Oc u lar My as the nia

about 60% of these cases prog ress to a gen er al ized type within the first 2 years. The di ag no sis of oc u lar my as the nia is of ten dif fi cult but is col lec tively con firmed by clin i cal eval u a tion and lab o ra tory re sults. Clin i cal man i fes ta tions, di ag nos tic ap proach, rel e vance, and ther a peu tic op tions are dis - cussed in this ar ti cle.

. My as the nia gra vis can af fect both males and females and has no race pref er ence [11,17,19,22].In OMG, there was no ticed a mi nor male pre dom i nance com pared to a slight fe male predominace in GMG [11,15,23].In women, the on set of the dis ease is ear lier and bi modal, around 30 and 60 years old, while in men it has one age peak, around 70 years old [17,19].Al though Yu and his col leagues show an age peak be tween 60-80 years for both sexes [24].Ac cord ing to a sys tem atic re view of pop u lation-based ep i de mi o log i cal stud ies in my as the nia gra vis by Carr et al., mor tal ity rates due to my as the nia cri sis vary from 0.06 to 0.89 cases per mil lion peo ple [21].How ever, my as the nia gra vis can oc cur/man i fest at any pe riod of life and have a dif fer ent course and out comes [15,23].

PATHOPHYSIOLOGY
Neuromuscular trans mis sion is in duced by the flow of calcium to the mo tor nerve through P/Q-type cal cium channels and the re lease of ace tyl cho line (ACh) from the synap tic ves i cles into the syn ap tic cleft.ACh then binds to AChR on the postsynaptic mem brane and causes de pola risa tion of the mus cle mem brane and mus cle con trac tion [18,22].Sev eral patho genic an ti bod ies at tack dif fer ent ele ments of the neuromuscular junc tion, and prob lems in the syn ap tic trans mis sion at the level of the junc tion be tween the mo tor nerve end ings and the mus cle in MG are iden tified [18].Autoantibodies against AChRs are the most frequently de tected an ti bod ies in pa tients with GMG (85-90% of all cases) al though they are much less pres ent in OMG (around 50%).How ever, it is con sid ered that acetyl cho line re cep tor an ti body test ing is less sen si tive in OMG than in gen er al ized MG [25].AChR-an ti bod ies block ACh and AChR bind ing site, ac ti vate com ple ment fac tors, and de struct the postsynaptic mem brane by increas ing the deg ra da tion of the AChRs [18,22].A smaller part of autoantibodies is di rected to wards mus cle-spe cific re cep tor ty ro sine kinase.These an ti bod ies may be pres ent in 70% of AChR-Ab seronegative MG pa tients but not in AChR-Ab se ro pos i tive MG pa tients, but they are rarely pres ent in iso lated oc u lar my as the nia [26,27].Re cent stud ies in di cate that low-den sity li po pro tein re cep tor-related pro tein 4 is an other im por tant tar get for autoantibodies in MG pa tients.How ever, data is still controversal.There are few stud ies ana lys ing LRP4 in MG pa tients.Zhang et al. found LRP4 autoantibodies to be pres ent in 9.2% of dou ble seronegative MG pa tients [28].Meanwhile, Pevzner et al. dis cov ered the same autoantibodies pres ent in 50% of dou ble seronegative MG pa tients [29].Fur ther data with greater num ber of pa tients and var i ous pop u la tions should be col lected in or der to better un derstand the eti ol ogy and pa thol ogy of LRP4 an ti body positive MG.

CLIN I CAL AS PECTS
Oc u lar my as the nia is lim ited to the weak ness of extraocular, levator palpebrae superioris, and orbicularis oculi mus cles, which in about 80% of pa tients pres ents as diplopia and/or ptosis.In my as the nia, the pu pils are al ways nor mal [38,39].It is com mon for symp toms to worsen through out the day and im prove af ter rest.Ex am i na tion of mul ti ple gaze di rec tions for about 30-60 sec onds is es sential as ptosis and extraocular move ments can fluc tu ate during ex am i na tion [18].

