VOGT-KOYANAGI-HARADA
DISEASE
AHMED M. ABU EL-ASRAR, MD, PhD
Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
Dr. Nasser Al-Rashid Research Chair in Ophthalmology
VKH Disease
• Multisystem disease
• Chronic, bilateral, granulomatous
panuveitis associated with central
nervous system, auditory and
integumentary manifestations
Moorthy et al: Surv Ophthalmol 1995; 39:265 (review)
Read et al: Am J Ophthalmol 2001;131:647
VKH Disease
Epidemiology
• Individuals with a predisposing genetic
background.
• Ethnic groups with more heavily
pigmented skin.
• Asians, Native Americans, Hispanics,
Asian Indians, Middle Easterners.
VKH Disease
Epidemiology
• Genetic background rather than
degree of skin pigmentation.
• Women more than men.
• 3rd – 4th decade.
• Pediatric age group.
Read et al: Curr Opin Ophthalmol 2000;11:437 (review)
Abu El-Asrar et al: Eye 2008;22:1124
Martin et al: Retina 2010 Feb 17. [Epub ahead of print]
VKH Disease
Etiology and Pathogenesis
• 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.
Okada et al: Graefe’s Arch Clin Exp Ophthalmol 1996;234:359
VKH Disease
Etiology and Pathogenesis
• 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;165:7323
Yamaki et al: Exp Eye Res 2000;71:361
VKH Disease
Etiology and Pathogenesis
 Th cells from peripheral blood of VKH patients
produce predominantly Th1 cytokines (IFNgamma, 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
VKH Disease
Etiology and Pathogenesis
 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 Disease
Etiology and Pathogenesis
 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;13:3137
Touitou et al: Am J Ophthalmol 2005;140:949
Papastathopoulos et al: J Infect 2006;52:e59
Kasahara et al: J Gastroenterol 2004;39:1106
Sylvestre et al: J Viral Hepat 2003;10:467
VKH Disease
Pathology
• Granulomatous panuveitis.
• Lymphocytes, epitheloid cells, few
plasma cells, multinucleated giant cells.
• Epitheloid cells and giant cells contain
melanin pigment.
VKH Disease
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;83:242
Inomata and Rao: Am J Ophthalmol 2001;131:607
VKH Disease
Genetic Factors
• Certain racial groups.
• Immunogenetic predisposition.
• Strong association with HLA-DR4 and HLA-DRw53
with the most significant risk allele being HLADRB1*0405.
• Causative pathogenic antigen binds with HLADRB1*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).
VKH Disease
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
VKH Disease
Clinical Features
Extraocular Manifestations
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.
VKH Disease
Clinical Features
Extraocular Manifestations
Neurologic Manifestations
•
•
•
•
Most common during prodromal stage.
Neck stiffness, headache, confusion.
Occasionally focal neurologic signs.
CSF pleocytosis.
VKH Disease
Clinical Features
Extraocular Manifestations
Auditory Manifestations
• May be presenting problem
• Sensorineural hearing loss usually involves
higher frequencies
• Tinnitus
• Vertigo
• May cause permanent hearing loss
VKH Disease
Clinical Features
Auditory Manifestations
VKH Disease
Clinical Course
4 phases
•
•
•
•
Prodromal
Acute uveitic
Convalescent or chronic
Chronic recurrent
VKH Disease
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
VKH Disease
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.
VKH Disease
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).
VKH Disease
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.
Fang and Yang: Curr Eye Res 2008;33:517 (review)
VKH Disease
Clinical Course
Acute Uveitic Phase: (cont.).
• Shallow anterior chamber
• Elevated IOP
• Acute angle closure glaucoma
VKH Disease
Clinical Course
Convalescent Phase:
• Integumentary and uvea depigmentation.
• Perilimbal vitiligo (Sugiura’s sign).
• Fundus exhibits an orange-red discoloration
(“sunset-glow” fundus).
VKH Disease
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.
VKH Disease
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
VKH Disease
