Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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Vogt-Koyanagi-Harada syndrome is an inflammatory condition in which ocular inflammation or uveitis is the most significant feature of the illness. Neurologists may be called on to diagnose the prodromal phase of the disease in which the predominant symptoms are headache, meningeal signs, and, less often, focal neurologic findings. CSF pleocytosis is also common. In this update, the authors cite data demonstrating that earlier initiation of either glucocorticoids or immunomodulatory measures is associated with a reduction in late visual morbidity in patients with Vogt-Koyanagi-Harada syndrome and that the neurologic manifestations can include cerebral ischemia in the adult and pediatric population.
• Vogt-Koyanagi-Harada syndrome is primarily an ocular inflammatory disease, but the prodrome often includes signs and symptoms that bring the patient to a neurologist, including headache, meningeal signs, and CSF pleocytosis.
• Melanin pigment-containing cells are often involved, including the retinal pigment epithelium in the eye producing “sunset glow” fundus appearance and cutaneous melanocytes producing vitiligo and poliosis.
• The disease is encountered more frequently in persons of Asian, Latin, and Mediterranean descent than in other ethnic groups.
The subject of this review is a clinical syndrome in which pigmentary alterations in various tissues are associated with ocular and meningeal inflammation. The combination of poliosis (the graying, or whitening, of a shock of scalp hairs, from the Greek for "gray"), and ocular inflammation was noted by the Arab physician Ali Ibn Isa (Ali ben Issa), who died in 1010 (89; 68), and by others including Vogt (120). Both Vogt and Koyanagi described cases that included the combination of primarily anterior uveitis (bilateral iridocyclitis) with extraocular manifestations, including pigment loss from skin (vitiligo), hair, and lashes (poliosis); hair loss (alopecia); and hearing loss with tinnitus (120; 53). Koyanagi's six cases were described in 1929, but in 1926, Harada had described similar extraocular manifestations with a primarily posterior uveitis, characterized by exudative retinal detachments and pleocytosis in the cerebrospinal fluid (27). Moorthy and colleagues credit Babel (05), and Bruno and McPherson (09) with recognizing the essential unity of the cases described by Vogt, Koyanagi, and Harada (68). Herbort and Mochizuki reviewed the historical development of the syndrome emphasizing that both Koyanagi and Harada perceived the inherent unity of cases with seemingly disparate multisystem signs and symptoms, whereas Vogt was lucky enough to describe the first case extremely well (30).
Most authors agree that the disease can be divided into four stages: (1) prodromal, (2) uveitic, (3) convalescent, and (4) chronic recurrent; however, the time at which the various manifestations occur is somewhat variable (61; 68). Although the disease-defining symptoms and signs are ophthalmic, they are rare in the prodromal phase, during which time neurologic symptoms predominate. Therefore, patients may initially present for neurologic care.
Prodromal phase. Central nervous system signs and symptoms are most common during the prodromal phase, which lasts a few days. Symptoms of meningeal irritation are the most common. Sugiura noted that a patient's hair and skin might be sensitive to touch during the prodromal stage (113).
Though rare, the central nervous system signs and symptoms during this prodromal phase may be severe, including alteration of cognitive function, confusional state, or psychosis. Focal findings, such as hemiparesis or generalized weakness with loss of sphincter control, or cranial nerve palsy (most commonly of the fifth through the seventh cranial nerves), are uncommon (89). Seizures and coma may occur rarely in the early stages, usually with more precipitous onset (14; 50). Analyzing a group of 87 patients with Vogt-Koyanagi-Harada syndrome in South India, Mondkar and colleagues found that 64% had extraocular symptoms at presentation, and of these, 96% had meningismus (67). Continuous diffuse headache lasting several months without other ocular or neurologic findings or symptoms may be the presenting symptom of Vogt-Koyanagi-Harada syndrome (52).
CSF pleocytosis is even more common than symptomatic meningitis, with CSF pleocytosis being recorded in about 80% of patients who underwent lumbar puncture (80; 62; 37).
CSF total protein is often normal or mildly elevated, and glucose is usually normal (62; 37). The presence of melanin-laden macrophages in CSF can distinguish Vogt-Koyanagi-Harada syndrome from other conditions such as syphilis giving CSF pleocytosis (47).
Because CSF pleocytosis can be present in patients with minimal or no neurologic findings, it is reasonable to consider that MRI manifestations of meningeal inflammation may provide a sensitive and non-invasive indicator for early diagnosis (26; 60). Thus, finding MRI evidence of either leptomeningitis or pachymeningitis may prove to be a non-invasive surrogate for CSF pleocytosis in early diagnosis of Vogt-Koyanagi-Harada syndrome.
