VOGT-KOYANAGI-HARADA DISEASE

VOGT-KOYANAGI-VOGT-KOYANAGI-HARADAHARADADISEASEDISEASE

AHMED M. ABU EL-ASRAR, MD, AHMED M. ABU EL-ASRAR, MD, PhDPhD

Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia Dr. Nasser Al-Rashid Research Chair in Ophthalmology

• Multisystem disease

• Chronic, bilateral, granulomatous panuveitis associated with central nervous system, auditory and integumentary manifestations

VKH DiseaseVKH Disease

Moorthy et al: Surv Ophthalmol 1995; 39:265 (review)Read et al: Am J Ophthalmol 2001;131:647


• Individuals with a predisposing genetic background.

• Ethnic groups with more heavily pigmented skin.

• Asians, Native Americans, Hispanics, Asian Indians, Middle Easterners.

Epidemiology


• Genetic background rather than degree of skin pigmentation.

• Women more than men.• 3rd – 4th decade.• Pediatric age group.

Epidemiology

Read et al: Curr Opin Ophthalmol 2000;11:437 (review)Abu El-Asrar et al: Eye 2008;22:1124Martin et al: Retina 2010 Feb 17. [Epub ahead of print]


• Remains unknown.• T-lymphocyte mediated

autoimmunity directed against one or more antigens found on or associated with melanocytes found in eye, skin and hair, inner ear, CNS.

Etiology and Pathogenesis

Okada et al: Graefe’s Arch Clin Exp Ophthalmol 1996;234:359Okada et al: Graefe’s Arch Clin Exp Ophthalmol 1996;234:359


• Tyrosinase family proteins are enzymes for melanin formation and are expressed in melanocytes.

• T-lymphocytes from VKH disease patients proliferate in response to tyrosinase, TRP1 or TRP2.

• Immunization of Lewis rats with tyrosinase, TRP1 or TRP2 produced an inflammatory disease that resembled VKH disease with skin lesions and meningitis.

Yamaki et al: J Immunol 2000;165:7323Yamaki et al: Exp Eye Res 2000;71:361



Th cells from peripheral blood of VKH patients produce predominantly Th1 cytokines (IFN-gamma, IL-2) especially when stimulated

T-cell clones specific to tyrosinase family proteins established from peripheral blood mononuclear cells of patients with VKH disease showed proliferative responses to tyrosinase and/or TRP1 and produced Th1-type cytokines. Imai et al: Curr Eye Res 2001;22:312

Gocho et al: Invest Ophthalmol Vis Sci 2001;42:2004



IL-23 stimulated production of IL-17 by CD4+ T cells may be responsible for the development of VKH disease.

Fang and Yang: Curr Eye Res 2008;33:517



VKH-like disease in patients treated with interferon-alpha and ribavirin therapy for chronic hepatitis C virus infection.

Al-Muammar et al: Int Ophthalmol 2010 Feb 23. [Epub ahead of print]Sene et al: World J Gastroenterol 2007;13:3137Touitou et al: Am J Ophthalmol 2005;140:949Papastathopoulos et al: J Infect 2006;52:e59Kasahara et al: J Gastroenterol 2004;39:1106Sylvestre et al: J Viral Hepat 2003;10:467



• Granulomatous panuveitis.• Lymphocytes, epitheloid cells, few

plasma cells, multinucleated giant cells.

• Epitheloid cells and giant cells contain melanin pigment.

Pathology


• Dalen-Fuchs’ nodules: Lymphocytes, epitheloid cells, pigment-laden macrophages, altered and/or proliferated RPE cells.

• Melanocytes disappear from choroid.

Perry and Font: Am J Ophthalmol 1977;83:242Perry and Font: Am J Ophthalmol 1977;83:242Inomata and Rao: Am J Ophthalmol 2001;131:607Inomata and Rao: Am J Ophthalmol 2001;131:607

Pathology


• Certain racial groups.• Immunogenetic predisposition.• Strong association with HLA-DR4 and HLA-

DRw53 with the most significant risk allele being HLA-DRB1*0405.

• Causative pathogenic antigen binds with HLA-DRB1*0405 molecule which presents the antigen to T cells to activate them.

