). A chest CT was also ordered to rule out thymus gland abnormality. AchR anti- body testing was positive and thyroid function tests returned normal. The Dr. Klemencic is an Associate Professor at the Illinois College of Optometry/Illinois Eye Institute chest CT was normal, with no evidence and Coordinator of the Primary Care/Ocular Disease Residency Program. of . The patient was referred Dr. Jessica Condie is an Assistant Professor at the Illinois College of Optometry/Illinois Eye to a neurologist, who confirmed the di- Institute. agnosis, for treatment and management Dr. Mei is a recent graduate of the Illinois College of Optometry. of his ocular myasthenia gravis. He was started on a course of oral pyridostig-

Optometric Education 129 Volume 39, Number 3 / Summer 2014 Table 1 Case 1 Initial Presentation

OD OS Best-corrected visual acuity 20/20 20/20

External exam Ptosis (variable); + orbicularis oculi weakness; + Normal Cogan’s lid twitch

Pupils ERRL, -APD ERRL, -APD

Extraocular motility Full Full

Confrontation visual field FTFC FTFC

Cover test 4-16 prism diopter intermittent, left hypertropia distance and near; variable and fatiguing Ice pack test See Figures 1 & 2 See Figures 1 & 2

Prolonged upgaze test See Figures 3 & 4 See Figures 3 & 4

Biomicroscopy Normal Normal

Intraocular pressure (GAT) 14 mmHg 14 mmHg

Dilated fundus exam Pink, flat, optic nerve distinct borders; 0.3 c/d; flat, Pink, flat, optic nerve distinct borders; 0.3 c/d; flat, intact retina 360 intact retina 360

FTFC = full to finger count; ERRL = equal, round and reactive to light; APD = afferent pupil defect; GAT = Goldmann applanation tonometry.

Figure 1 Figure 2 Case 1: Before Ice Pack Test Case 1: After Ice Pack Test

Figure 3 Figure 4 Case 1: Before Sustained Upgaze Test Case 1: After Sustained Upgaze Test

Optometric Education 130 Volume 39, Number 3 / Summer 2014 mine, which led to complete symptom resolution. Table 2 Case 2 Case 2 Initial Presentation

A 34-year-old African American female OD OS presented with complaints of intermit- Best-corrected visual acuity 20/20 20/25 tent diplopia and ptosis, worse at the end of the day, for the last year. (Table External exam Ptosis (variable); + orbicularis Ptosis (variable, but consistently oculi weakness; + Cogan’s lid worse than OD); + orbicularis 2) The diplopia fluctuated between twitch oculi weakness; + Cogan’s lid horizontal, vertical and diagonal. She twitch described her left eye as “lazy,” and Pupils ERRL, -APD ERRL, -APD stated it had been getting progressively worse. She also reported foreign body Color vision (Ishihara) normal normal sensation and tearing in her left eye Extraocular motility Restriction 360; see Figure 5 Minimal infraduction only; see for the last two months. Upon ques- Figure 5 tioning, she complained of generalized Exophthalmometry 24 mm 24 mm muscle weakness, difficulty swallowing Forced duction negative negative

and breathing for the last three months. Confrontation visual field FTFC FTFC Her primary care physician had treated her for bronchitis without resolution of Prolonged upgaze test Worsening of ptosis Worsening of ptosis the symptoms. She was sent to an oto- Ice pack test Improvement of ptosis Improvement of ptosis laryngologist, who treated her for post- Biomicroscopy Normal 2+ interpalpebral PEE nasal drip with the same result. The pa- tient’s ocular history was remarkable for Intraocular pressure (GAT) 21 mmHg 21 mmHg spectacle wear at distance and near. Her Dilated fundus exam Pink, flat, optic nerve distinct Pink, flat, optic nerve distinct borders; 0.3 c/d; flat, intact retina borders; 0.3 c/d; flat, intact retina medical history included osteoarthritis, 360 360 herpes simplex type two, depression, keloidosis and seasonal allergies. She FTFC = full to finger count; ERRL = equal, round and reactive to light; APD = afferent pupil defect; was taking Benadryl for seasonal aller- GAT = Goldmann applanation tonometry; PEE = punctate epithelial erosions. gies and naproxen for osteoarthritis. She was a non-smoker and was oriented to time, place and person. Table 3 Case 2 Follow-Up #1 Due to the variable and fatigable oph- thalmoplegia, ptosis, positive Cogan’s OD OS lid twitch and systemic symptoms, Best-corrected visual acuity 20/20 20/20 the patient was diagnosed with pre- sumed generalized myasthenia gravis External exam Ptosis variable and orbicularis Ptosis variable and orbicularis oculi weakness but improved oculi weakness but improved with ocular involvement. The left eye from last exam; see Figure 6 from last exam; see Figure 6 was also diagnosed with exposure kera- Pupils ERRL, -APD ERRL, -APD topathy secondary to incomplete blink.