Pattison noted the occasional presence of optic nerve swelling (89), but additional reports in which lumbar puncture was carried out on a significant number of patients have generally documented normal opening pressure or, at most, mild elevation of pressure (37). In his review, Fishman also notes that in some series, up to a quarter of the patients may have mild elevation of CSF pressure, but most reports indicate smaller percentages (21). There may also be optic disc swelling due to inflammation as discussed in the Ophthalmic manifestations section (below).
Transient dizziness and nystagmus were observed in about 60% of patients and were suggested to be secondary to labyrinthitis (81). This was later attributed to disease involvement of inner ear melanocytes (48).
Rare associations with Vogt-Koyanagi-Harada syndrome include ischemic stroke, myelopathy with enhancing lesions in the cervical cord (25), and Guillain-Barré syndrome and appear within weeks to months of Vogt-Koyanagi-Harada syndrome presentation (71).
Uveitic phase. Ophthalmic manifestations become apparent during the uveitic phase. The most common symptom in the uveitic phase is blurred vision, mostly from the cloudy opacity of the ocular refractive media (cornea, aqueous humor, crystalline lens, and vitreous humor). Reduction of visual acuity may also result from serous detachment of the macula. In about a third of cases, the disease starts symptomatically in one eye before the other, but the interval to involvement of the second eye is usually just a few days. In a study of 16 patients with Vogt-Koyanagi-Harada syndrome (32 eyes), all had decreased visual acuity, abnormal color vision, and abnormal visual fields at initial visit (128).
During the uveitic phase, which typically lasts several weeks, there is a bilateral posterior uveitis, with elevation of the retina and choroid around the optic disc, optic disc swelling, retinal edema, and serous retinal detachments. The retinal edema and retinal detachments are characteristically multifocal and may increase in number. Pigment epithelial detachment has also been described (45). Non-necrotizing granulomas consisting of epithelioid histiocytes (Dalen-Fuchs nodules) accumulate underneath the retinal pigment epithelium.
The optic disc is swollen, and there is subretinal fluid extending to the macula. Extensive patches of retinal edema (white) extend along the upper and lower vascular arcades. (Contributed by Dr. James Goodwin.)
Inflammation eventually spreads to involve the anterior segment and is manifest by inflammatory cells and flare in the anterior chamber aqueous humor. White-to-yellow greasy inflammatory precipitates (mutton fat keratoprecipitates) may be seen on the corneal endothelial surface. Inflammatory nodules may similarly accumulate at the pupil margin (Koeppe nodules) or on the iris surface (Busacca nodules). These are best seen on slit lamp examination in the ophthalmologist’s office. Caution should be exercised when assessing the pupil in eyes with active intraocular inflammation as posterior synechiae can give the appearance of an irregular or fixed pupil. Patients with anterior segment inflammation may experience decreased visual acuity and significant photophobia.
Optic disc swelling can result during the uveitic phase through a variety of mechanisms, including elevated intracranial pressure, inflammation, and ischemia. Some of these patients may have persistent visual field defects after resolution of swelling due to ischemic optic neuropathy (74; 73).
Acutely elevated intraocular pressure can occur and is characterized by intense ocular pain, conjunctival injection (perilimbal “ciliary flush”), a mid-dilated pupil, and corneal edema. This is a medical emergency, and these patients should be referred to an ophthalmologist without delay. Both acute and subacute elevations in intraocular pressure can cause irreversible damage to the optic nerves (secondary glaucoma). Mechanisms include inflammatory cells occluding the trabecular meshwork, thereby reducing aqueous outflow. Adhesions between the iris and the anterior capsule of the crystalline lens (posterior synechiae) may develop. If the pupil aperture is totally occluded by 360 degrees of posterior synechiae, the normal aqueous pathway is disrupted, and increasing posterior intraocular pressure causes anterior bowing of the iris stroma (iris bombe). Anterior rotation of the ciliary-iris complex from direct inflammatory infiltration may also lead to appositional angle closure. Finally, long-term use of topical and systemic steroid medications increases the risk of steroid-induced ocular hypertension (these are patients are so-called “steroid responders”). Glaucoma may persist beyond the resolution of the uveitic phase. Uveal effusion and an increased number of clinical recurrences of ocular inflammation were significant risk factors for the development of glaucoma in one study (85).
