**4. Diagnostic testing**

The diagnosis of OM may be made based on clinical grounds when no other conditions are consistent with a patient's examination and history. However, at times the clinical manifestations are difficult to detect by routine examination or may be absent at time of an examination leading to the need for additional evaluation. In addition, therapy for MG is not benign, and most clinicians and patients desire definitive confirmation of the diagnosis. However, the clinician must appreciate the limitations of tests used for diagnosis.

Ocular Myasthenia Analysis of Diagnostic and Treatment Options 109

patients without MG (Kubis et al. 2000). One value of these tests is that they may be

Serum AChR antibody examinations are performed concurrently, or instead of the clinical tests described (Howard et al. 1987). The sensitivity of AChR antibodies testing for OM ranges between 39 and 71 percent. The specificity achieved is 95-100 percent (Benatar 2006). The detection of AChR antibodies may increase the risk of progression to generalized MG, but studies are inconsistent (Seybold 1999; Kupersmith et al. 2003) AChR antibodies have been detected without evidence of MG among patients with autoimmune liver disease, systemic lupus erythematosus, rheumatoid arthritis, Lambert Eaton syndrome, inflammatory neuropathies, amyotrophic lateral sclerosis, thyroid ophthalmopathy, thymoma patients, in patients taking D-penicillamine, and first degree relatives of patients with MG (Lennon 1997). Therefore, their detection is not absolutely specific for the

The binding AChR antibody is the most sensitive test and the studies described above dealt with the binding assay. The modulating AChR antibody may increase the diagnostic yield slightly for generalized MG patients but has not been assessed for OM. The modulating AChR antibody suffers from higher rates of false positives. The third AChR antibody evaluation is the blocking antibody, but it may only slightly increase sensitivity of the binding assay. Therefore, the authors generally only order the binding AChR antibody

About a three percent of patients with generalized MG have antibodies against MuSK, a neuromuscular junction protein that provides the clustering signal for AChR (Hoch et al. 2001; Liyanage et al. 2002; Evoli et al. 2003; Vincent et al. 2003; Zhou et al. 2004). Rare cases of pure OM in association with MuSK antibodies are described (Caress et al. 2005; Bennett et al. 2006; Chan and Orrison 2007); however, large case series of MuSK antibody positive patients have not identified OM patients, but patients may present with ocular manifestions (Evoli et al. 2003; Zhou et al. 2004). MuSK examinations are about 16 times the cost of the binding AChR antibody test and therefore, should not be routinely requested unless

Patients with clinical symptoms of MG with electrophysiological evidence of neuromuscular junction impairment, but no evidence of serum autoantibodies are deemed to have seronegative MG (Argov 2010; Roh et al. 2011). Up to half of OM patients do not have detectable antibodies to the AChR. A small percentage (15%) of initially seronegative patients may become seropositive for AChR antibodies later in the disease course (Chan et al. 2007). With specialized testing two-thirds of patients with generalized MG without traditional antibodies for AChR or MuSK are positive for low-affinity IgG autoantibodies to AChR (Leite et al. 2008). Therefore, even in OM patients pathogenic antibodies may be

A significant proportion of OM patients will have negative AChR antibody evaluations and have non-definitive clinical assessments. Electrodiagnostic testing needs then to be performed to objectively confirm a diagnosis of OM. Repetitive nerve stimulation measures the action potential amplitude produced by repetitive low frequency stimulation. A decrement of 10% or more is considered positive for MG (Oh SJ 1992). The

directed against the AChR but be undetected by standard testing.

performed in patients in whom edrophonium infusion is contraindicated.

**4.3 Serum autoantibody evaluation** 

diagnosis.

examination.

clinically indicated.

**4.4 Electrodiagnosis** 

#### **4.1 Edrophonium test**

The edrophonium test involves intravenous infusion of edrophonium chloride, which inhibits the action of acetylcholinesterase (AChE). Procedures for edrophonium administration are not standardized, but in general, an initial 1 mg dose is given to assure patient tolerance followed by slow infusion over a few minutes until improvement in strength of a muscle is observed or a maximum of 10 mg is administered, although 7 mg is usually the maximum required to achieve a positive response (Kupersmith et al. 2003). Because of the objective nature of the response, unequivocal improvement in strength of a ocular muscle is the best endpoint to judge a test as positive (Daroff 1986).