Fang and Wang: Curr Eye Res 2008;33:517 (review).Read et al: Curr Opin Ophthalmol 2000;11:437 (review).Yamaki et al: Int Ophthalmol Clin 2002;42:13 (review).

Genetic Factors


VKH disease in monozygotic twins Familial VKH disease Familial cases shared HLA-DR4

Itho et al: Int Ophthalmol 1992;16:49 Rutzen et al: Am J Ophthalmol 1995;119:239 Sonoda et al: Jpn J Ophthalmol 1999;43:113

Genetic Factors


Integumentary Manifestations• Sensitivity of hair and skin to touch

(early in prodromal phase).

• Poliosis, vitiligo, alopecia (during convalescent stage).

• Ethnic groups may manifest varying systemic symptoms.

Clinical FeaturesExtraocular Manifestations

Clinical FeaturesExtraocular Manifestations


Neurologic Manifestations• Most common during prodromal

stage.• Neck stiffness, headache, confusion.• Occasionally focal neurologic signs.• CSF pleocytosis.

VKH DiseaseVKH DiseaseClinical Features

Extraocular Manifestations

Auditory Manifestations• May be presenting problem• Sensorineural hearing loss usually

involves higher frequencies• Tinnitus• Vertigo• May cause permanent hearing loss

VKH DiseaseVKH DiseaseClinical Features

Auditory Manifestations


4 phases• Prodromal• Acute uveitic• Convalescent or chronic• Chronic recurrent

Clinical Course


Prodromal Phase:• Mimics viral illness• Neurologic and auditory manifestations• Few days• Headache, orbital pain, stiff neck, malaise,

abdominal pain, nausea, fever, vertigo, tinnitus

• Cranial nerve palsies, optic neuritis (rare)• CSF pleocytosis

Clinical Course


Acute Uveitic Phase:• Bilateral in 70% of patients, delay of 1-3

days before 2nd eye becomes involved in 30%. In a few cases this interval may last up to 10 days.

• Hallmark is bilateral multifocal exudative retinal detachments, hyperemia and edema of the optic disc.

Clinical Course


Acute Uveitic Phase: (cont.).• Yellow-white lesions at level of RPE beneath

serous RD.

• Thickening of posterior choroid manifested by elevation of peripapillary retino-choroid layer.

• Retinal edema in posterior pole.

• Peripheral well-circumscribed yellow-white lesions (clinical equivalent of Dalen-Fuchs’ nodules).

Clinical Course


Acute Uveitic Phase: (cont.)• No inflammation of the anterior segment

or mild to moderate nongranulomatous anterior uveitis if the disease is not well controlled with appropriate treatment during the first two weeks.

Clinical Course

Fang and Yang: Curr Eye Res 2008;33:517 (review)


Acute Uveitic Phase: (cont.).• Shallow anterior chamber• Elevated IOP• Acute angle closure glaucoma

Clinical Course


Convalescent Phase:• Integumentary and uvea

depigmentation.• Perilimbal vitiligo (Sugiura’s sign).• Fundus exhibits an orange-red

discoloration (“sunset-glow” fundus).

Clinical Course


Convalescent Phase: (cont.)• Multiple small yellow well-

circumscribed areas of chorioretinal atrophy representing regressed Dalen-Fuchs’ nodules.

• RPE clumping or migration.

• Pigmented demarcation lines.

Clinical Course


Chronic Recurrent Phase:• Acute episodes of granulomatous

anterior uveitis with development of iris nodules

• Recurrent posterior uveitis is distinctly uncommon

• Complications are seen in this phase

Clinical Course


Chronic Recurrent Phase:• Patients with recurrent VKH disease had

a more intensive inflammation in the anterior segment and long-lasting dysfunction of the blood-aqueous barrier than those with initial onset VKH disease.

Clinical Course

Fang et al: Br J Ophthalmol 2008;92:182


• Fluorescein angiography

• Indocyanine green angiography

• Ultrasonography

• Optical coherence tomography

• Multifocal electroretinograms

• Lumbar puncture

Laboratory Investigations

Diagnosis is made by clinical examination and ancillary test findings


Ultrasonography:• Diffuse low to medium thickening

of choroid.• Overlying exudative RD.


