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vogt - koyanagi - harada disease ( vkh ) and sympathetic ophthalmia ( so ) are both considered ocular t - cell mediated autoimmune diseases .
although the pathogenesis and etiologies are different , the two entities share common clinical manifestations as well as similar pathological and immunohistochemical features [ 13 ] .
moreover , prompt and thorough treatment is essential for both vkh and so . systemic presentations and clinical history are important features that differentiate vkh from so .
extraocular findings such as dysacusis , vitiligo , poliosis often develop in vkh but are rare in so .
since females are more susceptible to a variety of autoimmune diseases , such as systemic lupus erythematosus , multiple sclerosis , and rheumatoid arthritis [ 46 ] , this paper reviews the literature of vkh and so focusing on whether gender predilection exists in these two diseases .
vkh disease is a multisystemic disorder that involves the eyes , ears , skin , hair , and meninges .
ocular manifestations are characterized by bilateral granulomatous panuveitis with exudative retinal detachments . in the majority of vkh patients ,
overall , females are more frequently affected with vkh than males [ 79 ] , although several studies found no such gender predilection [ 10 , 11 ] .
vkh tends to affect patients from asian , middle eastern , hispanic , and native american populations [ 7 , 12 ] .
the typical progression of vkh includes 4 stages : the prodromal , uveitic , chronic , and chronic recurrent stages .
the prodromal stage occurs 35 days before the ocular disease , mimicking a systemic viral - like presentation . the uveitic stage , which may last for several weeks to months , is characterized by acute anterior uveitis with mutton - fat keratic precipitates , aqueous cells and flare , iris nodules , and synechiae .
severe changes in the posterior segment include vitritis , optic disc swelling , retinal edema , hemorrhages , nonrhegmatogenous exudative retinal detachment , subretinal fibrosis , disciform scars , and rpe abnormality .
the focal yellowish - white nodular lesions , known as dalen - fuchs nodules , are presented at the subretinal pigment epithelium ( rpe ) level in the peripheral retina .
depigmentation of the perilimbus ( sugiura 's sign ) and a pale fundus ( sunset - glow fundus ) are revealed in the chronic stage .
the chronic recurrent stage often presents other complications such as cataract , glaucoma , subretinal neovascularization , and subretinal fibrosis [ 13 , 14 ] .
extraocular presentations including vitiligo , poliosis , alopecia , and dysacusis may also develop during the chronic or chronic recurrent stages .
so is a rare bilateral granulomatous uveitis that occurs after the uvea of one eye is subjected to a penetrating injury due to trauma or surgery .
the injury to one eye ( known as the exciting eye ) also results in an inflammatory response in the noninjured , contralateral eye ( known as the sympathizing eye ) . unlike the multisystemic involvements of vkh , extraocular manifestations are rare in so . due to the rarity of disease and great improvements in modern surgical techniques ,
the disease rarely occurs ; thus , it is difficult to estimate the prevalence of so .
an earlier study published the incidence of so after a penetrating injury to be approximately 2% prior to 1950 ; lower incidences0.20.5% following ocular trauma and 0.01% following ocular surgery  have been reported in more recent studies [ 16 , 17 ] .
the interval between ocular injury and the so onset varies to a large extent , ranging from 5 days to 66 years [ 16 , 18 , 19 ] . in general
, 65% of so occurs between 2 weeks and 2 months after injury and 90% occurs within 1 year [ 16 , 20 ] .
the clinical presentations are identical in both trauma- and injury - induced so with an insidious onset .
the classic presentation of so is characterized by an acute granulomatous inflammation in the anterior segment with mutton - fat keratic precipitates , aqueous cells and flare , iridocyclitis , and posterior synechiae .
moderate to severe vitritis with choroidal thickening and infiltration as well as optic disc swelling generally occurs in the posterior segment [ 2124 ] .