Improvement of ptosis in response to edrophonium may be as high as 95% and the specificity has been reported at 97%; however EOM weakness does not respond as well to an edrophonium challenge (Nicholson GA 1983; Evoli et al. 1988; Kupersmith et al. 2003; Pascuzzi 2003). However, these high response rates have been determined in the controlled environments of academic institutions and not in standard clinical practices. The specificity of the edrophonium is likely to be high as long as the evaluation is performed by experienced clinicians. The potential for false positives exists, in the busy office practice, especially when the examiner rarely performs such evaluations. Other neuromuscular transmission disorders, such as Lambert-Eaton syndrome and botulism, can also cause a positive response to edrophonium (Oh SJ 1990), and false positive tests are reported with Guillain-Barre syndrome, compressive cranial neuropathies, and brain stem pathology (Pascuzzi 2003; Daroff and Benatar 2009).

There has been concern raised regarding the safety of edrophonium testing, which has led to some institutions requiring cardiac monitoring during the procedure. However, serious complications of bradycardia and syncope are rare (Ing et al. 2000), and it is the authors' opinion that cardiac monitoring is not necessary for most patients. Cardiac dysrhythmias and bronchial asthma are relative contraindications for edrophonium administration. Beyond muscarinic effects of tearing, salivation, sweating, abdominal cramps, and nausea, the test has limited morbidity (Pascuzzi 2003; Daroff and Benatar 2009).

#### **4.2 Other clinical evaluations**

The ice pack, rest, and sleep tests are non-pharmacological evaluations, which have been developed in order to avoid the need for edrophonium infusion and have close to no morbidity. However, the limitation of all these evaluations is that sensitivity and specificity assessments have been performed (Benatar 2006). All studies have small sample sizes. Interobserver reliability is also not known.

The ice pack test is performed by placement of an ice pack across the eyes for two to five minutes followed by the examiner's assessment for improvement of ptosis or ocular motility deficit (Golnik et al. 1999; Ellis et al. 2000). Some patients may have difficulty tolerating the ice pack. The rest test requests the patient close their eyelids for up to 5 minutes, and then improvement in ptosis is assessed. For the sleep test, the patient lies with eyes closed in a quiet, dark room for 30 minutes and then ptosis and ophthalmoparesis are assessed for improvement. For the ice test, sensitivity of 80-97 percent and specificity of 97-100 percent are reported (Golnik 1997; Golnik et al. 1999; Benatar 2006). In a study of edrophoniumpositive patients all had positive sleep tests as well (Odell et al. 1991). A small, randomized trial compared the ice test to the rest test and found that the median improvement of ptosis with the rest test was 2 mm and with the ice test 4.5 mm, but no improvement found among patients without MG (Kubis et al. 2000). One value of these tests is that they may be performed in patients in whom edrophonium infusion is contraindicated.

#### **4.3 Serum autoantibody evaluation**

108 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

The edrophonium test involves intravenous infusion of edrophonium chloride, which inhibits the action of acetylcholinesterase (AChE). Procedures for edrophonium administration are not standardized, but in general, an initial 1 mg dose is given to assure patient tolerance followed by slow infusion over a few minutes until improvement in strength of a muscle is observed or a maximum of 10 mg is administered, although 7 mg is usually the maximum required to achieve a positive response (Kupersmith et al. 2003). Because of the objective nature of the response, unequivocal improvement in strength of a

Improvement of ptosis in response to edrophonium may be as high as 95% and the specificity has been reported at 97%; however EOM weakness does not respond as well to an edrophonium challenge (Nicholson GA 1983; Evoli et al. 1988; Kupersmith et al. 2003; Pascuzzi 2003). However, these high response rates have been determined in the controlled environments of academic institutions and not in standard clinical practices. The specificity of the edrophonium is likely to be high as long as the evaluation is performed by experienced clinicians. The potential for false positives exists, in the busy office practice, especially when the examiner rarely performs such evaluations. Other neuromuscular transmission disorders, such as Lambert-Eaton syndrome and botulism, can also cause a positive response to edrophonium (Oh SJ 1990), and false positive tests are reported with Guillain-Barre syndrome, compressive cranial neuropathies, and brain stem pathology

There has been concern raised regarding the safety of edrophonium testing, which has led to some institutions requiring cardiac monitoring during the procedure. However, serious complications of bradycardia and syncope are rare (Ing et al. 2000), and it is the authors' opinion that cardiac monitoring is not necessary for most patients. Cardiac dysrhythmias and bronchial asthma are relative contraindications for edrophonium administration. Beyond muscarinic effects of tearing, salivation, sweating, abdominal cramps, and nausea,

The ice pack, rest, and sleep tests are non-pharmacological evaluations, which have been developed in order to avoid the need for edrophonium infusion and have close to no morbidity. However, the limitation of all these evaluations is that sensitivity and specificity assessments have been performed (Benatar 2006). All studies have small sample sizes. Inter-

