**5.1 Non-pharmaceutical treatment options**

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 to pharmacological treatments.

Ocular Myasthenia Analysis of Diagnostic and Treatment Options 113

percentage of patients will have symptom recurrence. Patients will need an increase in dose when symptoms recur. Most patients require maintenance doses for years, which should be the lowest possible to prevent recurrence of visual complaints. More than three-quarters of patients experience significant improvement (Evoli et al. 1988; Sommer et al. 1997; Tackenberg et al. 2001; Kupersmith and Ying 2005). To reduce corticosteroid complications every other day dosing of prednisone may be used. Patients should be instructed to take a single morning dose, which mimics the diurnal peak of endogenous corticosteroid. Patients need to be educated about steroid side effects, which include weight gain, glucose tolerance, hypertension, osteoporosis, insomnia, anxiety, depression, and the numerous other complications of prednisone. The neurologist or ophthalmologist should work with the

Based on retrospective analysis, corticosteroids may delay or prevent the progression of OM to generalized MG (Agius 2000; Kaminski and Daroff 2000; Kupersmith 2004). However, there has not been a randomized, controlled trial to assess whether steroids have a disease modifying effect (Gilbert et al. 2007; Gilbert and Savino 2007). Future studies should consider visual outcome and quality of life to determine whether the benefits of

Some patients will not respond to corticosteroids, have contraindications to their use, or have intolerable adverse effects necessitating use of other immunotherapies (Tackenberg et al. 2001). Assessment of efficacy for immunosuppressives specific to treatment for OM is extremely limited and is entirely based on retrospective investigation. Support for their use also derives from administration for the generalized disease, but these studies are also not robust. Azathioprine was demonstrated to reduce corticosteroid requirements in a randomized, placebo-controlled trial of generalized MG patients (Palace et al. 1998), and retrospective analyses support its efficacy in OM patients (Mertens et al. 1981; Matell 1987; Hohlfeld et al. 1988; Mantegazza et al. 1988). The clinician and the patient then need to consider immunosuppressant therapy, and here the evidence base relies on data from the generalized disease and expert opinion. For generalized MG, cyclosporine, tacrolimus, and mycophenolate mofetil have steroid sparing effects demonstrated in double-blind, placebo-

The analysis provides a focused review of clinical manifestations, diagnosis, and treatment of OM and highlights the significant limitations of the literature. Diagnosis of OM is generally straightforward, when the clinician thinks of the disorder. Confirmation of clinical diagnosis is challenging for OM. Serum AChR antibodies are found in only half of patients, and while the MuSK antibody is detected in about three percent of the generalized MG population, it is found only rarely among patients with isolated OM. Therefore the majority of patients lack detectable autoantibodies and confirmation of a neuromuscular transmission disorder relies on specialized, electrophysiological testing. Although expert opinion suggests that treatment is highly effective, significant knowledge gaps exist as to severity of treatment complications and over-all quality of life of patients with OM. Only through prospective trials or multi-center, rigorously constructed outcome databases will

patient's primary care physician to monitor for complications.

controlled or retrospective studies (Sanders and Evoli 2010).

improvements in treatment be achieved.

**5.4 Immunotherapy** 

**6. Conclusion** 

corticosteriods outweigh the complications of chronic corticosteroid use.

Thymectomy is not generally indicated of OM, but case series do support its use (Schumm et al. 1985; Roberts et al. 2001). Of course, OM patients with a thymoma should undergo tumor removal and co-incident removal of the remainder of the thymus.

#### **5.2 Acetylcholesterase inhibition**

AChE inhibitors are the first line of medical treatment for OM, and pyridostigmine is the most commonly used drug in the class. While AChE inhibitors are effective for ptosis, diplopia is of often resistant to treatment (Sommer et al. 1993; Sommer et al. 1997; Mehndiratta et al. 2011). In some patients, unilateral ptosis "unmasks" ocular misalignment producing the symptom of diplopia which may be more troublesome for the patient (Daroff and Benatar 2009). Patients presenting with both ptosis and diplopia tend to have an inferior response to pyridostigmine (Chirapapaisan N 2007), and many OM patients move on to corticosteroid treatment(Kupersmith and Ying 2005).