VKH DiseaseVKH DiseaseLaboratory Investigations

OCTUseful in monitoring resolution of exudative retinal detachment

On presentation 4 weeks after systemic corticosteroid


May be useful in detecting early retinal damage.

Macular function is severely impaired in patients with active uveitis.

Treatment with immunosuppressive agents leads to delayed but limited recovery of macular function.

May be useful in guiding therapy.


Chee et al: Graefe’s Arch Clin Exp Ophthalmol 2005; 243:785.

Multifocal Electroretinogram

Yang et al: Am J Ophthalmol 2008; 146:767.


Patients displayed a markedly decreased BCVA, fixation stability and mean retinal sensitivity at baseline.

BCVA and fixation stability recovered earlier, faster and better than mean retinal sensitivity.

At final follow-up, retinal sensitivity was significantly reduced even in eyes with full recovery of BCVA.

Subclinical macular dysfunction is a permanent damage in VKH disease.

Retinal functional changes measured by microperimetry after immunosuppressive therapy

Abu El-Asrar et al: Eur J Ophthalmol 2012; 22:368

VKH DiseaseVKH DiseaseRetinal functional changes measured by microperimetry after immunosuppressive therapy


Lumbar Puncture:• Rarely necessary in a typical case.• CSF pleocytosis (mostly

lymphocytes).• Transient and resolves within 8

weeks.



Lumbar Puncture:• Frequency of CSF pleocytosis and

the number of cells in CSF at disease onset were significantly higher in patients who eventually developed sunset glow fundus.


Keino et al: Am J Ophthalmol 2006; 141:1140.


• Cataract• Secondary glaucoma• Choroidal neovascular membranes• Subretinal fibrosis• Severe chorioretinal atrophy• Significantly associated with longer

duration of disease and greater numbers of recurrences.

Complications

Read et al : Am J Ophthalmol 2001;131:599.Sonoda et al: Jpn J Ophthalmol 1999;43:113.


• Significantly associated with older age and more severe disease at presentation.

Complications

Al-Kharashi, Abu El-Asrar: Int Ophthalmol 2007;27:201


• Should be prompt and aggressive.• Systemic corticosteroids are mainstay

of therapy.• 1-1.5 mg/kg/day of oral Prednisone

(single morning-after-breakfast dose).• For 6-12 months with slow gradual

tapering during this time.• Hospitalization with careful follow-up.

Therapy


• Intravenous high-dose pulse steroid therapy (1g/day of Methylprednisolone given for 3 days) followed by oral Prednisone (1 mg/kg/day).

• Topical Prednisone 1% solution and cycloplegics for anterior uveitis.

• Patients adequately treated with corticosteroids have a fair visual prognosis.

• Recurrences are associated with rapid or early decrease in steroid doses.

Therapy


• Such treatment may shorten duration of disease, prevent progression into chronic stage, reduce incidence of extraocular manifestations.

• Failure to prescribe proper corticosteroid therapy in initial phase may lead to chronic recurrent uveitis that may result in severe visual loss due to extensive chorioretinal atrophy.

Therapy

Sonoda et al: Jpn J Ophthalmol 1999;43:113.


• Final VA of 20/20 was significantly associated with use of systemic corticosteroids for longer than 9 months and slow tapering.

• Recurrent inflammation was significantly associated with rapid tapering of systemic corticosteroids.

Therapy

Al-Kharashi, Abu El-Asrar: Int Ophthalmol 2007;27:201


• Patients treated initially with immunomodulatory drugs (mycophenolate mofetil, cyclosporine A, azathioprine, and methotrexate) combined with corticosteroids had a better visual outcome than those who received corticosteroids as monotherapy.

• Immunomodulatory therapy combined with corticosteroids should be considered as first-line therapy for patients with VKH.

Therapy

Paredes et al: Ocul Immunol Inflamm 2006;14:87Kim and Yu: Ocul Immunol Inflamm 2007;15:381Abu El-Asrar, et al: Acta Ophthalmol 2012;90:e603


Use of mycophenolate mofetil as first-line therapy combined with systemic corticosteroids is safe and effective in the treatment of acute uveitis associated with VKH disease.

It has marked corticosteroid-sparing effect and significantly reduced development of chronic recurrent inflammation and late complications and significantly improved visual outcome.