Both eyes were treated with one drop Extraocular motility Minimal restriction 360; see Moderate restriction primarily in of artificial tears four times per day and Figure 6 adduction; see Figure 6 lubricating ointment applied to the Confrontation visual field FTFC FTFC lower cul-de-sac before bedtime due to Biomicroscopy Normal Normal weakness observed with the orbicularis 18 mmHg 18 mmHg oculi muscles (OS>OD). The patient Intraocular pressure (GAT) was immediately sent to the emergency FTFC = full to finger count; ERRL = equal, round and reactive to light; APD = afferent pupil defect; room because of symptoms of dyspnea, GAT = Goldmann applanation tonometry. dysphagia, and concern for immediate risk of mortality in myasthenic crisis. The patient was given a referral letter pital the same day. Generalized myas- the diplopia and ptosis had improved reporting concern for myasthenic crisis thenia gravis with myasthenic crisis was since initiation of treatment. She also with documentation of her ophthal- confirmed. Sixty milligrams of Mesti- noted improvement of the dyspnea and mological findings and systemic com- non and 50 mg of were ini- dysphagia without complete resolution, plaints to present to the emergency tiated, and the patient was observed in and was under the care of a neurologist room when she arrived. The patient was the hospital for three days. whom she was seeing every two weeks. told to follow up in the eye clinic in one Case 2: Follow-Up #1 The patient’s ocular medication includ- month. ed artificial tears, one drop instilled two The patient was admitted to the hos- The patient returned to the eye clinic times per day in both eyes. The patient one month later. (Table 3) She reported

Optometric Education 131 Volume 39, Number 3 / Summer 2014 was not applying the lubricating oint- Figure 5 ment before bed as instructed at the Case 2: Initial Visit, Nine Cardinal Fields of Gaze last exam. The patient’s systemic medi- cations now included Mestinon 50 mg per day and 60 mg of prednisone per day. A CT of the chest was performed and no thymus gland abnormality was observed. The patient was scheduled to follow up with neurology in one month. The patient was assessed with gener- alized myasthenia gravis with ocular involvement with significant improve- ment of ocular signs with systemic therapy. Both eyes were assessed for exposure keratopathy. The patient was instructed to continue using artifi- cial tears four times per day OU, and instructions for the lubricating oint- ment at bedtime OU were reinforced. The patient was instructed to continue follow-up with neurology for systemic treatment of the generalized myasthe- nia gravis and to follow up in the eye clinic in three months. Figure 6 Learning Objectives Case 2: One Month Follow-Up After Treatment At the conclusion of the case discus- sion, participants should be able to: 1. Understand the pathophysiology of myasthenia gravis 2. Take an appropriate ocular and sys- temic history for patients present- ing with diplopia 3. List and differentiate key ocular and systemic signs and symptoms associated with myasthenia gravis 4. Perform in-office diagnostic testing to help diagnose myasthenia gravis 5. Differentiate myasthenia gravis from other ophthalmoplegias 6. Correlate clinical findings with the patient history to determine diag- nosis 7. Understand ocular and systemic treatment options for myasthenia gravis Key Concepts 1. Understand the neuromuscular anatomy and physiology in myas- thenia gravis 2. A history of variable and fatigable muscle weakness suggests myasthe- nia gravis