Convalescent phase. This phase lasts several months and is characterized by depigmentation in the skin and choroid. Loss of pigment in the choroid results in a shift of the background fundus color from the usual dusky red to a bright orange, which has been called "sunset glow fundus." There is often clumping of the retinal pigment in the pigment epithelial layer, which results in dense pigmented accumulations alternating with lighter areas throughout the posterior pole of the fundus. It is also during this convalescent phase that depigmentation of the skin (vitiligo) and of the hair on the eyebrows, eyelashes, and scalp (poliosis) occur. The vitiligo is symmetric on the head, trunk, and sacrum.
Many ophthalmic symptoms improve during the convalescent phase. Visual acuity and color vision may improve as early as 1 to 3 months after presentation, but visual field defects may not improve by much until 6 months after presentation. Just under 30% of patients still have visual field impairment after 12 months of treatment (128).
Chronic recurrent phase. After several months of convalescence, there may then follow a chronic recurrent phase during which there is a low-grade generalized uveitis, punctuated by acute episodes of predominately anterior uveitis. Choroidal or other uveal neovascularization may arise, leading to edema, hemorrhage, or serous retinal detachment. This may, in turn, lead to vision loss and macular scarring. Pigmented perivascular atrophy has been described (96).
It has been suggested that HLA-DR4 gene variations play a role in determining the clinical course, and that the presence of DRB1*0405, DRB1*0410, or both, is associated with a more protracted course (38; 39). Additional studies have shown HLA-DQA1*0301 and HLA-DQB1*0401 positive patients are more susceptible to Vogt-Koyanagi-Harada syndrome and HLA-DQA1*0103, 0401, 0501, and HLA-DQB1*0301, 0402, 0601, 0603 seem to be protective (59).
Early treatment may improve prognosis, decreasing the number of uveitic flares and risk of subretinal fibrosis (105).
Early initiation of immunomodulatory therapy has also been shown to improve final visual outcomes in patients with poor initial response to glucocorticoid therapy (119).
Complications. The neurologic signs and symptoms are most often limited to the prodromal phase of the disease, when cognitive dysfunction and headache characteristically occur.
Ocular complications include cataract (33% to 42%), glaucoma (24% to 27%), posterior synechiae, choroidal neovascular membrane (11%), subretinal scarring (6%), and optic atrophy (68; 67; 101).
Increased axial length leading to myopia progression has been described in the Japanese population, occurring as early as 1 month after onset and persisting at 6 months (116; 70).
A 16-year-old Hispanic boy developed new headaches for 2 weeks prior to admission. He also noted blurred vision in his right eye and described images as looking distorted and enlarged when viewed with his right eye. On the day of admission, he was confused and disoriented.
On admission, the neurologic examination was remarkable for mental confusion and mild disorientation in time, but no focal neurologic findings could be elicited. There was moderate nuchal rigidity, and Kernig and Brudzinski signs were present. Right eye visual acuity was 20/60 and left eye was 20/20; there was no relative afferent pupillary defect. Fundus examination revealed serous elevation of the right eye macula and swelling of both optic discs.
MRI showed mild patchy gadolinium enhancement of the meninges, but no focal signal abnormalities in the brain or brainstem parenchyma, and normal ventricles.
Lumbar puncture yielded clear cerebrospinal fluid under normal opening pressure. There were 60 white blood cells/mm3, of which 95% were lymphocytes and 5% were monocytes. Protein was 56 mg/dl and glucose 40 mg/dl (serum glucose 120 mg/dl). Cytology was negative for malignant or atypical cells. Protein electrophoresis revealed mild elevation of gamma globulin.
He was initially treated with intravenous methylprednisolone 1 gram/day for 3 days, followed by oral prednisone at an initial dose of 60 mg/day, followed by a tapering schedule over the next 3 weeks. His mental status cleared rapidly, and he was discharged to his home after 5 days in the hospital.
At the first office follow-up visit 2 weeks post discharge, the right eye visual acuity had improved to 20/25 and the symptom of blur and metamorphopsia had resolved. On fundus examination, the disc edema had resolved in both eyes, as had the subretinal fluid at the right macula. At 3 months from presentation, his vision remained normal off corticosteroids, and his neurologic status was also normal. The fundus exam showed patches of orange discoloration in the posterior pole and some broad bands of pigment clumping and dark discoloration at the level of the retinal pigment epithelium.
The prevailing etiological theory is that Vogt-Koyanagi-Harada syndrome represents a cell-mediated autoimmune response against melanocytes. Histopathologically, inflammation and loss of melanin-containing cells in the skin and the uvea of the eye have been observed. Melanocytes are also known to exist in the meninges and in the middle ear; however, their antigenic role in the central nervous system is not known.