The ice pack test is performed by placement of an ice pack across the eyes for two to five minutes followed by the examiner's assessment for improvement of ptosis or ocular motility deficit (Golnik et al. 1999; Ellis et al. 2000). Some patients may have difficulty tolerating the ice pack. The rest test requests the patient close their eyelids for up to 5 minutes, and then improvement in ptosis is assessed. For the sleep test, the patient lies with eyes closed in a quiet, dark room for 30 minutes and then ptosis and ophthalmoparesis are assessed for improvement. For the ice test, sensitivity of 80-97 percent and specificity of 97-100 percent are reported (Golnik 1997; Golnik et al. 1999; Benatar 2006). In a study of edrophoniumpositive patients all had positive sleep tests as well (Odell et al. 1991). A small, randomized trial compared the ice test to the rest test and found that the median improvement of ptosis with the rest test was 2 mm and with the ice test 4.5 mm, but no improvement found among

ocular muscle is the best endpoint to judge a test as positive (Daroff 1986).

the test has limited morbidity (Pascuzzi 2003; Daroff and Benatar 2009).

**4.1 Edrophonium test** 

(Pascuzzi 2003; Daroff and Benatar 2009).

**4.2 Other clinical evaluations** 

observer reliability is also not known.

Serum AChR antibody examinations are performed concurrently, or instead of the clinical tests described (Howard et al. 1987). The sensitivity of AChR antibodies testing for OM ranges between 39 and 71 percent. The specificity achieved is 95-100 percent (Benatar 2006). The detection of AChR antibodies may increase the risk of progression to generalized MG, but studies are inconsistent (Seybold 1999; Kupersmith et al. 2003) AChR antibodies have been detected without evidence of MG among patients with autoimmune liver disease, systemic lupus erythematosus, rheumatoid arthritis, Lambert Eaton syndrome, inflammatory neuropathies, amyotrophic lateral sclerosis, thyroid ophthalmopathy, thymoma patients, in patients taking D-penicillamine, and first degree relatives of patients with MG (Lennon 1997). Therefore, their detection is not absolutely specific for the diagnosis.

The binding AChR antibody is the most sensitive test and the studies described above dealt with the binding assay. The modulating AChR antibody may increase the diagnostic yield slightly for generalized MG patients but has not been assessed for OM. The modulating AChR antibody suffers from higher rates of false positives. The third AChR antibody evaluation is the blocking antibody, but it may only slightly increase sensitivity of the binding assay. Therefore, the authors generally only order the binding AChR antibody examination.

About a three percent of patients with generalized MG have antibodies against MuSK, a neuromuscular junction protein that provides the clustering signal for AChR (Hoch et al. 2001; Liyanage et al. 2002; Evoli et al. 2003; Vincent et al. 2003; Zhou et al. 2004). Rare cases of pure OM in association with MuSK antibodies are described (Caress et al. 2005; Bennett et al. 2006; Chan and Orrison 2007); however, large case series of MuSK antibody positive patients have not identified OM patients, but patients may present with ocular manifestions (Evoli et al. 2003; Zhou et al. 2004). MuSK examinations are about 16 times the cost of the binding AChR antibody test and therefore, should not be routinely requested unless clinically indicated.

Patients with clinical symptoms of MG with electrophysiological evidence of neuromuscular junction impairment, but no evidence of serum autoantibodies are deemed to have seronegative MG (Argov 2010; Roh et al. 2011). Up to half of OM patients do not have detectable antibodies to the AChR. A small percentage (15%) of initially seronegative patients may become seropositive for AChR antibodies later in the disease course (Chan et al. 2007). With specialized testing two-thirds of patients with generalized MG without traditional antibodies for AChR or MuSK are positive for low-affinity IgG autoantibodies to AChR (Leite et al. 2008). Therefore, even in OM patients pathogenic antibodies may be directed against the AChR but be undetected by standard testing.

#### **4.4 Electrodiagnosis**

A significant proportion of OM patients will have negative AChR antibody evaluations and have non-definitive clinical assessments. Electrodiagnostic testing needs then to be performed to objectively confirm a diagnosis of OM. Repetitive nerve stimulation measures the action potential amplitude produced by repetitive low frequency stimulation. A decrement of 10% or more is considered positive for MG (Oh SJ 1992). The

Ocular Myasthenia Analysis of Diagnostic and Treatment Options 111

\$11.99 (30) Anti-inflammatory effects related to: a)

macrophage.

regulatory cells.

