Vogt–Koyanagi–Harada Syndrome






Key concepts





  • Diagnostic criteria for both the complete and incomplete forms of the disease are becoming better defined.



  • Personality changes because of the CNS involvement may be seen in this entity.



  • Posterior pole disease should be treated very aggressively as the drop in vision may be very marked.



The Vogt–Koyanagi–Harada syndrome (VKH) is a systemic disorder involving many organ systems, including the eyes, ears, skin, and meninges. It includes a constellation of clinical signs and symptoms, and no definitive confirmatory diagnostic tests are yet available. In the 12th century a physician from the Arab world, Mohammad-al-Ghafiqi, described a disease with poliosis, neuralgias, and hearing changes. In more modern times, in 1906 Alfred Vogt presented one case, and Koyanagi in 1929 described in detail six patients with bilateral nontraumatic chronic iridocyclitis associated with poliosis, vitiligo, and dysacousia. Harada, in 1926, described an essentially posterior uveitis with an exudative retinal detachment associated with a pleocytosis in the cerebrospinal fluid (CSF). As more of these cases were recognized, it became clear that many of the features seen in each of these entities overlapped. Babel suggested that these symptoms were manifestations of the same underlying disorder, and that only intensity and distribution varied from one patient to the next; it therefore seemed appropriate to call the entity the Vog–Koyanagi–Harada syndrome, although it sometimes appears in the literature under other names, for example uveomeningitis.




Clinical aspects


Although VKH has been reported throughout the world, its appearance seems to be concentrated in certain racial and ethnic groups. Recently diagnostic criteria have been discussed and published ( Table 24-1 ). It is a common type of endogenous uveitis in Japan, constituting at least 8% of these cases. The same holds true for certain parts of Latin America, particularly Brazil. It is, however, relatively uncommon in the United States and seems to be an exceedingly unusual diagnosis in persons of northern European extraction. VKH patients seen in France were all of Mediterranean origin. Some years ago, when we reviewed our examinations of 75 patients with VKH, we noted that most (79%) were female ( Table 24-1 ). A similar observation has been made of patients in Latin America (Rubens Belfort Jr, personal communication, 1995). However, Ohno and coworkers, in their series of 186 patients, reported that more males than females had the disease. In our series, 44% of the patients were African-American, 37% were white, 11% were Hispanic, and 6% were Oriental. Of interest is the fact that a very high percentage of the patients with VKH whom we have seen have American-Indian heritage, albeit sometimes distant. This observation is a most provocative one, because certainly this may be the unifying genetic bond between patients in the United States and those in the Orient. VKH is commonly seen in the Hispanic population of Southern California, an ethnic group often with Native American ancestry as well. VKH is generally a disease of persons in the second to fourth decades of life, although the disease has been reported in children. Lacerda reported a case in a 7-year-old child. Tabbara and coworkers reported that 13 of 97 patients with VKH seen at the King Khaled Eye Hospital in Saudi Arabia were children, whereas Berker et al. reported that 15% of Turkish VKH patients were under 16 years of age. Rathinam and associates found that only three of their 98 patients with VKH were children. This latter number is closer to our experience. The visual prognosis is generally favorable.



Table 24-1

Characteristics of patients with VKH seen at the NEI. (From Lertsumitkul S, Whitcup SM, Chan CC, et al. Subretinal fibrosis and choroidal neovascularization in Vogt–Koyanagi–Harada syndrome. Graefes Arch Clin Exp Ophthalmol 1999; 237: 1039–1045.)






















































































Characteristics No. (%) Range
Gender
Male 16 (21.3)
Female 59 (78.7)
Race
White/Native American ancestry 17 (22.7) /3
African-American/Native American ancestry 39 (52.0) /16
Hispanic 9 (12.0)
Oriental 9 (12.0)
Asian Indian 1 (1.3)
Age (mean, yr) 32.8 ±12.6 11–72
Duration of disease (mean, mo) 29.0 ± 50.7 1–240
Systemic manifestations
Ocular only 12 (16.9)
Ocular + cutaneous 10 (14.1)
Ocular + neurologic 30 (42.3)
Ocular + cutaneous + neurologic 19 (26.7)
Glaucoma 16 (21.3)
Cataract 12 (16.0)
Visual acuity mean (ETDRS letters read) 41.7 ± 29.3 1–85
Subretinal fibrosis 30 (40)
Choroidal neovascularization 11 (14.7)