The histopathology of Vogt-Koyanagi-Harada syndrome has been sparsely documented in the literature. There tends to be choroidal infiltration with granulomas or nongranulomatous lesions primarily involving lymphocytes. The choriocapillaris is typically spared, and epithelioid cells in granulomas often have melanin in the cytoplasm (90; 68). All of the available pathologic material is in the form of enucleated eyes; therefore, the only mention of pathology in the central nervous system is the observation of lymphocytic infiltration in the leptomeninges along the amputated stump of the optic nerve (90).
Moorthy and colleagues reviewed the evidence that autoimmunity plays a pivotal role in the disease, indicating that cellular immune mechanisms are probably more important than humoral ones (68). Antibodies to a number of retinal antigens have been detected in these patients, but the question remains whether these are epiphenomena, rather than causal (11).
There is evidence that melanocytes are involved in the meningitic, as well as the ocular, component of Vogt-Koyanagi-Harada syndrome. Peripheral and cerebrospinal fluid lymphocytes from patients with Vogt-Koyanagi-Harada syndrome have been shown to exhibit cytotoxicity against melanoma cells and normal melanocytes (63; 77), as have lymphocytes derived from intraocular aqueous humor (78). Macrophages containing melanin granules have been found in the CSF of patients with Vogt-Koyanagi-Harada syndrome but not in patients with other meningeal inflammatory diseases (72).
In a study, T-cells constituted the majority of lymphocytes in aqueous humor, and aqueous humor lymphocytes from the patients with Vogt-Koyanagi-Harada syndrome were more activated than were peripheral blood lymphocytes. Of the lymphokines studied, interleukin-6 appeared to play an important role as an inflammatory mediator (78). Studies of the enucleated eyes from a patient with active Vogt-Koyanagi-Harada syndrome showed similar distribution of T-cell subsets in the inflammatory lesion within the uveal tract (44). Studies have also shown that the ratio of T-helper to T-suppressor cells is increased, and that cells expressing surface markers characteristic of both early (CD25) and late (CD26) lymphocyte activation are present in the inflammatory lesion. Also, class 2 major histocompatibility complex was expressed in the choroidal melanocytes, as well as in the endothelium of the choriocapillaris, indicating a probable primary role for the melanocyte in the pathogenesis of the lesion (104).
The MART-1/Melan-A (112), peptidase (51), P-36 (76), tyrosinase (126; 23), IgG anti-lens epithelium-derived growth factor (125), and KU-MEL-1 (83) antigens have also been implicated.
In a study of T-helper cells from nine patients with Vogt-Koyanagi-Harada disease versus nine controls, it was found that peripheral blood mononuclear cells from patients produced significantly higher levels of mRNA only for interferon-gamma and not for interleukin-2 or interleukin-4. Levels of interferon-gamma and interleukin-2 were significantly increased in the stimulated cell culture supernatant of patients as compared with controls (35).
Rathinam and colleagues described three patients who developed Vogt-Koyanagi-Harada syndrome shortly after skin injuries. All three patients developed vitiligo in the injured areas as the skin healed, and the uveitis began at the same time. The authors suggest that the onset of Vogt-Koyanagi-Harada syndrome following skin injury supports the idea that the disease involves systemic sensitization to shared melanocytic antigens (98). Wong and colleagues reporting in the dermatologic literature described a 68-year-old Chinese woman who developed uveitis, followed in 6 months by generalized cutaneous inflammation (erythroderma), and by vitiligo 6 months after that. This was the first report of cutaneous inflammation preceding vitiligo in a patient with Vogt-Koyanagi-Harada syndrome (124).
A Vogt-Koyanagi-Harada–like syndrome has been described in patients with metastatic melanoma following initiation of checkpoint inhibition or protein kinase inhibition therapy (22; 131; 15; 08). A similar syndrome has also been described following vaccination (16; 110), suggesting an exuberant immune reaction as a possible trigger.
Investigators have identified a subset of pathologically activated monocytes with gene expression indicative of inflammation, antiviral activity, and pathologic activation (32). Genome-wide association analysis has also identified new loci associated with Vogt-Koyanagi-Harada syndrome risk (94).
Vogt-Koyanagi-Harada syndrome is most common among more heavily pigmented populations including Asians, Hispanics, Native Americans, and Indians. In a series of 65 cases from southern California, Moorthy and colleagues reported that 78% were Hispanic, 10% Asian, 6% of African descent, and 3% of European ancestry (68). The racial breakdown of patients seen at the National Institute of Health was only 13% Hispanic, but fully 50% Caucasian (European), and 35% of African descent. Of the Caucasians, the majority were said to have had some Native American ancestry (79). In a study of the U.S. Native American population in Oklahoma, Native American patients were more likely to be younger and have fewer neurologic or systemic symptoms; however, they were more likely to develop cataracts (102).
