**1. Introduction**

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

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hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. *Am. J. Hum. Genet.* Vol. 85 (No. 4): Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction caused by antibodies directed towards the skeletal muscle nicotinic acetylcholine receptor (AChR), the muscle specific kinase (MuSK), and perhaps as yet undefined antigens, which compromise neuromuscular transmission (Figure 1) (Vincent et al. 2001; Conti-Fine et al. 2006). The disorder has a distinct predilection for the ocular muscles - the extraocular muscles (EOM), which move the globe, and the levator palpebrae that elevates the eyelid (Kusner et al. 2006). MG may produce weakness of any skeletal muscle to varying degrees with the potential for a broad range of clinical presentations (Seybold 1999; Kuks and Oosterhuis 2003); however, almost all patients will have ocular manifestations during the disease course, and a large subset will have manifestations restricted to the ocular muscles, so-called ocular myasthenia (OM) (Kusner et al. 2006). Diagnostic tests for OM include clinical evaluations, serum autoantibodies, and electrophysiological evaluation, all of which differ in their diagnostic predictive value depending on whether a patient has generalized MG or OM (Roh et al. 2011). Treatment for OM includes well-studied modalities; however, none that are supported by rigorous, controlled trials. This analysis will discuss the ocular manifestations, diagnostic testing, and treament of OM, with a focus on the current evidence to support clinical decision-making (Luchanok and Kaminski 2008).

#### **2. Epidemiology**

MG has a prevalence of 20-400 per million based on large population studies, and OM comprises approximately 20% of all cases (Somnier et al. 1991; Phillips et al. 1992; Christensen et al. 1993; Phillips and Torner 1996; MacDonald et al. 2000; Casetta et al. 2010). The classic statement of the disease being of old men and young woman is true with an age distribution being bimodal with incidence peaks in the 20's for women and 40's for men (Phillips and Torner 1996; Grob 1999; Mantegazza et al. 2003; Vincent et al. 2003; Matsuda et al. 2005). OM is more likely to present at a later age and is more often seen in men (Gilbert and Savino 2007). In Asian populations, OM is more common and has a distinct predilection for a juvenile onset, quite different from that observed in European and American populations (Chiu et al. 1987; Hawkins et al. 1989; Wong et al. 1992). One study from South Africa found that OM in the black population was more likely to be treatment resistant than in the white (Heckmann et al. 2007).

Ocular Myasthenia Analysis of Diagnostic and Treatment Options 107

gaze. During the refixation, the eyelid overshoots and appears retracted momentarily and

Other causes of ptosis may rarely be confused with OM. Senile ptosis and levator dehiscence are readily differentiated by absence of significant fluctuation. Chronic progressive external ophthalmoplegia produces symmetric ptosis and ophthalmoparesis, but with slow saccades which should distinguish it from OM (Barton et al. 1995; Leigh and Zee 1999; Hirano and DiMauro 2001). Brainstem disorders of the third nerve nuclear complex will usually have associated central nervous system pathology. Horner's syndrome is identified by miosis and elevation of the lower lid, while the ptosis in complete third nerve palsy is associated with pupillary dilatation. Clinically evident pupillary abnormalities *never* occur in MG, although subclinical alterations in pupillary

Ophthalmoparesis is the second most common manifestation of OM. Most MG patients complain of frank double vision; however, complaints may include dizziness, gait instability, or visual blurring without significant complaints of diplopia. Symptoms may improve with closure of one eye. Nearly 90% of patients who present with diplopia have associated ptosis, and the combination should immediately lead to the consideration of MG as a diagnosis (Barton and Fouladvand 2000; Elrod and Weinberg 2004; Fouladvand et al. 2005; Daroff and Benatar 2009). The eye movement abnormalities of MG mimic any peripheral or central nervous system ocular motility abnormality, and the degree of impairment varies from paralysis to subtle weakness with isolated nystagmus. Dissociated gaze-evoked nystagmus contralateral to a paretic eye may be observed in OM, which represents adaptive increases in innervational pulse. On dynamic testing, saccadic velocity may be preserved or increased in a limited range of movement (highly suggestive of MG) or intrasaccadic fatigue may be identified when a fast eye movement suddenly slows and becomes disconjugate in mid-flight (Khanna et al. 2007). Graves ophthalmopathy can mimic OM by presence of a restrictive deficit but ptosis is absent and if the patient is thyrotoxic, lid retraction may be present. Ptosis in a