Systemic findings


VKH is a systemic disorder, and the extraocular findings are most important in securing the diagnosis. Perry and Font stressed that in patients with the Harada form of the disease some extraocular findings, such as hair and skin alterations, are uncommon. However, in our opinion, even patients with ocular lesions typical of this disorder cannot definitively be said to have VKH without these extraocular findings. A ‘revised’ guideline for diaganosis has been developed that reflects these concerns (see below).


The disease may be preceded by a prodromal stage, in which the patient may complain of headache, orbital pain, stiff neck, and vertigo. There may also be a fever. In the group of mostly Hispanic patients of Beniz and coworkers, headache was by far the most common neurologic complaint. Others , have reported presentation with a mild facial weakness, migraine-like headaches with a sensorimotor hemisyndrome, and cognitive brain dysfunction.


The patient complaining of central nervous system symptoms needs to be evaluated rapidly. A lumbar puncture will reveal a pleocytosis in 84%, with mostly lymphocytes and monocytes present. The CSF glucose level should show a normal relationship to the serum glucose level. A lumbar puncture should be performed early in the course of the disease because the pleocytosis will ultimately disappear, even though the inflammatory disease in the eye may continue. These CSF findings were central to the diagnosis criteria as proposed by Sugiura, and not to the revised criteria (see below). The CSF pleocytosis and the number of cells noted are significantly higher in those patients who develop a sunset glow fundus (see below). Further, it is occasionally very helpful in terms of determining the severity of the disease. If we see a pleocytosis we know we need to be very aggressive in our therapeutic approach. On occasion it can help with the diagnosis, as in a case where melanin-laden macrophages in the CSF specimen helped to make the diagnosis in a patient with titers positive for syphilis.


The auditory difficulties associated with this disorder are central and will often occur concurrently with the ocular disease. The auditory disorder may be the presenting problem, however. The hearing loss usually involves the higher frequencies and may affect more than three-quarters of patients with the disorder. Dysacousia, which was observed in 74% of patients in one study, may resolve after several months; however, we and others have noted that it may persist for years. Some patients will have tinnitus without an objective decrease in hearing. When we reviewed 24 patients, we noted that some may indeed present with tinnitus and even sudden hearing loss. However, audiology revealed many more with hearing alterations. Detailed auditory testing, carried out by competent professionals, is important to rule out a noncentral reason for a reduction in hearing.


Skin lesions may also be a prominent part of the disease complex. Approximately 72% of patients report sensitivity to touch of both hair and skin during the active phase of their disease. Vitiligo and poliosis occur in a large number of patients (63% and 90%, respectively) during the convalescent stage, whereas alopecia was reported in 70–73% of one group with VKH , ( Fig. 24-1 ). It should be noted that ethnic groups may manifest varying systemic symptoms, as suggested by the study of Beniz and colleagues, in which the authors found dermatologic involvement only rarely in the group of mostly Hispanic patients with VKH whose cases they followed. One area frequently overlooked during an examination for such changes is the axilla.




Figure 24-1.


A, Area of vitiligo and poliosis of the cilia in a patient with VKH. (Courtesy of D. Cogan, MD.) B, Alopecia in a patient with VKH. The hair ultimately regrew.