In Japan, the annual incidence was estimated to be 6.5 per million and the prevalence was 15.5 per million. Females were slightly more commonly affected than males, and the peak age at first presentation was in the fifth decade, with a median age of 42.3 years (69).
In Asian countries, Vogt-Koyanagi-Harada disease represented the largest proportion of panuveitis cases (121; 07). On the other hand, in Saudi Arabia, only 2.5% of 200 patients with uveitis had Vogt-Koyanagi-Harada syndrome (40).
Sympathetic ophthalmia is an autoimmune condition that closely mimics Vogt-Koyanagi-Harada syndrome. It is characterized by a bilateral non-necrotizing granulomatous uveitis. It is an autoimmune response against uveal autoantigens exposed by penetrating trauma or surgery. Extraocular manifestations are far fewer in sympathetic ophthalmia than in Vogt-Koyanagi-Harada syndrome (127). A negative history for trauma or ocular surgery makes a diagnosis of sympathetic ophthalmia highly unlikely.
Lymphoma can present simultaneously in the eye and in the brain as a space-occupying lesion or diffuse meningeal infiltration (49; 68; 03; 123). Subretinal deposits, as well as vitreous cells, may be seen. The vitritis may initially respond to steroid therapy but will recur once stopped. Acute lymphoblastic leukemia presenting as Vogt-Koyanagi-Harada syndrome has also been described (29).
Sarcoidosis is another granulomatous cause of panuveitis. Ocular sarcoidosis tends to produce retinal perivenous sheathing, called "candle-wax drippings" when profuse, whereas the serous retinal detachment that is characteristic of Vogt-Koyanagi-Harada syndrome is not seen in sarcoidosis uveitis. The neurologic findings in sarcoidosis are focal, often involving the cranial nerves, whereas diffuse symptoms of headache and cognitive impairment are most common in Vogt-Koyanagi-Harada syndrome, although both may have chronic CSF pleocytosis (68).
A rare, immune complex–mediated choroidal vasculitis in systemic lupus erythematosus mimics Vogt-Koyanagi-Harada syndrome by causing serous retinal detachments (41; 68). Patients often exhibit systemic manifestations of systemic lupus erythematosus.
Infectious posterior uveitis, including syphilis and tuberculosis, can present as subretinal nodules, posterior or anterior uveitis, and serous retinal detachment. It must be ruled out prior to starting corticosteroid or other immunomodulating therapy (58).
Other diseases in the differential diagnosis of Vogt-Koyanagi-Harada syndrome that are of primarily ophthalmologic interest include acute multifocal placoid pigment epitheliopathy, multiple evanescent white dot syndrome, and posterior scleritis (108). The two features that most reliably distinguish Vogt-Koyanagi-Harada syndrome from other forms of uveitis are exudative retinal detachment in the acute uveitic phase and sunset glow fundus in the late phases (97).
With the advent of antineoplastic immune checkpoint inhibitors, Vogt-Koyanagi-Harada–like syndrome is an emerging association that has been described in several case reports. Of the adverse reactions reported in the WHO international pharmacovigilance database, immune checkpoint inhibitors and protein kinase inhibitors were associated with a Vogt-Koyanagi-Harada–like syndrome (04).
Vogt-Koyanagi-Harada syndrome and Vogt-Koyanagi-Harada–like syndrome after COVID infection and COVID vaccination have been described (75; 106; 130).
Vogt-Koyanagi-Harada syndrome has been described in patients with autoimmune diseases, including ulcerative colitis (20), IgA nephropathy (132), and erosive seronegative polyarthritis (82), suggesting an association with autoimmunity. A case of Vogt-Koyanagi-Harada disease has been reported as a complication of treating hepatitis C with interferon alpha-2b and ribavirin combination therapy (114). In general, it has been known to exacerbate or trigger de novo autoimmunity.
Vogt-Koyanagi-Harada syndrome is associated with HLA-DR4 positivity (38; 39; 109; 122; 93; 103) and HLA-DQ4 (83% vs. 32% in controls). Among variants, HLA-DQA1*0301 positivity is associated with the Vogt-Koyanagi-Harada syndrome phenotype, whereas HLA-DQB1*0604 is considered protective. The DRB1*0405 or DRB1*0410 variants portend to a longer disease course (38; 39).