The outcomes of mycophenolate mofetil combined with systemic corticosteroids in acute uveitis associated with VKH disease

Abu El-Asrar et al: Acta Ophthalmol 2012; 90:e603


• Visual prognosis is generally favorable.

• 87.5% achieved V.A. of ≥20/40.

• High-dose systemic corticosteroids for >9 months with slow tapering significantly improves the prognosis and decreases risk of recurrence.

• Age older than 18 years is significantly associated with the development of complications.

• Visual prognosis is generally favorable in children.

Prognosis

Al-Kharashi, Abu El-Asrar: Int Ophthalmol 2007;27:201Abu El-Asrar et al: Eye 2008;22:1124


Poor visual acuity and severe anterior segment inflammation at presentation are significantly associated with a worse outcome.

Chronic recurrent disease is significantly associated with more severe anterior segment inflammation and less exudative retinal detachment at presentation, more ocular complications and a worse visual outcome compared with initial-onset disease.

Use of immunomodulatory therapy as first-line therapy combined with systemic corticosteroids significantly improved clinical outcomes.

Prognostic factors for clinical outcomes in patients treated with high-dose corticosteroids

Abu El-Asrar et al: Acta Ophthalmol. In press.

Sympathetic Sympathetic OphthalmiaOphthalmia

Ahmed M. Abu El-Asrar, MD, Ahmed M. Abu El-Asrar, MD, PhDPhD

Sympathetic OphthalmiaSympathetic Ophthalmia

Rare bilateral granulomatous Rare bilateral granulomatous panuveitis that occurs as a panuveitis that occurs as a complication of a penetrating injury complication of a penetrating injury that involves the uvea of one eye.that involves the uvea of one eye.

Accidental trauma or surgery.Accidental trauma or surgery. Injured eye is referred to as the Injured eye is referred to as the

exciting eye and fellow eye as the exciting eye and fellow eye as the sympathizing eye.sympathizing eye.


In 0.1% to 0.3% of patients after In 0.1% to 0.3% of patients after accidental trauma.accidental trauma.

In 0.015% of patients following ocular In 0.015% of patients following ocular surgery.surgery.

5.8% and 0.67% after noncontact 5.8% and 0.67% after noncontact and contact Nd:YAG cyclotherapy, and contact Nd:YAG cyclotherapy, respectively.respectively.

Incidence

Allen: JAMA 1969;209:1090Liddy, Stuart: Can J Ophthalmol 1972;7:157Gass: Am J Ophthalmol 1982;93:552

Lam et al: Ophthalmology 1992;99:1818


Role of ocular surgeryRole of ocular surgery Sole cause in:Sole cause in:

– 45% of cases 45% of cases (Gass: Am J Ophthalmol 1982;93:552)(Gass: Am J Ophthalmol 1982;93:552)

– 17% of cases17% of cases (Hakin et al: Eye 1992;6:453)(Hakin et al: Eye 1992;6:453)

– 28% of cases28% of cases (Chan et al: Arch Ophthalmol 1995;113:597)(Chan et al: Arch Ophthalmol 1995;113:597)

– 56% of cases56% of cases (Kilmartin et al: Br J Ophthalmol 2000;84:259)(Kilmartin et al: Br J Ophthalmol 2000;84:259)

– 70% of cases 70% of cases (Su and Chee: Graefes’ Arch Clin Exp Ophthalmol (Su and Chee: Graefes’ Arch Clin Exp Ophthalmol 2006;244:243)2006;244:243)

– 38% of cases38% of cases (Galor et al: Am J Ophthalmol 2009;148:704)(Galor et al: Am J Ophthalmol 2009;148:704)

Incidence


Role of ocular surgeryRole of ocular surgery

Ocular surgery, particularly retinal Ocular surgery, particularly retinal surgery, is now a greater risk than surgery, is now a greater risk than accidental trauma.accidental trauma.

Risk of one in 1152 retinal surgical Risk of one in 1152 retinal surgical proceduprocedures.res.