Ocular findings


VKH is a bilateral ocular condition. Although only one eye may be inflamed initially, in 94% of patients the disease involves the second eye within 2 weeks. There is a tendency for the ocular disease to occur in spring and autumn. The inflammatory disease is granulomatous in nature, with mutton-fat keratic precipitates on the corneal endothelium. Perilimbal vitiligo (Sugiura’s sign) may be a striking feature, occurring in 85% of Oriental patients. The inflammatory activity can be quite severe and involves both the anterior chamber and the anterior vitreous in about 56% of patients. Nodules may be noted on the pupillary margin, as well as in the iris stroma ( Fig. 24-2 ). An early finding in the disease is the shallowing of the anterior chamber and a moderate increase in intraocular pressure. This appears to be related to a swelling of the ciliary processes, which has been noted to occur early in this disease. This finding is apparent only with careful gonioscopic evaluation. Other patients, however, may have hypotony, probably as a result of the edema of the ciliary body. A high incidence of neovascularization of the angle has been reported by one group of Japanese investigators, but this has not been our personal experience. The severity of the inflammatory response is reflected by the fact that pupillary membranes often develop, and cataract formation occurs. The glaucoma associated with VKH can be difficult to control. In a series reported by Forster and coworkers, 16 of 42 patients with VKH required either surgical or medical therapy for their glaucoma, with nine having open-angle glaucoma and seven having angle closure due to pupillary block. A thickened iris is commonly noted in this disease. This is important for at least two reasons. The first is that laser iridotomy is very difficult to perform and the hole created by the laser often closes quickly. The second is that the patient may experience angle closure with a plateau iris, which often adheres completely to the lens, making it impossible to bow forward as one would expect in a more typical case of iris bombé. A rare presentation in dark-skinned persons is scleral perforation, presumably at the site of emergence of the scleral nerves, which are involved as innocent bystanders in the immune response directed against the melanocytes surrounding them ( Fig. 24-3 ).




Figure 24-2.


Iris nodules and mutton-fat keratitic precipitates in a patient with VKH.



Figure 24-3.


VKH with areas of focal scleritis and thinning of sclera anterior to insertion of rectus muscles. There is a large sector iridectomy superiorly.

(Reproduced with permission from Tabbara KF: Scleromalacia associated with Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 105:694–695, 1988)


Severe and rather characteristic changes are noted to occur in the posterior portion of the eye as this disorder evolves. A swelling of the optic nerve head is seen early in 87% of patients; this usually occurs concurrently with a severe vitreous inflammatory response. In addition, retinal edema may be one of the first signs of the disease and may be seen in the posterior pole. As the disease process continues, an exudative nonrhegmatogenous retinal detachment may occur, which is an important diagnostic finding. The inferior portion of the retina is most frequently involved. In the periphery of the retina, yellow-white, well-circumscribed lesions may appear, similar to those seen in sympathetic ophthalmia (see Chapter 23 ). It had been thought that these were the clinical equivalent of Dalen–Fuchs nodules; however new findings would suggest that perhaps that is not always the case (see below). Macular edema, although relatively rare, is seen in eyes with a more protracted inflammation or those that have epiretinal membranes.


Several fundus alterations occur as the disease process continues. Neovascularization of the retina and optic nerve can be seen, with subsequent recurrent and clinically significant vitreous hemorrhages. Subretinal neovascularization of the macula can also occur. Also, extramacular disciform lesions have been reported, presumably in areas of reactive proliferation of the retinal pigment epithelium (RPE) and perturbation of Bruch’s membrane. Moorthy and coworkers reported that subretinal neovascular membranes developed in seven of 58 patients with VKH they were following. They found that these seven affected patients showed more anterior and vitreous inflammation as well as more pigmentary disturbances in the fundus. As expected, the visual outcomes for these patients were also significantly poorer than those for patients with less severe alterations.


The nonrhegmatogenous detachments frequently do not persist after the initial presentation, although the other signs of inflammation continue to be present – for example ‘demarcation lines’ representing the extent of previous detachments. Rhegmatogenous detachments may also occur in these eyes, and constant surveillance for such changes is vital.


Diagnostic criteria for both the complete and incomplete forms of the disease have been published ( Box 24-1 ). There have been mixed reviews concerning the use of the criteria. A report by Gaspar et al. from Brazil reported a 100% concordance in a retrospective review of 67 patients, 46 of whom were in the early phase of the disease. Rao et al. reported a very good concordance rate as well when the criteria were applied retrospectively. However, Yamaki et al. found that the criteria were effective for the final diagnosis but not for the early stage of the disease. They felt it better to include criteria suggested by Sugiura, namely pleocytosis in the CSF and HLA typing. Retrospective studies are helpful as starting points, but prospective studies are very much needed to effectively evaluate the usefulness of any criteria.