Seven of 62 clones from patients with Vogt-Koyanagi-Harada disease that were reactive with tyrosinase or tyrosinase-related protein showed proliferative responses to peptides that match the motif of the strong binding site for HLADRB1*0405 (23). Weisz and colleagues determined human leukocyte antigen specificities in 25 Hispanic patients living in Southern California and compared them to 217 healthy Hispanic control subjects (122). HLA-DR4 was present in 56% of the patients and in 29% of the control subjects. HLA-DR1 was present in 36% of the patients and in 9% of the control subjects. Combinations of HLA-DR4 and HLA-DR1 characterized 84% of patients but only 35% of control subjects. The authors suggest that these findings point to a common immunogenic predisposition to Vogt-Koyanagi-Harada syndrome among different racial groups that are differentially susceptible. They also suggest that there may be a common epitope shared by DR1 and DR4 that is involved in the pathogenesis of the disease.
Diagnostic criteria. Consensus criteria, developed in 1978 by the American Uveitis Society, were updated following the First International Workshop on Vogt-Koyanagi-Harada Disease in 1999. This newer set of criteria recognizes that Vogt-Koyanagi-Harada is a disease that has distinct features in different stages of the natural history and establishes criteria for early diagnosis when many of the characteristic cutaneous findings have not yet occurred (100) (Table 1).
Complete Vogt-Koyanagi-Harada disease (criteria 1 to 5 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).
4. Neurologic and auditory findings (may have resolved by time of examination)
5. Integumentary finding (not preceding onset of central nervous system or ocular disease)
Early manifestations of disease
• There must be evidence of a diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction, or optic disc hyperemia), which may manifest as one of the following:
- focal areas of subretinal fluid
• With equivocal fundus findings, both of the following must be present as well:
- focal areas of delay in choroidal perfusion, multifocal areas of pinpoint leakage, large placoid areas of delay in choroidal perfusion, pooling within subretinal fluid, and optic nerve staining by fluorescein angiography
- diffuse choroidal thickening, without evidence of posterior scleritis by ultrasonography
Late manifestations of disease
• History suggestive of prior presence of findings
• Ocular depigmentation (either of the following manifestations is sufficient):
- sunset glow fundus
• Other ocular signs:
- nummular chorioretinal depigmented scars
Incomplete Vogt-Koyanagi-Harada disease (criteria 1 to 3 and either 4 or 5 must be present)
Probable Vogt-Koyanagi-Harada disease (isolated ocular disease; criteria 1 to 3 must be present)
In 2018, Yang and colleagues proposed new diagnostic criteria using retrospective data from 1257 patients in China, which they termed the “Diagnostic Criteria for Vogt-Koyanagi-Harada Disease” (129). The criteria consist of a 3-class model grouping patients into early-phase Vogt-Koyanagi-Harada disease, late-phase Vogt-Koyanagi-Harada disease, or non-Vogt-Koyanagi-Harada uveitis. They compared 37 variables, 21 of which were deemed important in the diagnosis of Vogt-Koyanagi-Harada disease as they were associated with high-specificity or high-positive rates (Table 2). The Diagnostic Criteria for Vogt-Koyanagi-Harada Disease showed higher sensitivity (94.6% vs. 71.9%) and negative predictive value (94.3% vs. 76.6%) than the revised diagnostic criteria. The positive predictive value showed no difference when compared to the revised diagnostic criteria. As these criteria were developed retrospectively, they need to be evaluated in prospective studies for further investigation (129).
A. No history of penetrating ocular trauma or intraocular surgery preceding the initial onset of uveitis
B. Bilateral ocular involvement (time interval between the two eyes should be 2 weeks)
C. No evidence of infectious uveitis or accompanying systemic rheumatic diseases or evidence suggestive of other ocular disease entities
D. Early-phase Vogt-Koyanagi-Harada disease:
1. Signs of diffuse choroiditis and exudative retinal detachment
2. Serous retinal detachment on optical coherence tomography or B-scan ultrasonography
3. Choroidal thickening on enhanced depth imaging-optical coherence tomography (B-scan can be used where enhanced depth imaging-optical coherence tomography not available, though it is not as precise)
4. Early punctate staining and late subretinal dye pooling on fluorescence fundus angiography
5. Hyperfluorescence of the optic disc on fluorescence fundus angiography
Variant 1: In patients presenting with A+B+C+ D(1)
Variant 2: In patients without clinically visible exudative retinal detachment, ie, A+B+C+ D(2) + D(3) or A + B + C + D(4)
Variant 3: In patients already treated with systemic corticosteroids or combined with other immunosuppressive agents, a history of typical appearances of variant 1 or 2, and A+B+C+ D(5)
E. Late-phase Vogt-Koyanagi-Harada disease:
1. Signs of definite sunset glow fundus or retinal pigment epithelium clumping/migration
2. Signs of bilateral recurrent granulomatous anterior uveitis
3. Signs of Dalen-Fuchs nodules or multifocal chorioretinal atrophy
4. Window defects/moth-eaten fluorescence on fluorescence fundus angiography
5. Previous history of characteristic findings corresponding to diagnosis of early-phase Vogt-Koyanagi-Harada disease
Variant 1: In patients presenting with A+B+C+ E(1) + E(2)
Variant 2: In patients without sunset glow fundus or visible pigment alternations due to early and appropriate treatment, ie, A+B+C+ E(2) + E(3) or A+B+C+ E(2) + E(4)
Variant 3: In patients with significant media opacity, ie, A+B+C+ E(2) + E(5)
Criteria are evolving to include modern ophthalmic imaging findings. Indocyanine green angiography is a diagnostic imaging procedure that examines blood flow through the choroid. The fluorescent molecule indocyanine green is infused intravenously, and a series of fluorescent photographs are taken with a specialized fundus camera. Indocyanine green angiography findings have been reported to be positive in nearly 100% of cases but are not currently included in the diagnostic criteria (06). As such, these findings would be valuable to include in the future.