Optometric Education 132 Volume 39, Number 3 / Summer 2014 3. Recognize clinical findings of my- 1. What are the classes of medi- is considered a separate diagnosis from asthenia gravis cation used to treat myasthenia generalized MG; yet, most cases of gen- 1 4. Understand the risks and benefits gravis? eralized MG have ocular symptoms. of various diagnostic testing for 2. What are the goals of treat- Epidemiology myasthenia gravis ment for myasthenia gravis pa- The prevalence of MG is approximately 5. Differentiate between emergent tients? 20/100,000/year in the United States.2 and non-emergent referrals for 3. How do you determine what MG has no racial or geographic predi- patients presenting with signs and warrants an emergent vs. non- lection and can affect any age group, symptoms of myasthenia gravis emergent referral? although it is rarer in the first or after 2,4 6. Understand the significance of a 4. What other physicians should the sixth decade of life. Onset tends multidisciplinary approach when co-manage a patient with my- to occur at an earlier age in women than managing individuals with myas- asthenia gravis? in men. In patients with onset prior to thenia gravis age 40, women tend to predominate, 5. How do you manage the pa- whereas over the age of 50 men pre- 7. Understand how to select clinically tient’s ocular symptoms? dominate. In generalized MG the fe- appropriate problem-based testing 6. What surgical treatment op- male to male ratio is 3:2; however, in tions are available? OMG men are more frequently affect- Discussion Points ed, especially after age 40.2,4 MG in the D. Patient Education A. Knowledge of Potential Clinical North American and European pedi- Findings 1. What are potential conse- atric population comprises 10-15% of quences associated with non- MG cases. However, in Asian countries, 1. Describe the classic signs and compliance to the treatment symptoms of ocular myasthe- up to half have an onset before 15 years plan? 3 nia gravis. of age, and most are purely ocular MG. 2. What pertinent information Pathophysiology 2. Describe the classic symptoms should be used to educate pa- Acetylcholine is a neurotransmitter that of systemic myasthenia gravis. tients on the condition? stimulates nicotinic Ach receptors at the 3. Describe the mechanism of 3. Discuss appropriate responses action of the pharmaceutical postsynaptic muscular junction result- to a patient’s anxiety about the 2 agents involved in the diagno- ing in muscle contraction. Neuromus- ocular and/or systemic condi- cular synapses are initiated by action sis and treatment of myasthe- tion, and long-term disease nia gravis. potentials that depolarize motor nerve consequences associated with axons and cause an increase in calcium 4. What in-office tests can op- the condition. permeability. This increase in perme- tometrists perform to aid in ability elicits the release of acetylcho- the diagnosis of myasthenia Educator’s Guide line into the synaptic cleft. Ach diffuses gravis? The educator’s guide includes the neces- across the synaptic space and binds to 5. What history questions should sary information to discuss the case. the Ach receptors on the crests of the one ask every patient suspected convoluted folds located on the post- of having myasthenia gravis? Literature Review synaptic membrane. This opens the receptor’s ion channels and depolarizes 6. What is the definition of myas- Myasthenia gravis (MG) is an autoim- the post-synaptic membrane causing thenic crisis? mune disease targeting nicotinic acetyl- the muscle to contract. Upon comple- 7. What medications should be choline (Ach) receptors in post-synaptic tion of each synapse, Ach is removed 1,2,3 avoided in patients with myas- connections of skeletal muscle. It from synaptic space by diffusion and thenia gravis? affects voluntary skeletal muscle either acetylcholinesterase enzyme activity.4 only in the eye (ocular) and/or the en- B. Comprehension of Clinical Data tire body (generalized). The process by In MG, are directed 1. What diagnostic tests were which muscular weakness manifests is a against the Ach receptors at the end- done in this case to help diag- result of competitive inhibition. Anti- plates of neuromuscular junctions. nose myasthenia gravis? antibodies block They prevent neuromuscular synapses, or destroy Ach receptors, thus decreas- characterizing the muscle weakness in 2. How does one differentiate be- MG.4,5 The pupillary sphincter muscle tween myasthenia gravis and ing the number of sites available for Ach binding;2 therefore, the initial weakness does not have nicotinic Ach receptors; other ophthalmoplegias? 2 observed is transient and improves with therefore, the pupils are not affected. 3. What blood work and other rest.1 The production of autoantibodies diagnostic tests should be or- It is estimated that 85-90% of MG cases against Ach receptors in MG is a T-cell dered in patients suspected to dependent process due to a breakdown have myasthenia gravis? present with ocular symptoms; 20-50% of cases have been reported as purely oc- in the immune system’s recognition of C. Management ular. Ocular myasthenia gravis (OMG) self-antigens. It is not understood why this occurs, but several factors indicate Optometric Education 133 Volume 39, Number 3 / Summer 2014 that thymus gland abnormalities (thy- Respiratory muscle weakness can lead Diplopia, secondary to paresis of ex- mus hyperplasia or thymoma) are im- to myasthenic crisis, which can be life- traocular muscles, is the second most portant. First, this theory is supported threatening. Myasthenic crisis is defined frequent initial symptom of ocular and by the fact that thymectomy alters the as acute respiratory failure due to wors- generalized MG. Like ptosis, the oph- course of the disease. Second, there are ening MG, requiring mechanical venti- thalmoplegia worsens at the end of the histopathologic changes to the thymus lation.10 Symptoms of respiratory