Eye lid symp toms
Ptosis is a very com mon symp tom [38].It is typ i cally painless, fluc tu at ing, uni lat eral, bi lat eral or al ter nat ing; if bi lateral, it is of ten asym met ric, but may be ab sent [40].Ptosis of one lid can be de tected if the ex am iner raises the contralateral lid (Her ring's law); the sign is trig gered by bi lateral and equal innervation.If the pa tient's gaze is held upward for a pro longed pe riod of time, ptosis may also be enhanced [38].The Cogan's lid twitch is an other char ac ter istic sign; pa tients are guided to look down for 10 sec onds and then im me di ately move their eyes up to the orig i nal posi tion.The up per eye lid twitches up wards briefly be fore mov ing into the ptotic po si tion [18,40].Orbicularis weakness is also fre quently no ticed in OMG; there fore, the func tion of the orbicularis oculi mus cle should be assessed.When the pa tient closes the eye lids with force, the so called "peek sign" may ap pear -the lids sep a rate leading to sclera ex po sure [17,40].In com plete blink ing can cause pain and tear ing.21% of pa tients with oc u lar my asthe nia may have dry eyes syn drome [39].

Extraocular mus cles symp toms
Ophthalmoplegia may in volve a sin gle extraocular mus cle (EOM) or may im pair any com bi na tion of EOMs [18].Although many pat terns of EOMs weak ness might be present, the me dial rectus, in fe rior rectus, and su pe rior oblique mus cles are most fre quently af fected [16].Diplopia is very com mon among pa tients with OMG be cause even a slight weak ness of the EOMs can be symp tom atic [23].Ac cording to Roh et al. study re sults, diplopia is pres ent in 93% of OMG pa tients [39].How ever, diplopia may be pres ent but not re lated with eye move ment de fi ciency.
Hypermetric sac cades, intersaccadic fa tigue, re duc tion in the saccadic ve loc ity, gaze evoked nys tag mus, and incomitant stra bis mus are less com mon symp toms in myas thenic pa tients [38].

RISK FAC TORS FOR THE DE VEL OP MENT OF GEN ER AL IZED MY AS THE NIA GRAVIS
Var i ous au thors in di cate that 60% of pa tients with only ocu lar on set even tu ally de velop a gen er al ized form within the first 2 years [13,15,17].Some stud ies show that the gen er al iza tion pro cess de pends on sev eral risk fac tors, and the con ver sion rate to GMG is around 20%.How ever, all of these stud ies in cluded ste roid ther apy which may modify the risk of gen er al iza tion [10,14,41,42].It was found that bi lat eral ptosis, older age at on set, the pres ence of thymoma, as well as the pres ence of AChR-an ti bod ies, and high lev els of seropositivity are risk fac tors for the con version of OMG to GMG [7, 9,11,14,[41][42][43].The role of gen der is still con tro ver sial in the prog no sis of oc u lar myas the nia, but one co hort study has shown that fe males tend more of ten to de velop GMG than men, be cause of the HLA-DR3 and B8 gene-al leles ge net ics [14,44].Pos i tive or ab nor mal sin gle-fi ber electromyography (sfEMG) is also con sid ered to in crease the risk of trans form ing to GMG [11].

DIF FER EN TIAL DI AG NO SIS
There are many neuromuscular junc tion and neu ro log i cal dis or ders that can im i tate the symp toms of OMG, so a differ en tial di ag no sis is nec es sary to iden tify a spe cific impair ment.Graves ophthalmopathy re sults in ab nor mal move ment of the eyes due to the con stric tive ophthalmopathy but no signs of ptosis.Con stric tive ophthalmopathy can rarely re sem ble pa re sis of the su pe rior oblique eye mus cle [45].In abil i ties of eye move ment, ptosis, and diplopia may in di cate stroke, nerve pal sies, and Hor ner's syn drome ini ti a tion [46].Myo tonic dys tro phy (MD) should also be exluded with it's symp toms such as ptosis, ex ter nal ophthalmoplegia, and bi lat eral op tic nerve at rophy.Dif fer en tial di ag no sis in cludes ge netic test ing for the pres ence of ex panded cy to sine-thy mine-gua nine re peat in the myo tonic dys tro phy pro tein kinase gene, mus cle biopsy, and electromyography [47].Bot u lism can mimic ocu lar my as the nia due to blurred or dou ble vi sion and drooping eye lids.Bot u lism is usu ally ver i fied by clin i cal neu rolog i cal ex am i na tion, de tec tion of bot u li num toxin in the serum and/or fe ces of pa tients [48].Lam bert-Eaton my asthenic syn drome (LEMS) is an au to im mune dis ease that should also be con sid ered.Pure oc u lar weak ness is un common as an ini tial pre sen ta tion of LEMS and in cludes less oc u lar, more prox i mal limb weak ness.Of the eye symptoms in LEMS, ptosis and diplopia are most char ac ter is tic.
The di ag no sis is clar i fied by us ing se rol ogy (radioimmuno assay test) -find ing an ti bod ies against P/Q subtype volt age gated cal cium chan nel.Electromyography can show low mus cle ac tion po ten tial at rest and a decremental re sponse at low rate re pet i tive nerve stim u lation (RNS) [49].