Incidence

Kilmartin et al: Br J Ophthalmol 2000;84:448

Kilmartin et al: Br J Ophthalmol 2000;84:259Su and Chee: Graefe’s Arch Clin Exp Ophthalmol 2006;244:243


Role of vitrectomyRole of vitrectomy In 0.06% of casesIn 0.06% of cases In 0.01% when vitrectomy was the In 0.01% when vitrectomy was the

only operative procedure and only operative procedure and penetrating wound.penetrating wound.

A prospective surveillance for SO in A prospective surveillance for SO in UK and Ireland showed risk of one in UK and Ireland showed risk of one in 799 vitrectomies.799 vitrectomies.

Incidence


Gass: Am J Ophthalmol 1982;93:552Gass: Am J Ophthalmol 1982;93:552


Role of vitrectomyRole of vitrectomy Vitreoretinal surgery is an important risk Vitreoretinal surgery is an important risk

factor.factor. It may be appropriate to counsel patients It may be appropriate to counsel patients

about risk of SO before performing about risk of SO before performing vitrectomyvitrectomy

Any bilateral uveitis following Any bilateral uveitis following vitreoretinal surgery should alert the vitreoretinal surgery should alert the surgeon to the possibility of SO.surgeon to the possibility of SO.

Incidence



Evisceration versus enucleationEvisceration versus enucleation

Uveal tissue may be left behind after evisceration and act as the source of the immune response.

Controversy involving evisceration and risk of SO.

Incidence


Evisceration versus enucleationEvisceration versus enucleation Four cases of SO following evisceration

Six cases of SO after evisceration.

A case of SO following evisceration of a blind, painful, post-traumatic, glaucomatous eye.

Incidence

Green et al: Trans Am Acad Ophthalmol Otolaryngol 1972; 76:625

Ikui et al: Nippon Ganka Kiyo1965; 16:458

Griepentrog et al: Ophthal Plast Reconstr Surg 2005; 21:316


Evisceration versus enucleationEvisceration versus enucleation

Evisceration is safe with little risk of SO.

High degree of clinical suspicion is required.

Incidence

Levine et al: Ophthal Plast Reconstr Surg 1999; 15:4.Toit et al: Br J Ophthalmol 2008;92:61.


Interval between injury and onset of Interval between injury and onset of inflammation ranges from 5 days to inflammation ranges from 5 days to 66 years.66 years.

70 to 80% occur within 3 months and 70 to 80% occur within 3 months and 90% within 1 year of injury.90% within 1 year of injury.

Peak incidence occurs at 4 to 8 Peak incidence occurs at 4 to 8 weeks following injury.weeks following injury.

Clinical Manifestations

Lubin et al: Ophthalmology 1980;87:109Zaharia et al: Can J Ophthalmol 1984;19:240Manak: Surv Ophthalmol 1979;24:141


50-year-old man. Underwent successful retinal reattachment

surgery with pars plana vitrectomy and gas tamponade.

Developed SO 5 weeks after surgery Treatment: I.V. and oral steroids +

cyclosporin A. Control of inflammation and good visual

prognosis.

After successful retinal reattachment surgery with vitrectomy


31-year-old man. Underwent retinal reattachment surgery

with silicone oil tamponade in his left eye 3 mos. prior to presentation.

VA: CF OU Treatment: I.V. and oral steroids +

mycophenolate mofetil Control of inflammation and good visual

prognosis.

After retinal reattachment surgery with silicone oil tamponade


50-year-old man. Developed SO 8 weeks after cataract

surgery. Treatment: Oral steroids +

cyclosporin A + pars plana vitrectomy and removal of IOL.

Control of inflammation and good visual prognosis.

After complicated cataract surgery and IOL implantation


28-year-old man. Developed SO 12 weeks after

sustaining penetrating trauma. Treatment: Oral steroids +

cyclosporin A. Control of inflammation and good

visual outcome.

After penetrating trauma

38-year-old lady.38-year-old lady. Lt. eye blind since childhood with Lt. eye blind since childhood with

no known clear cause.no known clear cause. Developed SO 9 weeks after left Developed SO 9 weeks after left

eye cyclophotocoagulation that eye cyclophotocoagulation that was done prior to referral.was done prior to referral.