failure day or upon exertion. It may mimic any in up to 85% of patients. Third, Ach re- include dyspnea (shortness of breath), disorder of eye movements or exhibit ceptor antibody producing cells can be dysphagia, tachypnea (rapid breathing), complete external ophthalmoplegia. found in the thymus, bone marrow and or bradypnea (slowed breathing). It can Reduced accommodative amplitudes, peripheral blood. The latter two explain be precipitated by infections and certain facility, and near point of convergence why thymectomy changes the course of medications such as aminoglycosides, stamina may also be associated in MG the disease but is not curative.5 telithromycin, neuromuscular blocking patients.1,8 agents, magnesium sulfate, beta block- Clinical Presentation and Diagnostic 3 Orbicularis oculi weakness is also a com- Testing ers, and fluoroquinolone antibiotics. mon finding and can be assessed by hav- Not every patient with an exacerbation Fifty to eighty percent of MG patients ing the patient tightly squeeze the eye- of MG requires mechanical ventilation, lids shut while the examiner uses finger present with visual complaints of diplo- but all need close monitoring and im- pia or ptosis. Half of the patients that pressure to attempt to pry open the eye- mediate access to resuscitation facili- lids. A positive result is a successful at- present with ocular signs progress to ties.10 generalized MG weakness in six months tempt to overcome the blepharospasm. and 80% will generalize within two Ptosis is the most frequent initial symp- In a normally functioning orbicularis years. The disease will likely be limited tom of ocular and generalized MG. oculi muscle, the examiner should not Ptosis may be unilateral or bilateral and be able to overcome the tight lid closure to ocular MG if there are no generalized 1 symptoms past three years.1 is often asymmetric between the two by finger pressure alone. eyes. Ptosis in MG has clinically dis- The muscle weakness seen (generalized Corneal exposure is rarely a problem, tinct characteristics that are absent from but punctate keratitis can occur due or ocular) is variable in nature, often other causes: it is variable and fatigable. increased at the end of the day or after to incomplete closure of the lids dur- A fatigue test may be performed several ing blinking. Bell’s phenomenon (pro- sustained, repetitive muscle contrac- ways. One includes having the patient tion, and improves with rest.8 Weakness tective measure of eyes rolling up and perform any physical activity, such as laterally during forced eyelid closure is worsened with exposure to heat, in- climbing a flight of stairs. It is followed 3 against resistance) may also be dimin- fection and stress. The weakness typi- by re-evaluation of signs and symptoms cally involves specific skeletal muscle ished or absent, usually consistent with of ocular MG. The most common sign the amount of upgaze restriction. groups. The distribution is generally: is worsening of the ptosis.1 Another fa- ocular (extraocular muscles, levator tigue test has the patient look up for Saccadic movements can be abnormal. palpebrae superioris, orbicularis oculi), 30 seconds and then return to primary A common observation in MG patients bulbar (speech, swallowing chewing gaze to fatigue the levator. The examiner is hypometric (undershooting) large muscles), limb extremities (arms more looks for lid lag or an increase in ptosis, saccades and hypermetric (overshoot- affected than legs), neck muscles, and known as Pseudo Von Graphe’s sign.1,8 ing) small saccades. This is speculated 2,3 respiratory muscles in the chest. Some examiners look for levator fatigue to be the central nervous system’s adap- Generalized MG can present in a vari- by having the patient look in extreme tation to muscle weakness. ety of additional ways. Bulbar muscle upgaze for 1-2 minutes. A positive pro- can also be seen in MG and may be uni- longed upgaze test result is an increase lateral, bilateral, horizontal or vertical in involvement can be seen in 60% of pa- 8 tients, presenting as fatigable chewing, in ptosis while the eyes are in upgaze.1 presentation. painless dysarthria (impaired speech) If one eyelid is manually elevated, the Optometrists may use simple, non- 3,9 and dysphagia (difficulty swallowing). contralateral upper eyelid becomes pharmacologic, screening tests to aid in These signs occur due to weakness of more ptotic due to Hering’s law of equal the diagnosis of MG. The ice pack test is palatal, facial and oro-pharyngeal mus- innervation. This has been labeled “see- performed by placement of an ice pack cles. Changes in facial expressions and saw ptosis.” Cogan’s lid twitch is fre- across the patient’s eyes for two to five flattened nasolabial fold may be seen, quently seen in MG and occurs when minutes. The localized decrease in tem- giving the patient an “expressionless” the eyes are rapidly moved from down perature slows the breakdown of acetyl- appearance. Weakness may also occur gaze to primary gaze. This is generally choline, increasing its availability in the in axial and limb muscles. When these tested by having the patient look down . The clinician are involved, the patient may pres- for 15 seconds and then look at a target then looks for improvement of ptosis 3 ent with unsteady gait and weakness in primary gaze.7 Upon returning to pri- or ophthalmoplegia after removing. A 4 of arms, hands, legs and neck. Neck mary gaze, the upper eyelid overshoots positive result is an improvement in the 1 muscles are commonly affected, with and elevates excessively before returning ptosis of greater than 2 mm. the weight of the head overtaking the to its ptotic state. This is attributed to The sleep test requires the patient to extensor muscles, producing a “dropped the fatigability and rapid recovery of a 3 lie in a quiet dark room for 30 min- head syndrome.” myasthenic muscle.8 utes with his/her eyes closed. Having