Box 24-1

Revised criteria for diagnosis of VKH (Modified from Read et al. Vogt–Koyanagi–Harada disease diagnostic criteria. Int Ophthalmol 2007; 27:195–199)


Complete VKH: Criteria 1–5 must be present


Incomplete VKH: Criteria 1–3 and either 4 or 5 must be present


Probable VKH (isolated ocular disease): Criteria 1–3 must be present



  • 1.

    No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis


  • 2.

    No clinical or laboratory evidence suggestive of other ocular disease entities


  • 3.

    Bilateral ocular involvement (a or b must be met, depending on the stage of disease when the patient is examined)



    • a)

      Early manifestations of disease



      • (1)

        Evidence of diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction or optic disc hypermia) which may manifest as (a) focal areas of subretinal fluid or (b) bullous serous retinal detatchments



    • b)

      Late manifestations of disease



      • (1)

        History suggestive of prior presence of early findings noted in 3a and either (2) or (3) below, or multiple signs from 3.


      • (2)

        Ocular depigmentation: either (a) nummular chorioretinal depigmented scars or (b) retinal pigment epithelium clumping and/or migration or (c) recurrent or chronic anterior uveitis




  • 4.

    Neurological/auditory findings (may resolve by time of evaluation)



    • (a)

      Meningismus (malaise, fever, headache, nausea, abdominal pains, stiffness of the neck and back or a combination of these factors); Note that headache alone is not sufficient to meet the definition of meningismus


    • (b)

      Tinnitus


    • (c)

      Cerebrospinal fluid plenocytosis



  • 5.

    Intergumentory finding (not preceding onset of central nevous system or ocular disease)



    • (a)

      Alopecia, or


    • (b)

      Poliosis, or


    • (c)

      Vitiligo





As the disease process begins to wane, a characteristic depigmentation of the posterior portion of the globe occurs. This ‘sunset glow’ appearance to the fundus, which reflects the changes occurring at the level of the RPE or choroid, is seen commonly in Oriental patients. Keino and colleagues found that the sunset glow fundus was more commonly seen in eyes with a chronic inflammation that persisted for months. In the United States, the fundus of a white person with this disease has a more mottled appearance as well as a profound loss of pigment, causing what is known as a ‘blond’ fundus. At times profound subretinal changes, such as subretinal fibrosis, disciform scars, and RPE migration, can be quite striking ( Figs 24-4 to 24-6 ).




Figure 24-4.


Sunset glow fundus in Asian patient after inflammatory disease of the posterior segment due to VKH. Note ‘blond’ appearance of fundus.

(Courtesy of K. Masuda, MD, and M. Mochizuki, MD.)



Figure 24-5.


Dramatic subretinal alterations with subretinal fibrosis can occur in severe posterior pole inflammatory attacks.



Figure 24-6.


A–D, A Hispanic woman with poor vision in the left eye after having uveitis due to VKH. Fluorescein angiography findings demonstrated a subretinal neovascular net.


Mondkar and colleagues reported their experience with VKH in India, which represented only 2.2% of referrals. Extraocular manifestations were seen in 64% of patients at the time of presentation. More than 95% of these patients had a meningismus. In the 78 patients with VKH we reviewed, the disease manifested predominantly as posterior pole changes. We have not seen patients with only anterior segment disorders. In our experience there can be a wide distribution of visual acuities in patients with VKH. However, the acuities appear to be ‘bunched’ at the extremes of the vision chart. A large number of the eyes will demonstrate visual acuities that are 20/200 or worse, whereas a large proportion have a visual acuity of 20/40 or better. This reflects the observations of Ohno and coworkers. We have noted that our patients have had a far more persistent ocular inflammatory disease than is generally described in the literature. Rubsamen and Gass found in their series of 26 patients that the disease recurred in nine of 21 patients in the first 3 months, sometimes associated with a rapid taper of therapy. This may reflect referral patterns.