Ptosis may be improved by eyelid tape or crutches; however, patients often are intolerant of these approaches finding them uncomfortable. Also, scleral irritation may occur by exposure and lead to drying or abrasion. Visual occlusive devices, such as eye patches or opaque contact lenses, eliminate diplopia but reduce the visual field. Custom corrective lenses with prisms may correct diplopia temporarily, but because patients with OM have fluctuation of their visual axes, they require frequent correction of their prism. Prism therapy may be considered in patients with stable strabismus for six months to a year. Eye muscle surgery may be beneficial in rare patients when a fixed strabismus occurs and non-variable ptosis (Ohtsuki et al. 1996; Bentley et al. 2001). Botulinum toxin may also be considered to correct ocular alignment by chemodenervation of the involved extraocular muscles, but it must be used cautiously given the potential for systemic neuromuscular transmission blockade. Although there are challenges associated with the treatments, non-pharmacological options may be favored by some patients and be the only options for patients with disease resistant

Inhibits acetylcholinesterase at neuromuscular junction but also at muscarinic synapses

redistribution of lymphocytes and reduction of production and differentiation, b) alterations of function of TNF, IL-1 and IL-2, c) inhibition of antigen processing and presentation by

Inhibits T- and B-cell proliferation

Inhibits T- and B-cell proliferation through inhibition of guanosine nucleotide synthesis. Also

molecules thus reducing lymphocyte recruitment,

Calcineurin mediated pathway inhibition of T-cell and IL-2 production. Modulates the activity of Tcells, increases their apoptosis and may enhance T

produces: a) apoptosis of activated Tlymphocytes, b) decrease in cell adhesion

c) reduction of inducible NOS activity.

**Drug Cost in USA Mechanism of action** 

\$17.99 (30 tabs)

\$137.99 (30)

\$159.99 (30)

\$27.99 (30)

\$951.33 (100)

\$129.99 (100)

\$409.94 (100)

\$345.97 (100)

\* From Epocrates® online Searched April 2011. Table 1. Ocular Myasthenia Treatment Options

**5.1 Non-pharmaceutical treatment options** 

to pharmacological treatments.

Pyridostigmine 60

Pyridostigmine 180 mg controlled release (time span)

mg tablets

Prednisone 20 mg tablet

Immuran® 50 mg

Azathioprine 50 mg tablet

CellCept® 500 mg

Mycophenolate mofetil 500 mg

Prograf® 1 mg capsule

Tacrolimus 1 mg

capsule

tablet

tablet

sensitivity of repetitive nerve stimulation for OM is poor (11-54 percent), but specificity is high (89-98 percent) (Roh et al. 2011). Evaluation of the orbicularis oculi (especially the lower orbicularis oculi), orbicularis oris, or nasalis will increase the percentage of patients identified, but such evaluations are much more difficult to tolerate for patients than extremity evaluations (Mercelis and Merckaert 2011). Although identification of decremental responses in non-ocular muscles indicates subclinical disease in other muscles, the finding does not indicate the presence or predict progression to generalized MG.

Single fiber electromyography (SFEMG) involves repetitive measures of the time between action potentials of two fibers in a muscle during a slight contraction. Abnormalities occur because of a fiber's slowed transmission of an action potential because of a compromised endplate potential that does not reach threshold. A fiber may not be activated which produces a neuromuscular block. If the mean jitter - time between activation of all fiber pairs (or endplates) - exceeds the upper limit of normal for that muscle, or if more than 10% of pairs have jitter that exceeds the upper limit of jitter during voluntary activation, then the study is considered abnormal. SFEMG is 62 to 99 percent sensitive for detection of MG, and its specificity is reported to be from 66 to 98 percent (Ukachoke et al. 1994; de Entrambasaguas et al. 2007; Mercelis and Merckaert 2011); however, it implementation is limited due to the requirements of specially-trained, experienced examiners. Although it is labor-intensive, SFEMG should be considered in patients with a strong clinical suspicion for OM in which repetitive nerve stimulation is negative, due to its higher sensitivity (Srivastava et al. 2007). The SFEMG is also useful in ruling out myasthenic weakness. If the SFEMG is normal in a clinically weak muscle, then the weakness is not due to a neuromuscular transmission disorder (Sanders and Stalberg 1996; Katirji and Kaminski 2002; Meriggioli and Sanders 2004; Sanders 2004).

#### **4.5 Other evaluations**

When the clinician thinks the OM diagnosis is likely additional testing is necessary. Thyroid dysfunction is a common co-morbidity and therefore, it is appropriate to screen all OM patients for hypo- or hyperthyroidism. Identification of concurrent thyroid dysfunction may improve MG related weakness. If clinically indicated the co-existence of other autoimmune disorders should be evaluated, in particular pernicious anemia, Chest imaging should be performed to exclude thymoma although thymoma is rare in OM patients. In anticipation of immunosuppressive treatments, screening for tuberculosis is appropriate.