Optometric Education 134 Volume 39, Number 3 / Summer 2014 the patient rest reduces the demand for generalized MG and 40-77% in OMG. diplopia and/or ptosis should be consid- acetylcholine. Also, the 30-minute rest Rarely, a false positive titer is found in ered. Thorough case history and clinical time allows for replenishing of avail- first-degree relatives of MG patients or exam may help rule out the differen- able acetylcholine. A positive result is other autoimmune diseases.11 tials below as they will not demonstrate any improvement of ptosis and/or eye Research has shown antibodies to mus- variability or fatigability and some may movement deficit.1,3 have pupil involvement, thus helping to cle-specific kinase (MuSK) are found in 1 Some examiners may ask patients to 40-70% of seronegative AchR antibody differentiate from myasthenia gravis: take at-home, full-face, early morning patients. No positive MuSK titers were • Mechanical: levator aponeurosis and late evening pictures for three days. found in patients with positive AchR dehiscence, involutional, iatrogen- Lid position and ocular alignment are antibody titers. Reports also found no ic/ocular surgery, trauma, cicatriza- evaluated. If ocular signs of MG are patients with strictly OMG to have tion, eyelid mass present, there will be a worsening of the positive MuSK titers. Clinicians are us- • Myogenic: Chronic progressive ex- ptosis and/or ocular misalignment later ing this titer when AchR antibody test- 8 12 ternal ophthalmoplegia, myotonic in the day. ing is negative. This subgroup of se- dystrophy, oculopharyngeal dysto- Pharmacological testing using intrave- ronegative AchR antibody patients with nia nous chloride (Tensilon MuSK-positive MG have a marked female predominance and frequent • Neurogenic: , test) is considered the gold standard Horner’s syndrome, cranial nerve diagnostic test for MG. Edrophonium oculo-bulbar weakness leading to respi- ratory crisis.2 palsies, internuclear ophthalmo- inhibits the enzyme acetylcholinester- plegia ase and results in an increase in ace- Electrophysiological testing such as sin- tylcholine at neuromuscular junctions. gle fiber electromyography (SFEMG) • Mass: thyroid orbitopathy, idio- A positive test results is a decrease in is the most sensitive diagnostic test for pathic orbital inflammation, or- muscle weakness usually observed in MG and can be helpful in confirming bital neoplasia levator function or ocular motility. On- the diagnosis for seronegative patients.2,3 • Pseudoptosis: enophthalmos, hy- set of action begins in 30-60 seconds It is done by using a special needle elec- potropia, contralateral lid retrac- and effects usually subside in less than trode that allows identification of ac- tion five minutes due to rapid hydrolyza- tion potentials from individual muscle Treatment and Management tion. During the test, blood pressure fibers.3 However, this test is not readily and electrocardiographic monitoring available in every community, and ab- MG must be treated aggressively, and are sometimes recommended because normalities are not specific for MG.2,3 therapy is individualized to each pa- tient. Treatment early in the course of of the rare risk of bradycardia, hypo- Repetitive nerve stimulation is used to the disease provides the best overall tension and cardiac arrest. Mild side ef- assess neuromuscular transmission. It is clinical response. Long-term medi- fects of edrophonium include epiphora, done by supra-maximally stimulating cal and surgical treatments are used to perioral fasciculations, salivation, mild the nerve. A 10% decrease between the sweating, abdominal cramps, vomiting manage the disease.3 3 first and the fifth evoked muscle con- and flush. Sensitivity of the test using traction is diagnostic for MG. How- Medical treatment includes palliative ptosis measurement has been reported ever, this test lacks the sensitivity as treatment in the form of acetylcholin- as high as 86-97% in OMG and 82- compared to SFEMG. It is abnormal in esterase inhibitors and immunosuppres- 100% in generalized MG. Extraocular 75% of patients with generalized MG sive therapy. Surgical treatment includes muscle movement did not respond well and 50% of patients with OMG.3 thymectomy. The goals of treatment are in most studies. False positives have to prevent mortality with the fewest A CT or MRI of the chest with attention been reported in Lambert-Eaton syn- side effects and to improve the patient’s to the thymus gland is also performed