Pyridostigmine 30-60 mg three to four times per day are typical starting doses and may be increased to 90 to 120 mg every 3-4 hours per day, if symptoms respond and adverse effects are kept to a minimum. Complications are primarily related to muscarinic effects, in particular abdominal cramps, nausea, vomiting and diarrhea, which occur in at least a third of patients (Beekman et al. 1997). Atropine or glycopyrrolate may be used to limit muscarinic activity. AChE inhibitor treatment should be used with caution in patients with bradycardia and prostatic hypertrophy. Patients with MG treated with AChR inhibitors, who have reactive airway disease, may have worsening of respiratory function secondary increased respiratory secretions leading to a false conclusion that respiratory insufficiency is caused by myasthenic weakness. An open label prospective trial demonstrated improved quality of life with the sustained-release form of pyridostigmine, which requires less frequent administration (Sieb and Kohler 2010). However, in the author's experience, more reliable improvements in strength occur with the standard preparation. Cholinergic weakness is often discussed but probably does not occur in this era that patients move to immunotherapy and do not rely on extremely high doses of AChE inhibitors. However, if a clinician is concerned that cholinergic weakness is a cause of worse OM symptoms, the AChE inhibitor may be reduced.

#### **5.3 Corticosteroid treatment**

Most patients will not receive significant benefit from the non-pharmacological and AChE inhibitor treatments and will choose to proceed to immunosuppressive treatment (Kupersmith and Ying 2005). Prednisone is the most frequently used immunosuppressive treatment for OM, and unless corticosteroids are contraindicated due to comorbities, it is the first-line immunosuppressive for OM. Although this is based on retrospective analysis(Benatar and Kaminski 2007, Bhanushali et al. 2008).

Dosing regimens vary but typically, 10-20 mg once a day is started and increased by 5-10 mg every 3 days until visual symptoms are improved significantly, which usually occurs in the first few weeks of therapy (Kupersmith et al. 2003; Mee et al. 2003; Papapetropoulos et al. 2003). 60-80 mg per day is a maximum dose. At times mild double vision that does not impair function may persist and need to be tolerated. After symptom resolution is maintained for a month, a slow taper is instituted at a rate of 5-10 mg per day every 2 weeks until a dose of 20 mg every day is achieved and the dose reductions slowed further. Rapid tapers often lead to recurrence of symptoms, but even with gradual dose reductions a large percentage of patients will have symptom recurrence. Patients will need an increase in dose when symptoms recur. Most patients require maintenance doses for years, which should be the lowest possible to prevent recurrence of visual complaints. More than three-quarters of patients experience significant improvement (Evoli et al. 1988; Sommer et al. 1997; Tackenberg et al. 2001; Kupersmith and Ying 2005). To reduce corticosteroid complications every other day dosing of prednisone may be used. Patients should be instructed to take a single morning dose, which mimics the diurnal peak of endogenous corticosteroid. Patients need to be educated about steroid side effects, which include weight gain, glucose tolerance, hypertension, osteoporosis, insomnia, anxiety, depression, and the numerous other complications of prednisone. The neurologist or ophthalmologist should work with the patient's primary care physician to monitor for complications.

Based on retrospective analysis, corticosteroids may delay or prevent the progression of OM to generalized MG (Agius 2000; Kaminski and Daroff 2000; Kupersmith 2004). However, there has not been a randomized, controlled trial to assess whether steroids have a disease modifying effect (Gilbert et al. 2007; Gilbert and Savino 2007). Future studies should consider visual outcome and quality of life to determine whether the benefits of corticosteriods outweigh the complications of chronic corticosteroid use.