Course of disease


The clinical course of VKH is quite varied. The ideal patient is the one with severe acute finding, followed by a period of quiescence during which there is a depigmentation of tissue, with a later stage of recurrent anterior segment inflammation disease. Some patients may have a limited period of severe ocular inflammatory activity, followed by rapid depigmentation and no further episodes. Other patients, however, continue to have ongoing, chronic disease. It is this group that requires constant vigilance. Anterior segment alterations, such as cataract and secondary glaucoma, occur in about one-third of patients. Peripapillary atrophy >2 disc diopters was associated with greater visual dysfunction, and interestingly the use of a multivariate analysis steroid was the main determinant for peripapillary atrophy. , With aggressive therapy, one can assume that the nonrhegmatogenous detachment will reattach. Reattachment usually results in reasonably good vision. However, a close evaluation of the retina will demonstrate changes, such as preretinal membranes, RPE stippling, extensive posterior pole atrophy, and subtle folds in the retina precluding a return to previous levels of vision and subretinal fibrosis. In a report of 75 patients seen at the National Eye Institute (NEI) ( Table 24-2 ), 30 (40%) had subretinal fibrosis, and 14.7% of eyes had choroidal neovascularization. The subretinal fibrosis was associated with longer duration of disease and a worse visual acuity. The disease in children appears to be aggressive. Tabbara and colleagues reported that 61% of children with VKH versus 17% of adults needed cataract surgery, and that the final visual acuity in those children needing surgery was worse than that seen in adults. Rathinam and associates found that all of their small number of pediatric patients with VKH had cataracts. Clinical findings at presentation, the duration of the disease, as well as the development of extraocular manifestations all are prognostic factors relating to final visual acuity and recurrent inflammation.



Table 24-2

Clinical features of patients with subretinal fibrosis, choroidal neovascularization, history of glaucoma, cataract, and treatment with immunosuppressive agents. (From Lertsumitkul S, Whitcup SM, Chan CC, et al. Subretinal fibrosis and choroidal neovascularization in Vogt–Koyanagi–Harada syndrome. Graefes Arch Clin Exp Ophthalmol 1999; 237: 1039–1045.)























































































































Clinical features Yes (%) No (%) p Value
Subretinal fibrosis
Visual acuity (ETDRS letters read) 26.2 52.0 0.0001
Duration of disease (mo) 42.6 19.1 0.074
Age (yr) 31.5 33.6 0.48
Vitreous haze (0.5–4) 0.50 0.43 0.65
Choroidal neovascularization
Visual acuity (ETDRS letters read) 27.8 44.0 0.074
Duration of disease (mo) 44.5 26.5 0.43
Age (yr) 30.3 33.2 0.52
Vitreous haze (0.5–4) 0.44 0.46 0.91
Glaucoma
Visual acuity (ETDRS letters read) 35.2 43.4 0.32
Duration of disease (mo) 32.9 27.9 0.68
Age (yr) 30.3 33.5 0.28
Vitreous haze (0.5–4) 0.65 0.42 0.21
Cataract
Visual acuity (ETDRS letters read) 28.3 44.2 0.10
Duration of disease (mo) 66.0 21.5 0.10
Age (yr) 37.1 32.0 0.30
Vitreous haze (0.5–4) 0.68 0.42 0.20
Use of immunosuppressive agent
Visual acuity (ETDRS letters read) 46.2 39.8 0.33
Duration of disease (mo) 21.8 31.7 0.31
Age (yr) 28.5 34.6 0.07
Vitreous haze (0.5–4) 0.53 0.44 0.61