the presence of dalen - fuchs nodules , measuring 60 to 700  m in diameter , is typical and is most often found at the midperipheral retina in so . in extremely rare situations , patients with so may experience extraocular symptoms , such as hearing loss , headache , vitiligo , and alopecia [ 26 , 27 ] .
most studies have reported that females are affected with vkh more frequently than males ( table 1 ) .
earlier studies in north america have noted that 6078% of vkh patients are females [ 10 , 12 , 13 , 28 , 29 ] . by reviewing 75 vkh patients seen at the national eye institute between 1978 and 1996 , 78.7% of patients were females . in other areas ,
the recently reported proportions of affected females with vkh are 78.9% in mexico ; 62.975% in saudi arabia [ 8 , 30 , 31 ] ; 65.3% in tunisia , north africa ; 73.7% in japan ; 84.44% in south india ; 70% in brazil ; and 71.1% in turkey .
reported that females constituted 62.5% of patients in 48 case series in a hispanic population .
found that only 38% of patients were females in their 47 case series of vkh in a japanese population .
even reported more male patients in more than 500 chinese with vkh [ 11 , 39 ] .
however , no gender predisposition of the disease was also reported from the same group in other studies [ 4045 ] .
other vkh studies have also reported no gender differences in prevalence ; interestingly , most of these conclusions come from studies of asian populations [ 4649 ] .
these data might indicate that there are geographic variations in the gender predilection in the vkh patients .
interestingly , ocular manifestations of vkh are variable and race dependent , and the  sunset - glow  appearance is more commonly seen in hispanic and asian patients . a study of 134 eyes ( 67 vkh patients ) conducted in singapore reported that male vkh patients ( 50 eyes ) were clinically associated with a higher risk of chorioretinal degeneration and vitiligo .
pregnancy is reported to play a role in vkh prognosis and has a beneficial effect on disease activity [ 10 , 5052 ] . in general ,
two patterns of prognosis during pregnancy have been described [ 10 , 5052 ] . in some females with vkh , the ophthalmic presentations improved during pregnancy , but with recurrence after delivery [ 10 , 51 , 53 ] .
several studies have documented less uveitis reactivity with lower numbers / rates of flare - up during pregnancy , but many of these females experienced a rebound in activity within 6 months of delivery [ 5355 ] . however , in the other cases , vkh developed in females during pregnancy who were then cured with corticosteroids without recurrence following delivery . because vkh is a t - cell mediated autoimmune disease , changes in immunity and humoral constituents during pregnancy may account for the remissions in female patients .
in addition , elias et al . showed that better final visual acuity is positively correlated with female patients , whereas male gender in vkh is significantly associated with worse visual acuity .
sex hormones , including estrogen and progesterone , are believed to mediate the immune response and account for gender differences in the prevalence of autoimmune diseases .
an increased incidence or severity of inflammation has been reported in the late phase of the menstrual cycle for women with asthma , rheumatoid arthritis , and psoriatic arthritis [ 5861 ] . as a systemic autoimmune disorder and subtype of uveitis
literature showing vkh amelioration during pregnancy has suggested that sex hormones may influence the course of vkh [ 10 , 51 ] . to further evaluate the protective role of pregnancy
, we used the experimental autoimmune uveitis ( eau ) mouse model mimicking human uveitis .
our results suggest that protection from eau during pregnancy is primarily due to a selective reduction of antigen - specific th1 responses with only marginal enhancement of th2 function
. these effects may in part be secondary to elevated systemic levels of tgf-. we measured serum levels of the female hormones ( estrogen , progesterone , and prolactin ) , th1 ( il-2 and ifn- ) , th2 ( il-4 , il-5 , il-6 , and il-10 ) , and tgf- cytokine levels in 4 women with uveitis during their 5 normal , full term pregnancies .
uveitic activities decreased after the first trimester but flared up in early postpartum period , suggesting an association of female hormones and elevated tgf- with uveitis .
evaluated 76 regularly menstruating women with acute anterior uveitis and found that the disease commences more frequently in the postovulatory phase of the menstrual cycle .