drome, botulism, Guillain-Barre syn- quality of life by remission of symptoms 4 to rule out the presence of thymoma. drome and other cranial neuropathies. and lowering the risk of transition from MG also often coexists with thyroid dis- ocular to generalized MG.3 Serologic testing may also be used to ease, so thyroid function tests are also confirm the diagnosis of MG. An el- obtained in patients with MG.3 Palliative Treatment evated acetylcholine receptor (AchR) antibody titer confirms the diagnosis. Differential Diagnoses Acetylcholinesterase inhibitors such as pyridostigmine bromide (Mestinon) However, obtaining a negative titer does The diagnosis of myasthenia gravis may and neostigmine bromide (Prostigmin) not exclude the disease. 15% of gener- be a challenge because it mimics any are used as first-line treatment to relieve alized MG patients have no detectable pupil-sparing ophthalmoplegia. MG muscle weakness in MG. The mecha- antibodies to AchRs, meaning they are should be considered in any patient nism of action works to prevent the “seronegative.” About half of ocular presenting with diplopia and/or ptosis. hydrolysis and breakdown of Ach in MG patients are seropositive. Titers in However, the keys to diagnosis are the neuromuscular junctions. With more seropositive patients cannot be used variable and fatigable signs and symp- Ach available in the neuromuscular to predict the severity of the disease as toms and that they improve with rest. junctions, there is an improved effi- levels of the antibody correlate poorly The pupils are not involved in patients 1,2 ciency activating the remaining viable with clinical status. Recent studies with myasthenia gravis. Keeping that Ach receptors. The onset of action for have shown sensitivities of 98-99% in information in mind, other causes of Optometric Education 135 Volume 39, Number 3 / Summer 2014 pyridostigmine, the most commonly Cyclosporine A inhibits calcineurin. for generalized MG in the 1940s and used acetylcholinesterase inhibitor, is The mechanism blocks helper T-cell 1950s. Approximately 85% of MG within 15-30 minutes orally and two synthesis of interleukin-2 and prevents patients have thymic abnormalities, to five minutes intravenously. The dura- helper T-cell dependent function. It is including hyperplasia and . tion of action is six to eight hours orally mainly used when patients are intoler- Surgical thymectomies have shown and two to three hours intravenously.13 ant of AZA or corticosteroids. Side ef- therapeutic effect, but the benefit is Side effects include gastrointestinal dis- fects include hypertension, renal failure, controversial. Stable remission has been turbance, pallor, cold sweats, epiphora, hirsutism, gingival hyperplasia, gastro- reported in the range of 15-64%.9 Wide increased urinary urgency and muscle intestinal disturbance, flu-like symp- variability is likely due to differing sur- weakness. Most patients have symp- toms, paresthesias, myalgia and head- gical techniques. The benefits are some- tomatic relief but do not have disease ache.3 times delayed months to years after sur- 13 remission. Very seldom is this used as Other long-term immune suppressive gery. monotherapy. Immunosuppressive agents used in the treatment of MG Myasthenic Crisis agents are needed to suppress the ongo- include mycophenolate mofetil (used Presentation of myasthenia gravis is a ing immune attack on the remaining to prevent transplant rejection), cyclo- Ach receptors.14 non-emergent referral with one excep- phosphamide, rituximab, tacrolimus, tion: signs of dyspnea or dysphagia. Long-Term Immunosuppressive methotrexate and etanercept. All of Weaknesses to bulbar (speech, chew- Treatment these agents have been successfully used ing, swallowing) muscles and respira- Corticosteroids such as prednisone are as second-line agents to treat MG. With tory muscles, including the diaphragm, usually the first recommendation for all immunosuppressive agents, side ef- produce symptoms that define myas- fects must be monitored closely and the in patients with 3 thenic crisis. Myasthenic crisis requires moderate to severe generalized disease cost-benefit ratio must be weighed. immediate referral to the emergency and have been shown to lower the risk Short-Term Immunosuppressive room for prevention of respiratory ar- of progression from OMG to general- Agents rest and ultimately death. Close ob- 3,15 ized disease. There is no established Plasmapheresis and intravenous immu- servation, intubation