Ice test
Dur ing this test, an ice pack is placed on the ptotic eye for 2-5 min utes.El e va tion of the up per eye lid by 2 milimeters or more can be con sid ered as a pos i tive re sult for oc u lar my as the nia.Ac cord ing to Chatzistefanou et al., sen si tiv ity and spec i fic ity of the ice pack test was found to be 76.9% and 98.3% re spec tively [50].

min utes rest test
Be fore the test, it is nec es sary to eval u ate eye move ments and the po si tion of the eye lids.The pa tient should rest for 30 min utes with his eyes closed.Af ter rest, im prove ment of ptosis or eye move ments could be ob served in oc u lar my as the nia [51].

Edrophonium test
Edrophonium is a short-act ing acetylcholinesterase (AChE) in hib i tor that works by in creas ing the amount of avail able ace tyl cho line in the syn ap tic junc tion.It is injected in tra ve nously at ini tial dose of 2 mg and has its on set of ac tion af ter 10-30 sec onds.Edrophonium pre vents the peak of ACh by com pet i tively in hib it ing AChE in the neuromuscular junc tion.As a pos i tive test re sult, ptosis and eye move ment de fi ciency are re lieved [52].

Neostigmine test
Neostigmine is a lon ger act ing AChE in hib i tor.The peak ef fect is achieved at about 30 min utes af ter an in tra mus cular in jec tion, al though the re sponse may be seen within 15 minutes.The du ra tion of ef fect may last for sev eral hours.The usual dose for adults is 2.5 mg/mL [53].

Blood test for an ti bod ies
The di ag no sis of OMG can be con firmed by seropositivity to AChR an ti bod ies or, less of ten, to other pro teins of neuromuscular junc tion, in clud ing an ti bod ies against MuSK and LRP4 [54,55].AChR an ti body test ing is the most com mon and spe cific im mu no logic way to clar ify OMG di ag no sis, but ap prox i mately 50% of pa tients do not have an ti bod ies against AChRs and are seronegative [25].Ap prox i mately 10% of pa tients with my as the nia gra vis will have neg a tive se ro logic test ing for AChRs, anti-MuSK, and LRP4.It is known that pa tients can have other autoantibodies, such as titin, agrin, col la gen Q, and coarctin, but these an ti bod ies are not rou tinely tested, and their util ity in di ag nos ing my as the nia gra vis is un clear [56,57].

Electrophysiological tests
Re pet i tive nerve stim u la tion and sin gle-fi ber electromyography are two ba sic electrophysiological tests used for MG and OMG di ag no sis.RNS shows the ef fi cacy of neuromuscular trans mis sion.RNS is per formed by stim ulat ing the nerve at a fre quency of 2-3 Hz. 10% and higher dec re ment is com mon for MG.In the ab sence of a dec rement, ex er cises can be used to in duce the ex haus tion of mus cles and doc u ment the dec re ment.The test is ab nor mal in ap prox i mately 75% of pa tients with MG and 50% of patients with OMG [58].

Thy mus gland eval u a tion
Com puted to mog ra phy (CT) or mag netic res o nance im aging (MRI) of the chest should be done to de tect thymoma.Thymoma is found in ap prox i mately 15% of all MG cases [59].

TREAT MENT
Treat ment is aimed to al le vi ate symp toms, ex tend re mission pe ri ods, and de lay/avoid the gen er al iza tion pro cess.Any treat ment mea sure, sin gle or com bi na tion of drugs, should be se lected in di vid u ally [60].