After cyclophotocoagulation


After cyclophotocoagulation


Vogt-Koyanagi-Harada diseaseVogt-Koyanagi-Harada disease

(No previous ocular trauma or surgery)

Differential Diagnosis


ImmunogeneticsImmunogenetics−Genetics predisposition which is very

similar to VKH disease.−Increased frequency of HLA-A11

antigen in patients with SO.

−Associated with HLA-DRB1*04, DQA1*03, DQB1*04 among Japanese, British, Irish patients.

Pathogenesis

Reynard et al: Am J Ophthalmol 1983;95:216

Shindo et al; Tissue Antigens 1997;49:111Kilmartin et al: Br J Ophthalmol 2001;85:281.


− Similar in both exciting and sympathizing eyes.

− Classic description is that of a diffuse non-necrotizing granulomatous choroidal inflammation with Dalen-Fuchs nodules.

− Relative sparing of the choriocapillaris or retina (uncharacteristic feature).

Pathological Features


PreventionPrevention− Careful microsurgical

management of the wound with prompt closure of all penetrating injuries.

Management


PreventionPrevention− Enucleation of the traumatized eye if

unsalvageable by modern surgical methods within two weeks after injury is the only known preventive way.Problems:• No proof that this is actually of value.• Incidence of SO after penetrating injury

is decreasing.• With current advanced surgical

techniques many eyes may have a fair prognosis. .

Management


Controversy regarding any advantage of enucleating the exciting eye once SO has started in the sympathizing eye.

Management


− Enucleation within 2 weeks of onset is associated with a relatively benign clinical course and improves visual outcome.

− Enucleation is valueless and should not be performed.

− Enucleation of the exciting eye did not result in improved visual function in the sympathizing eye.

Management

Winter: Am J Ophthalmol 1955;39:340

Lubin et al: Ophthalmology 1980;87:109Reynard et al: Am J Ophthalmol 1983;96:290


− Exciting eye may eventually have the better vision, or diagnosis may be incorrect.

− Enucleation should be considered only in eyes with nil visual prognosis.

Management


− It is not justified to remove a functionally useful injured eye in established cases of SO for the purpose of decreasing inflammation.

− Not all inciting eyes are “lost eyes” as commonly believed.

Management


- Early diagnosis.

- Prompt and effective treatment with systemic immunosuppressive agents has improved the prognosis.

Management


− Corticosteroids are the mainstay of treatment.

− I.V. pulses, I g/day methylprednisolone, 3 consecutive days for immediate control of inflammation.

− Followed by oral prednisone 1-1.5 mg/ Kg/day.

− Dose is reduced gradually following clinical resolution of uveitis.

− Continued for at least 6 months.

Management


Successful control of inflammation and good visual prognosis is related to prompt and adequate systemic immunosuppression using combination of systemic steroids and steroid sparing agents such as cyclosporin A, azathioprine, mycophenolate mofetil.

Management

- Hakin et al: Eye 1992;6:453- Chang et al: Arch Ophthalmol 1995;113:597- Kilmartin et al: Br J Ophthalmol 2000;84:259- Abu El-Asrar, Al-Obeidan: Eur J Ophthalmol 2001;11:193


− Rare disease.− Major sight-threatening disorder.− High index of suspicion must be

maintained whenever inflammation occurs in fellow eyes of an eye that has suffered penetrating trauma or intraocular surgery.

− Infection should be carefully ruled out.

Conclusions


− Diagnosis is made clinically, Diagnosis is made clinically, histological proof is not required.histological proof is not required.

− Injured eyes which have potential Injured eyes which have potential vision should not be enucleated in vision should not be enucleated in an attempt to prevent or lessen SO an attempt to prevent or lessen SO or to provide confirmatory or to provide confirmatory pathology.pathology.

Conclusions


− Prognosis was considered poor prior to Prognosis was considered poor prior to the use of systemic immunosuppression.the use of systemic immunosuppression.

− Today, it should no longer be regarded Today, it should no longer be regarded as a blinding disease.as a blinding disease.

− Prompt and adequate systemic Prompt and adequate systemic immunosuppressive therapy with immunosuppressive therapy with systemic steroids and steroid-sparing systemic steroids and steroid-sparing agents has improved prognosis.agents has improved prognosis.

Conclusions

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VOGT-KOYANAGI-HARADA DISEASE