and feeding sup- protocol for initiation of treatment. noglobulin therapy (IVIg) have rapid port may be instituted. In addition to Some clinicians advocate starting the onset and lead to improvement within supportive therapy, the focus of action patient on high-dose steroid treatment days, but effects are transient. They are may be reducing circulating antibod- until remission is reached, then tapering used in situations of severe exacerba- ies with plasmapheresis, or administra- when symptoms are improved. Others tions of MG, myasthenic crisis and be- tion of autoimmune modifying drugs, recommend starting with alternate day fore surgical procedures. They can also such as corticosteroids and intravenous treatment and gradually increasing the be used intermittently in patients whose immunoglobin. While corticosteroid dosage until remission to limit cortico- disease is not well-controlled despite treatment is initiated, patients must be steroid complications. Fifty percent of 3 closely observed due to the risk of acute chronic immunomodulating therapies. 18 patients develop worsening of weakness Plasmapheresis works by removing worsening of weakness. in the first month, usually within the AchR antibodies from circulation. One Approximately 15-20% of patients with first few days after initiation of corti- exchange is done every other day, four generalized MG experience myasthenic costeroids. Certain high-risk general- to six times.3 crisis at some point during the course ized myasthenia gravis patients, such as of the disease. Current statistics report a those in myasthenic crisis, are required The mechanism of IVIg on the autoim- mune response is complex. It acts by 3-8% mortality rate from MG. Seventy to remain hospitalized during initiation percent of myasthenic crisis cases are of treatment.9 Side effects include obesi- suppressing antibody production and the immunoreactivity of autoantibod- provoked by concurrent infections or ty, hypertension, diabetes, opportunis- fever that include the upper and lower tic infections, osteoporosis, glaucoma, ies via anti-idiotypic antibodies. In ad- dition, it inhibits complement activa- respiratory tracts. Other risk factors in- cataracts and corneal ulcer. Side effects clude certain medications and surgical are dependent on dosage and duration tion and the formation of membrane 16 interventions. The remaining patients of treatment.9 attack complexes. Other mechanisms include preventing the binding of Fc present in crisis because of inadequate Azathioprine (AZA) is a purine ana- control or delayed diagnosis and treat- receptors on macrophages, Ig recep- 18 logue that inhibits the synthesis of tors on B-cells, and antigen recognition ment of the disease. nucleic acids thereby interfering with by T-cells.17 Plasmapheresis has been Ocular Management T-cell and B-cell proliferation. AZA is shown to be equally effective for exac- Ocular management of MG is focused used as monotherapy or as an adjunct erbations of MG, but IVIg is better tol- to corticosteroids.10 Improvement in on relief of symptoms. The most el- erated by patients and thus used more ementary technique to relieve variable symptoms is gradual and may continue frequently.10 for up to two years of treatment. AZA diplopia is teaching patients the use of side effects include malignancy, leuko- Surgical Treatment head turn. Through the use of a head penia, thrombocytopenia, nausea, vom- Thymectomy was the first immune- turn, the patient can find a position of iting and hepatotoxicity.3 modulating treatment used in MG. It gaze where fusion can be appreciated. became a generally accepted treatment Occlusion therapy may be indicated Optometric Education 136 Volume 39, Number 3 / Summer 2014 for persistent or non-tolerable diplo- signs and symptoms require emergent sive care unit results in favourable pia. Occlusion patching or high-plus referral to prevent respiratory failure long-term prognosis. European contact lenses can be used. When or- and ensuing death. These teaching cases Journal of Neurology. 