Orbicularis oculi weakness in combination with ptosis or ophthalmoparesis is a strong indicator of MG (Barton and Fouladvand 2000; Fouladvand et al. 2005). OM may mimic any pupil-sparing ocular motility disorder including fourth, sixth, and partial third nerve palsies, and central gaze disorders, such as internuclear ophthalmoplegia, the one and a half syndrome, and chronic progressive external ophthalmoplegia (Leigh and Zee 1999; Fouladvand et al. 2005; Daroff and Benatar 2009). Other neuromuscular junction disorders may mimic OM such as Lambert-Eaton myasthenic syndrome, botulism, or organophosphate poisoning, but purely ocular presentations of these disorders are rare. Appropriate history, physical examination, and ancillary testing should distinguish these

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.

then becomes ptotic again (Cogan 1965).

constriction are reported (Tsiptsios et al. 2008).

patient with Graves disease suggests the coexistence MG.

conditions from MG.

**4. Diagnostic testing** 

Fig. 1. Summary of Myasthenia Gravis Pathogenesis. Antibodies directed at neuromuscular junction proteins are produced by B cells under T cell regulation. Antibodies compromise the AChR density at the neuromuscular junction and thereby impair neuromuscular transmission producing weakness. Treatments used for ocular myasthenia are indicated. APC-antigen presenting cell.

#### **3. Ocular manifestations of myasthenia gravis**

Over seventy-five percent of MG patients initially present with ptosis or diplopia and almost all MG patients experience ocular manifestations sometime during the course of the disease (Beekman et al. 1997; Barton and Fouladvand 2000; Daroff and Benatar 2009). About half of patients who present with isolated ocular manifestations develop generalized weakness within six months and up to eighty percent will generalize within 2 years (Bever et al. 1983; Oosterhuis 1989; Kupersmith et al. 2003). It is likely that symptoms will remain restricted to the ocular muscles once a patient has had restricted ocular manifestations for over two years (Evoli et al. 1988; Oosterhuis 1989; Grob 1999; Verschuuren et al. 2010). The natural history of the disease impacts therapeutic decision-making.

The hallmark of MG manifestations is their variable nature, which may range in severity over a day, over weeks to months, and include periods of complete resolution. The variations in severity assist in diagnostic recognition of MG but may complicate clinical recognition, if a patient is examined at a time of relative good strength. Ptosis may be unilateral or bilateral, and usually differs in severity between lids. OM is the only diagnostic consideration in a patient with a history of alternating or recurrent painless ptosis (Daroff and Benatar 2009). Some patients do not immediately appreciate lid droop and complain primarily of blurred vision secondary to the lid's obstruction of the pupil. Due Hering's law of equal innervation, central compensation for unilateral ptosis may lead to hyper-retraction of a less affected lid leading to ocular irritation from exposure. When the ptotic lid is manually elevated, the retracted lid droops, a sign commonly considered specific for MG. The presence of Cogan's sign also strongly supports the diagnosis of MG. Cogan's sign is elicited by instructing the patient to look down and then rapidly return the eyes to primary

Fig. 1. Summary of Myasthenia Gravis Pathogenesis. Antibodies directed at neuromuscular junction proteins are produced by B cells under T cell regulation. Antibodies compromise the AChR density at the neuromuscular junction and thereby impair neuromuscular transmission producing weakness. Treatments used for ocular myasthenia are indicated.

Over seventy-five percent of MG patients initially present with ptosis or diplopia and almost all MG patients experience ocular manifestations sometime during the course of the disease (Beekman et al. 1997; Barton and Fouladvand 2000; Daroff and Benatar 2009). About half of patients who present with isolated ocular manifestations develop generalized weakness within six months and up to eighty percent will generalize within 2 years (Bever et al. 1983; Oosterhuis 1989; Kupersmith et al. 2003). It is likely that symptoms will remain restricted to the ocular muscles once a patient has had restricted ocular manifestations for over two years (Evoli et al. 1988; Oosterhuis 1989; Grob 1999; Verschuuren et al. 2010). The