When patients manifest the classic findings of acute VKH, there is little difficulty in making the diagnosis. However, when the patient is examined at a later stage, the sequelae of the inflammatory disease cannot reliably help one to decide what the original problem had been, particularly if the nonocular findings are absent. The problems faced in diagnosing this condition were considered by Kayazawa and Takahashi, who described two patients, both of whom had multiple yellow-white placoid lesions and a decrease in vision. On the basis of fluorescein angiographic findings, one patient was believed to have acute posterior multifocal placoid pigment epitheliopathy. However, the fluorescein angiographic findings in the other patient showed multiple pinpoint leaks, and later the fundus developed a sunset glow appearance. Rao and Marak reported four patients with sympathetic ophthalmia, all of whom had penetrating wounds, and in whom two or more extraocular manifestations usually associated with VKH developed, that is, vitiligo, poliosis, dysacousia, and meningitis (see Chapter 23 ). Other disorders that can mimic VKH include sarcoidosis (see Chapter 22 ) (particularly if there is choroidal involvement and subretinal changes) and some of the white-dot syndromes (see Chapter 29 ). One patient was reported as presenting with an aseptic meningitis ( Fig. 24-7 ) and only manifesting ocular findings typical of VKH many months later. Kouda and associates reported a patient with VKH who first presented with a unilateral posterior scleritis and 12 months later was found to have a bilateral, severe granulomatous uveitis. Other diseases may rarely mimic the fundus picture seen in VKH. Bartonella has been reported to present as an unilateral VKH. In addition, another patient, who had an ICG and IVFA compatible with VKH ultimately was diagnosed as having an intravascular lymphoma. Admittedly, these are rare occurrences. A short note to alert the treating physician that interferon therapy given for other indications (such as hepatitis) can induce a serous detachment simulating VKH. While recognizing this possible complication, some have argued that the positive therapeutic value of interferon outweighs any possible negative adverse events.




Figure 24-7.


Basophilic granules in a melanin-laden macrophage taken from the cerebrospinal fluid of the patient described in reference .

(Reproduced with permission from Kamondi A, Szegedi A, Papp A et al: Vogt-Koyanagi-Harada disease presenting initially as aseptic meningoencephalitis, Eur J Neurol 7:719–722, 2000.)


The observer should set minimal ocular criteria for the diagnosis of this condition, because diagnosis is mainly a clinical decision. Our minimal criteria include a bilateral acute inflammatory response, with retinal edema and typical pinpoint leakage at the level of the RPE early on, as noted on examination with fluorescein angiography (see next section). Disc edema (and leakage seen on the fluorescein angiogram) is an important confirmatory sign, and many patients will have a central nervous system pleocytosis early in the disease. The presence of other extraocular findings already enumerated is helpful but these may be missed late in the disease. A history of Native American heritage is helpful information. We have no knowledge of the presence of Sugiura’s sign in white patients with this disease.




Laboratory tests, etiology, and histopathology


Several tests can be performed to evaluate alterations occurring in the eye as a result of the inflammatory disease. The use of fluorescein angiography is helpful in evaluating the extent of the disease in the posterior segment of the globe. Early in the disease, multiple pinpoint areas of leakage are noted at the level of the RPE. The later frames of the angiogram may show a large confluent area of leakage ( Fig. 24-8 ), and late leakage of the disc usually occurs. Subretinal neovascularization can be evaluated best with fluorescein angiography (see Fig. 24-6 ). Manger and Ober reported the presence of retinal arteriovenous anastomoses in a young woman with VKH. By using fluorescein angiography, they noted that these vessels were collaterals that had developed in areas of damaged RPE. Both fluorescein angiographic changes and ICG findings have been well described. Herbort and coworkers describe four general findings in VKH. First there is an early choroidal stromal vessel hyperfluorescence and hypofluorescent dark dots. In addition, one sees a fuzzy vascular pattern to the large stromal vessels and disc hyperfluorescence. With adequate immunosuppressive therapy the dark dots will resolve. Others have used ICG to examine the peripheral lesions usually identified as Dalen–Fuchs nodules. They found one group of patients whose nodules, which were more common inferiorly and temporally, to be hyperfluorescent in the early phase and then becoming hypofluorescent in the later frames. They felt that these patients had shorter disease. Those with nodules that showed small round hypofluorescent lesions early had longer disease.


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