#### **5.4 Immunotherapy**

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

Thymectomy is not generally indicated of OM, but case series do support its use (Schumm et al. 1985; Roberts et al. 2001). Of course, OM patients with a thymoma should undergo

AChE inhibitors are the first line of medical treatment for OM, and pyridostigmine is the most commonly used drug in the class. While AChE inhibitors are effective for ptosis, diplopia is of often resistant to treatment (Sommer et al. 1993; Sommer et al. 1997; Mehndiratta et al. 2011). In some patients, unilateral ptosis "unmasks" ocular misalignment producing the symptom of diplopia which may be more troublesome for the patient (Daroff and Benatar 2009). Patients presenting with both ptosis and diplopia tend to have an inferior response to pyridostigmine (Chirapapaisan N 2007), and many OM patients move on to

Pyridostigmine 30-60 mg three to four times per day are typical starting doses and may be increased to 90 to 120 mg every 3-4 hours per day, if symptoms respond and adverse effects are kept to a minimum. Complications are primarily related to muscarinic effects, in particular abdominal cramps, nausea, vomiting and diarrhea, which occur in at least a third of patients (Beekman et al. 1997). Atropine or glycopyrrolate may be used to limit muscarinic activity. AChE inhibitor treatment should be used with caution in patients with bradycardia and prostatic hypertrophy. Patients with MG treated with AChR inhibitors, who have reactive airway disease, may have worsening of respiratory function secondary increased respiratory secretions leading to a false conclusion that respiratory insufficiency is caused by myasthenic weakness. An open label prospective trial demonstrated improved quality of life with the sustained-release form of pyridostigmine, which requires less frequent administration (Sieb and Kohler 2010). However, in the author's experience, more reliable improvements in strength occur with the standard preparation. Cholinergic weakness is often discussed but probably does not occur in this era that patients move to immunotherapy and do not rely on extremely high doses of AChE inhibitors. However, if a clinician is concerned that cholinergic weakness is a cause of worse OM symptoms, the

Most patients will not receive significant benefit from the non-pharmacological and AChE inhibitor treatments and will choose to proceed to immunosuppressive treatment (Kupersmith and Ying 2005). Prednisone is the most frequently used immunosuppressive treatment for OM, and unless corticosteroids are contraindicated due to comorbities, it is the first-line immunosuppressive for OM. Although this is based on retrospective

Dosing regimens vary but typically, 10-20 mg once a day is started and increased by 5-10 mg every 3 days until visual symptoms are improved significantly, which usually occurs in the first few weeks of therapy (Kupersmith et al. 2003; Mee et al. 2003; Papapetropoulos et al. 2003). 60-80 mg per day is a maximum dose. At times mild double vision that does not impair function may persist and need to be tolerated. After symptom resolution is maintained for a month, a slow taper is instituted at a rate of 5-10 mg per day every 2 weeks until a dose of 20 mg every day is achieved and the dose reductions slowed further. Rapid tapers often lead to recurrence of symptoms, but even with gradual dose reductions a large

tumor removal and co-incident removal of the remainder of the thymus.

**5.2 Acetylcholesterase inhibition**

AChE inhibitor may be reduced.

**5.3 Corticosteroid treatment** 

analysis(Benatar and Kaminski 2007, Bhanushali et al. 2008).

corticosteroid treatment(Kupersmith and Ying 2005).

Some patients will not respond to corticosteroids, have contraindications to their use, or have intolerable adverse effects necessitating use of other immunotherapies (Tackenberg et al. 2001). Assessment of efficacy for immunosuppressives specific to treatment for OM is extremely limited and is entirely based on retrospective investigation. Support for their use also derives from administration for the generalized disease, but these studies are also not robust. Azathioprine was demonstrated to reduce corticosteroid requirements in a randomized, placebo-controlled trial of generalized MG patients (Palace et al. 1998), and retrospective analyses support its efficacy in OM patients (Mertens et al. 1981; Matell 1987; Hohlfeld et al. 1988; Mantegazza et al. 1988). The clinician and the patient then need to consider immunosuppressant therapy, and here the evidence base relies on data from the generalized disease and expert opinion. For generalized MG, cyclosporine, tacrolimus, and mycophenolate mofetil have steroid sparing effects demonstrated in double-blind, placebocontrolled or retrospective studies (Sanders and Evoli 2010).