The hallmark of MG manifestations is their variable nature, which may range in severity over a day, over weeks to months, and include periods of complete resolution. The variations in severity assist in diagnostic recognition of MG but may complicate clinical recognition, if a patient is examined at a time of relative good strength. Ptosis may be unilateral or bilateral, and usually differs in severity between lids. OM is the only diagnostic consideration in a patient with a history of alternating or recurrent painless ptosis (Daroff and Benatar 2009). Some patients do not immediately appreciate lid droop and complain primarily of blurred vision secondary to the lid's obstruction of the pupil. Due Hering's law of equal innervation, central compensation for unilateral ptosis may lead to hyper-retraction of a less affected lid leading to ocular irritation from exposure. When the ptotic lid is manually elevated, the retracted lid droops, a sign commonly considered specific for MG. The presence of Cogan's sign also strongly supports the diagnosis of MG. Cogan's sign is elicited by instructing the patient to look down and then rapidly return the eyes to primary

Cyclosporine, Tacrolimus Myocophenolate

**AChR-Ab producing B cells**

Pyridostimine

Azathioprine

**C' C' Neuromuscular Junction Injury**

**MAC**

**C**

**AChR or MuSK**

APC-antigen presenting cell.

**B cell**

**3. Ocular manifestations of myasthenia gravis** 

natural history of the disease impacts therapeutic decision-making.

**APC T cells**

**FcR**

gaze. During the refixation, the eyelid overshoots and appears retracted momentarily and then becomes ptotic again (Cogan 1965).

Other causes of ptosis may rarely be confused with OM. Senile ptosis and levator dehiscence are readily differentiated by absence of significant fluctuation. Chronic progressive external ophthalmoplegia produces symmetric ptosis and ophthalmoparesis, but with slow saccades which should distinguish it from OM (Barton et al. 1995; Leigh and Zee 1999; Hirano and DiMauro 2001). Brainstem disorders of the third nerve nuclear complex will usually have associated central nervous system pathology. Horner's syndrome is identified by miosis and elevation of the lower lid, while the ptosis in complete third nerve palsy is associated with pupillary dilatation. Clinically evident pupillary abnormalities *never* occur in MG, although subclinical alterations in pupillary constriction are reported (Tsiptsios et al. 2008).

Ophthalmoparesis is the second most common manifestation of OM. Most MG patients complain of frank double vision; however, complaints may include dizziness, gait instability, or visual blurring without significant complaints of diplopia. Symptoms may improve with closure of one eye. Nearly 90% of patients who present with diplopia have associated ptosis, and the combination should immediately lead to the consideration of MG as a diagnosis (Barton and Fouladvand 2000; Elrod and Weinberg 2004; Fouladvand et al. 2005; Daroff and Benatar 2009). The eye movement abnormalities of MG mimic any peripheral or central nervous system ocular motility abnormality, and the degree of impairment varies from paralysis to subtle weakness with isolated nystagmus. Dissociated gaze-evoked nystagmus contralateral to a paretic eye may be observed in OM, which represents adaptive increases in innervational pulse. On dynamic testing, saccadic velocity may be preserved or increased in a limited range of movement (highly suggestive of MG) or intrasaccadic fatigue may be identified when a fast eye movement suddenly slows and becomes disconjugate in mid-flight (Khanna et al. 2007). Graves ophthalmopathy can mimic OM by presence of a restrictive deficit but ptosis is absent and if the patient is thyrotoxic, lid retraction may be present. Ptosis in a patient with Graves disease suggests the coexistence MG.

Orbicularis oculi weakness in combination with ptosis or ophthalmoparesis is a strong indicator of MG (Barton and Fouladvand 2000; Fouladvand et al. 2005). OM may mimic any pupil-sparing ocular motility disorder including fourth, sixth, and partial third nerve palsies, and central gaze disorders, such as internuclear ophthalmoplegia, the one and a half syndrome, and chronic progressive external ophthalmoplegia (Leigh and Zee 1999; Fouladvand et al. 2005; Daroff and Benatar 2009). Other neuromuscular junction disorders may mimic OM such as Lambert-Eaton myasthenic syndrome, botulism, or organophosphate poisoning, but purely ocular presentations of these disorders are rare. Appropriate history, physical examination, and ancillary testing should distinguish these conditions from MG.