they concluded that the onset of the acute anterior uveitis is partially dependent on the levels of estrogen and/or progesterone .
the withdrawal of these hormones , with their proven anti - inflammatory effects , may provoke the onset of uveitis .
based on the association of pregnancy and menstrual cycle with vkh , it is important to assess the menstrual history and to consider adjustments of immunosuppressants , such as corticosteroid treatment , during pregnancy and postpartum . although the precise mechanism of vkh is still not clear , genetic factors are thought to play an important role in vkh [ 61 , 62 ] .
the associations of hla - dr53 , hla - dr4 , and hla - dq4 antigens with vkh have been reported [ 6568 ] . additionally , a strong association with hla - drb104:05 allele has been documented in vkh [ 69 , 70 ] .
recently , alez et al . in mexico compared 76 vkh patients ( 78.9% females ) and 256 healthy controls using the hla - dqb1/drb1 genotyping method .
they found that hla - drb104:05 , hla - drb104:04 , and hla - dqb103:02 alleles were restricted only to female gender .
in trauma - induced so , males are reported to have a higher prevalence than females ; this gender predominance may be attributable to a higher incidence of ocular injury in males , especially during historical wartime .
reviewed 85 patients with so and showed a slight male predilection of male gender ( 60% ) with a higher incidence of traumatic etiology ( 62% ) .
we reviewed 32 patients with so presented at the national eye institute , including 23 patients with so resulting from trauma and 9 resulting from surgery .
the numbers of males and females are equally distributed in the case series from 1982 to 1992 .
al - halafi et al . reported no gender difference in disease incidence in 34 males and 26 females with so due to ocular injury during a 10-year period in saudi arabia .  
this is due to the fact that intraocular surgeries including glaucoma surgery , cataract extraction , and pars plana vitrectomy are equally performed in both male and female patients [ 20 , 74 ] .
there are no clinical differences between males and females in so due to either trauma or ocular surgery . due to the rarity of so , it is difficult to compare gender differences in the prognosis of so .
however , because so and vkh share many clinical and pathological similarities , the role of sex hormone and pregnancy could also affect disease severity and presentation , further clinical and/or experimental studies are required to draw a conclusion .
both vkh and so are types of bilateral granulomatous panuveitis that can lead to severe visual loss without effective management .
in addition to clinical features , gender predilection in vkh and so could provide more appropriate therapies for patients . in vkh , with the protective role of estrogen / progesterone , female patients
, the evidence that certain hla - dr alleles are exclusively associated with vkh in females implies an important genetic background in the pathogenesis of vkh . in so , although gender differences only exist in the incidence of ocular trauma , we can not rule out the possible role of gender - based factors in the initiation , progression , and prognosis of so .
additional gender - based studies may identify other genes or risk factors related to these two autoimmune diseases .
vogt - koyanagi - harada disease ( vkh ) and sympathetic ophthalmia ( so ) are types of t - cell mediated autoimmune granulomatous uveitis . 
 although the two diseases share common clinical features , they have certain differences in gender predilections . 
 vkh classically has been reported as more prevalent in females than males , yet some studies in japan and china have not found differences in gender prevalence . 
 male patients have a higher risk of chorioretinal degeneration , vitiligo , and worse prognosis . 
 conversely , the changing levels of estrogen / progesterone during pregnancy and the menstrual cycle as well as higher levels of tgf- show a protective role in females . 
 potential causes of female predilection for vkh are associated with hla - dr and hla - dq alleles . 
 so , a bilateral granulomatous uveitis , occurs in the context of one eye after a penetrating injury due to trauma or surgery . 
 in contrast to the female dominance in vkh , males are more frequently affected by so due to a higher incidence of ocular injury , especially during wartime . 
 however , no gender predilection of so has been reported in postsurgical cases . 
 no clinically different manifestations are revealed between males and females in so secondary to either ocular trauma or surgery . 
 the potential causes of the gender difference may provide hints on future treatment and disease evaluation .