Nonpharmacological treat ment
Nonpharmacological treat ment is rea son able to re lieve symp toms of OMG (diplopia).One-eye patch ing, cus tomized prisms may be also help ful for pa tients not re spond ing to med i cal ther apy [18].

Acetylcholinesterase in hib i tors
Acetylcholinesterase in hib i tors are the first line treat ment with pyridostigmine as the pri mary op tion.Pyridostigmine is a safe, fast-act ing med i ca tion with a rec om mended starting dose of 30 mg three to four times a day, which can be in creased up to 150 mg four times a day if nec es sary.If satis fac tory re sults are achieved, no other drugs are prescribed.Pyridostigmine is some times only par tially ef fective for ophthalmoplegia, there fore, other treat ment options may be nec es sary [17].

Corticosteroids
Pred ni sone is used as a sec ond ther apy op tion for OMG if pyridostigmine fails [61].Ini tially, pred ni sone is started at low doses and grad u ally in creased un til the symp toms resolve; a dos age of 20 mg daily is usu ally suf fi cient [17].
Sev eral stud ies sug gest that early corticosteroid ther apy could pre vent the gen er al iza tion of OMG [60,62].However, fur ther stud ies are needed to de ter mine whether immunosuppression re duces the risk of con ver sion of OMG to GMG.

Ste roid-spar ing agents
When pred ni sone is in ef fec tive or in tol er a ble, or the patient has se vere co ex ist ing con di tions (i.e., el derly di a betics with os teo po ro sis), azathioprine and mycophenolate mofetil are typ i cally of fered [17,61].These med i ca tions can be ad di tion ally added for pa tients who re quire higher dos ages of ste roids or are at high risk of com pli ca tions caused by ste roids [18,60].Tacrolimus and cyclosporine are more of ten used for pa tients with GMG and only in rare cases of OMG [40].
The dose of azathioprine is de ter mined by the weight of the pa tient and is usu ally 2.5-3 mg/kg.In gen eral, azathioprine is a well tol er ated med i ca tion, how ever, it's ther a peu tic ef fect fre quently oc curs af ter 3-10 months of con tin u ous ther apy [17].Com plete blood count, liver func tion, and thiopurine methyltransferase ac tiv ity should be mon i tored reg u larly to pre vent life-threat en ing side effects such as thrombocytopenia, leukopenia, hepatotoxicity, and neo pla sia [17,18].Mycophenolate mofetil is admin is tered at a standart dose of 1000 mg twice a day.It has mi nor side ef fects but com plete blood count needs to be monthly tracked [61].

Sur gi cal treat ment
Thymectomy is in ev i ta bly per formed in the pres ence of thymoma and should be con sid ered for nonthymomatous pa tients when other med i cal ther a pies fail and pa tients are AChR an ti bod ies se ro pos i tive [17].Blepha ro plasty can be per formed to im prove the qual ity of life of pa tients with fixed and treat ment-re sis tant ptosis last ing at least 2 years [40,63].Stra bis mus sur gery may be rec om mended for patients with sta ble diplopia and sta ble oc u lar align ment for at least 6 months, con firmed by an oph thal mol o gist [61].

RE SEARCH AT THE HOS PI TAL OF LITH U A NIAN UNI VER SITY OF HEALTH SCI ENCES KAUNO KLINIKOS
Our study per formed at the Hos pi tal of Lith u a nian Uni versity of Health Sci ences Kauno Klinikos ana lysed 140 cases of my as the nia gra vis.MG was di ag nosed in 55 (39.3%) men and 85 (60.7%) women.The mean age of men was 63.42 years, and the mean age of women was 58.40 years.Oc u lar my as the nia was di ag nosed in 32 (22.9%) cases, but the gen er al ized type of my as the nia dom i nated -108 (77.1%) cases.In ad di tion, it is note wor thy that many cases were well con trolled: ex ac er ba tions were di ag nosed once per year in 124 (88.6%) cases, 1-2 times per year in 13 (9.3%)cases, 3-4 times per year in 2 (1.4%) cases, more than 5 times per year only in 1 (0.7%) pa tient, and my asthenic cri sis was pres ent only in 5 (3.5%) cases.In our study, only 10 (7%) pa tients had eye move ment de ficiency, but diplopia occured in as many as 50 (35.7%)cases [64].