Ophthalmic ancillary testing. During the acute uveitic stage, indocyanine green angiography demonstrates multifocal areas of delayed choroidal filling. In the late stages, peripapillary and multifocal choroidal pinpoint leakage can be seen. Indocyanine green may pool late in the areas of serous retinal detachment.
Fluorescein angiography demonstrates similar punctate hyperfluorescence in the choroid and retinal pigment epithelium, with progressive staining in areas of active choroiditis in the later phase of the angiogram. Dye can similarly accumulate in the areas of serous retinal detachments. This pattern of hyperfluorescence is said to give a “moth-eaten” appearance. Optic nerve head leakage is found in 70% of cases (68).
Due to differences in protein binding and wavelengths used, there are differences between indocyanine green angiography and fluorescein angiography leakage patterns. Indocyanine green angiography is advantageous for evaluating the choroid and retinal pigment epithelium, with less interference from the retinal pigment epithelium (28).
Melanin accumulation may be seen with near-infrared photography with corresponding hyper-reflectivity on optical coherence tomography. These lesions may resolve with treatment (64). Spectral domain optical coherence tomography (sdOCT) is another noninvasive diagnostic modality used to assess the retina, retinal pigment epithelium, and choroid. This technique can be used to monitor retinal and choroidal thickness, as well as the extent of subretinal fluid. It is routinely performed in the office, and acquisition is rapid, thus, making it one of the most commonly used imaging modalities to monitor disease activity (42).
Swept-source and enhanced depth imaging optical coherence tomography have also been used to evaluate increased choroidal thickness in acute Vogt-Koyanagi-Harada syndrome. Swept-source optical coherence tomography has better resolution for the choroid than enhanced depth imaging optical coherence tomography and can be used to follow resolution of inflammation after treatment with steroids (92).
Optical coherence tomography angiography is a noninvasive imaging technique that provides an angiogram of the retinal and choroidal vasculature without the need for intravascular fluorophores. Optical coherence tomography angiography has shown multiple dark foci at the level of the choriocapillaris corresponding with hypocyanescence on indocyanine green angiography, indicating hypoperfusion and ischemia. Microvascular density is significantly decreased in eyes with sunset glow fundus (19). Flow defects, as well as vascular density, have been shown to improve with glucocorticoid treatment (92; 33). Thus, optical coherence tomography angiography can be used to detect subclinical disease activity as well as monitor response to treatment.
Ultrasound biomicroscopy may show ciliochoroidal detachment (20%) and unclear ciliary processes (15%), which are characteristic in the uveitic phase. These changes improve with treatment but may be observed in recurrent uveitis (84).
Neurologic ancillary testing. Lumbar puncture yields diagnostically useful information in the form of lymphocytic pleocytosis in a high percentage of patients, if fluid is sampled within the first 8 weeks. There may be a lag in the development of pleocytosis, as the percentage of patients with this finding rises from 80% in the first week of symptoms to 97% by the third week (113; 68). Tsai and colleagues question the necessity of CSF examination and found that fluorescein angiography along with clinical examination were diagnostic even in patients without cerebrospinal fluid pleocytosis (118).
Though MRI is often obtained for workup of neurologic symptoms, findings are often nonspecific related to leptomeningeal inflammation. Le described a case of Vogt-Koyanagi-Harada syndrome presenting with bilateral optic nerve swelling and leptomeningeal enhancement (56). Ikeda and Tsukuguchi report a case of Vogt-Koyanagi-Harada syndrome with multiple hyperintense signal abnormalities in the cerebral white matter. One patient had high signal abnormalities in the periventricular cerebral white matter (34).