2013. E-pub bicularis oculi weakness is exhibited, exemplify the importance of optomet- doi:10.1111/ene.12115. incomplete blinking causing exposure ric in-office history skills, diagnostic 11. Elrod RD, Weinberg DA. Ocular keratopathy can be observed. This is testing and clinical decision-making myasthenia gravis. Ophthalmol usually successfully treated with topical for effectively diagnosing and manag- Clin N Am. 2004;17(3):275-309. lubrication. In extreme cases, eyelid tap- ing emergent and non-emergent cases 12. Zhou L, MeConville J, Chaudhry ing may be used. Due to the fluctuation of myasthenia gravis. Thorough history, V, et. al. Clinical comparison of of the ophthalmoplegia, no prism is in- prompt diagnosis, and referral may be muscle-specific tyrosine kinase dicated in the setting of MG. life-saving for patients with myasthenia (MuSK) antibody-positive and – Surgical treatment options are mainly gravis. negative myasthenic patients. Mus- cle Nerve. 2004;30(1):55-60. for symptomatic relief of persistent pto- References sis. They include ptosis repair surgery, 13. Matney SE, Huff DR. Diagnosis blepharoplasty, frontalis suspension, 1. Pruitt JA, Ilsen PF. On the front- and treatment of myasthenia gra- external levator advancement and tar- line: What an optometrist needs vis. Consult Pharm. 2007;22:239- somyectomy. Other non-surgical op- to know about myasthenia gravis. 48. tions to treat ptosis are botulinum toxin Optometry. 2010;81(9):454-460. 14. Antonio-Santos AA, Eggenberger type A injections and the use of a pto- 2. Vaphiades MS. Bhatti MT, Lesser ER. Medical treatment options sis crutch. The ptosis crutch is made of RL. Ocular myasthenia gravis. Curr for ocular myasthenia gravis. Curr Teflon or plastic and is mounted onto a Opin Ophthalmol. 2012;23:537- Opin Opthalmol. 2008;19:468- spectacle frame to pull back the eyelids. 542. 478. Topical lubrication may also be needed 3. Jayam TA, Dabi A, Soliman N, 15. Agius MA. Treatment of ocular if eyelid taping or ptosis crutch is used Kurukumbi M, Kalyanam N. My- myasthenia with corticosteroids: due to the risk of exposure keratopathy.1 asthenia gravis: A review. Autoim- yes. Arch Neurol. 2000;57:750- mune Dis. 2012;2012:874680. 751. Medications that may Exacerbate 16. Dalakas MC. Intravenous Im- Myasthenia Gravis doi: 10.1155/2012/874680. Epub 2012 Oct 31. munoglobulin in Autoimmune Many medications have been implicat- 4. Luchanok U, Kaminski HJ. Ocu- Neuromuscular Diseases. JAMA. ed in either inducing or worsening my- lar myasthenia: diagnosis and treat- 2004;291(19):2367-2375. asthenia gravis. The reasons for the ex- ment recommendations and the doi:10.1001/jama.291.19.2367. acerbation are likely multifactorial and evidence base. Curr Opin in Neu- 17. Samuelsson A, Towers TL, Ra- may or may not be solely related to the rology. 2008;21:8-15. vetch JV. Anti-inflammatory activ- medication. These medications include 5. Weinberg DA, Lesser RL, Vollmer ity of IVIG mediated through the aminoglycosides, telithromycin, neuro- TL. Ocular myasthenia: A protean inhibitory Fc receptor. Science. muscular blocking agents, magnesium disorder. Surv Ophthalmol. 1994: 2001;291(5503):484-486. sulfate, beta blockers and many antibi- 39:169-210. 18. Jani-Acsadi A, Lisak RP. Myasthen- otic therapies.3 The Myasthenia Gravis 6. Lavrinc D, Losen M, Vujic A, De ic crisis: Guidelines for prevention Foundation has a report for healthcare Baets M, Hajdukovic LJ, Stoja- and treatment. Journal of the Neu- professions on “Medications and Myas- novic V, Trikic R, Djukic P, Apos- rological Sciences. 2007;261:127- thenia Gravis,” which can be found at: tolski S. The features of myasthe- 133. http://www.myasthenia.org/HealthPro- nia gravis with autoantibodies to fessionals/EducationalMaterials.aspx. If MuSK. J Neurol Neurosurg Psy- a MG patient needs an oral medication chiatry. 2005;76:1099-1102. for management of an unrelated ocular 7. Kusner LL, Puwanant A, Kaminski condition, a consultation with the pa- HJ. Ocular myasthenia: diagnosis, tient’s co-managing neurologist is war- treatment, and pathogenesis. The ranted prior to initiation of treatment. Neurologist. 2006; 12:231-239. 8. Covalito J, Cooper J, Ciuffreda KJ. Conclusion Non-ptotic ocular myasthenia gra- With diplopia and ptosis being the vis: a common presentation of an most common presenting symptoms of uncommon disease. Optometry. myasthenia gravis, optometrists may be 2005;76(7):363-375. the first to encounter an undiagnosed 9. Kaminski HJ. Neuromuscu- patient. The cases presented here dem- lar Junction Disorders. Marcel onstrate classic signs of purely ocular Dekker, Inc. 2004. (case 1) and generalized myasthenia 10. Spillane J, Hirsch NP, Kullman gravis with ocular involvement (case 2). DM, Taylor C, Howard RS. My- Recognition of bulbar and respiratory asthenia gravis-treatment of acute severe exacerbations in the inten- Optometric Education 137 Volume 39, Number 3 / Summer 2014