MRI may show choroidal thickening, indicating a concurrent ocular process (43; 68; 91). Theta-range slowing of the EEG is often present, but this is so nonspecific as to be relatively unhelpful in establishing the diagnosis of Vogt-Koyanagi-Harada syndrome.
High-dose systemic corticosteroid treatment is recommended during the uveitic stage, with slow dosage tapering over the subsequent 3 to 6 months. Treatment is generally monitored by ophthalmologic parameters, and patients should be under the care of an ophthalmologist for this. High-dose corticosteroid treatment can induce central serous choroidopathy in patients with Vogt-Koyanagi-Harada as with other forms of chronic uveitis and this must be considered if a patient has worsening of visual acuity with treatment (107).
The neurologic problems are generally limited to the prodromal and early uveitic stages. Specific management of these problems is seldom an issue. Recurrences during steroid tapering may become refractory to corticosteroid treatment and require the use of cytotoxic agents such as cyclophosphamide, chlorambucil, or azathioprine, or cytostatic agents such as cyclosporine (68).
Case reports and case series have shown stable control achieved with mycophenolate mofetil (01), rituximab (17), infliximab (133), tofacitinib (18), and adalimumab (111; 54; 117). Small series have demonstrated improved visual acuity outcomes in patients treated early with immunomodulatory therapy (87). Large reviews suggest that steroidal and nonsteroidal dual therapy given at onset is better than steroid monotherapy alone (31; 86).
In case reports, intravitreal dexamethasone implant (10; 12) or intravitreal fluocinolone acetonide implant combined with intravitreal methotrexate (88) has shown efficacy.
Bioinformatics analysis has identified interferon gamma and interleukin 6 as key mediators of Vogt-Koyanagi-Harada syndrome and, thus, possible targets for future therapeutics (13).
A study of 97 consecutive patients presenting in Riyadh, Saudi Arabia, included 13 children and 84 adults (115). Sixty-one percent (8 patients) of those younger than 14 years of age (children) required cataract surgery, as compared with 17% (14 patients) of the adults. Sixty-one percent of the children had final visual acuity equal to or worse than 20/200, whereas only 26% of adults had that severe visual consequence.
Of 98 patients with Vogt-Koyanagi-Harada syndrome seen at the Aravind Eye Hospital in Madurai, India, between 1993 and 1995, three were children (under 16 years of age), and all required cataract surgery (99). Visual outcome was good, despite the eventual development of retinal pigment epithelial atrophy in two children and glaucoma in one child. Patients with Vogt-Koyanagi-Harada syndrome who develop a bullous retinal detachment have an 8 times higher risk of developing subretinal fibrosis (24).
Small series have demonstrated improved visual acuity outcomes in patients treated early with immunomodulatory therapy (87; 57). More aggressive treatment with intravenous methylprednisolone compared to conventional dose oral corticosteroids showed fewer recurrences and better long-term visual outcomes (65). Finally, it has also been shown that patients whose initial corticosteroid treatment was continued for 6 months or longer have significantly fewer late recurrences of ocular inflammation than patients initially treated for less than 6 months (55).
Patients on high-dose corticosteroid or immunomodulatory therapy are at increased risk of opportunistic infections. Some of these infections may also manifest as posterior uveitis, complicating the management and clinical picture. Cases of tuberculosis uveitis and cytomegalovirus retinitis during therapy for Vogt-Koyanagi-Harada syndrome have been described (46; 02).
The course of uveitis during and after pregnancy was studied in a cohort of 50 women and 76 pregnancies. Thirty-three pregnancies were in women with Vogt-Koyanagi-Harada disease, and these women characteristically had flare-ups in the early part of the pregnancy. Postpartum flare-up was frequent, especially among patients with Behçet disease (95).
Several drugs used in the treatment Vogt-Koyanagi-Harada syndrome are contraindicated during the first trimester of pregnancy, if not throughout pregnancy. Difficult judgments as to corticosteroid and cytotoxic drug usage must be made if a pregnant woman develops Vogt-Koyanagi-Harada syndrome because it is a disease with a high risk of causing severe visual disability if untreated. A limited experience with successful treatment of 3 pregnant women with Vogt-Koyanagi-Harada using topical and systemic corticosteroids without obvious infant complication has been reported (66). A case of azathioprine added to high-dose corticosteroid therapy in the first trimester of pregnancy has been described, with good maternal–fetal outcome (36).
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