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.
Fang et al: Br J Ophthalmol 2008;92:182
VKH Disease
Laboratory Investigations
Diagnosis is made by clinical examination
and ancillary test findings
• Fluorescein angiography
• Indocyanine green angiography
• Ultrasonography
• Optical coherence tomography
• Multifocal electroretinograms
• Lumbar puncture
VKH Disease
Laboratory Investigations
Ultrasonography:
• Diffuse low to medium thickening of
choroid.
• Overlying exudative RD.
VKH Disease
Laboratory Investigations
OCT
Useful in monitoring resolution of exudative retinal
detachment
On presentation
4 weeks after systemic corticosteroid
VKH Disease
Laboratory Investigations
Multifocal Electroretinogram
 May be useful in detecting early retinal damage.
Chee et al: Graefe’s Arch Clin Exp Ophthalmol 2005; 243:785.
 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.
Yang et al: Am J Ophthalmol 2008; 146:767.
VKH Disease
Retinal functional changes measured by
microperimetry after immunosuppressive
therapy
 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.
Abu El-Asrar et al: Eur J Ophthalmol 2012; 22:368
VKH Disease
Retinal functional changes measured by
microperimetry after immunosuppressive
therapy
VKH Disease
Laboratory Investigations
Lumbar Puncture:
• Rarely necessary in a typical case.
• CSF pleocytosis (mostly lymphocytes).
• Transient and resolves within 8 weeks.
VKH Disease
Laboratory Investigations
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.
VKH Disease
Complications
•
•
•
•
•
•
Cataract
Secondary glaucoma
Choroidal neovascular membranes
Subretinal fibrosis
Severe chorioretinal atrophy
Significantly associated with longer duration of
disease and greater numbers of recurrences.
Read et al : Am J Ophthalmol 2001;131:599.
Sonoda et al: Jpn J Ophthalmol 1999;43:113.
VKH Disease
Complications
• Significantly associated with older age
and more severe disease at presentation.
Al-Kharashi, Abu El-Asrar: Int Ophthalmol 2007;27:201
VKH Disease
Therapy
• 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.
VKH Disease
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.
VKH Disease
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.
Sonoda et al: Jpn J Ophthalmol 1999;43:113.
VKH Disease
Therapy
• 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.
Al-Kharashi, Abu El-Asrar: Int Ophthalmol 2007;27:201
VKH Disease
Therapy
• 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.
Paredes et al: Ocul Immunol Inflamm 2006;14:87
Kim and Yu: Ocul Immunol Inflamm 2007;15:381
Abu El-Asrar, et al: Acta Ophthalmol 2012;90:e603
VKH Disease
The outcomes of mycophenolate mofetil
combined with systemic corticosteroids in acute
uveitis associated with VKH disease
 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.
Abu El-Asrar et al: Acta Ophthalmol 2012; 90:e603
VKH Disease
Prognosis
• 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.
Al-Kharashi, Abu El-Asrar: Int Ophthalmol 2007;27:201
Abu El-Asrar et al: Eye 2008;22:1124
VKH Disease
Prognostic factors for clinical outcomes in
patients treated with high-dose corticosteroids
 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.
Abu El-Asrar et al: Acta Ophthalmol. In press.
Sympathetic Ophthalmia
Ahmed M. Abu El-Asrar, MD, PhD
Sympathetic Ophthalmia



Rare bilateral granulomatous panuveitis
that occurs as a complication of a
penetrating injury that involves the uvea
of one eye.
Accidental trauma or surgery.
Injured eye is referred to as the exciting
eye and fellow eye as the sympathizing
eye.
Sympathetic Ophthalmia
Incidence


In 0.1% to 0.3% of patients after
accidental trauma.
In 0.015% of patients following ocular
surgery.
Allen: JAMA 1969;209:1090
Liddy, Stuart: Can J Ophthalmol 1972;7:157
Gass: Am J Ophthalmol 1982;93:552

5.8% and 0.67% after noncontact and
contact Nd:YAG cyclotherapy, respectively.
Lam et al: Ophthalmology 1992;99:1818
Sympathetic Ophthalmia
Incidence
Role of ocular surgery

Sole cause in:
–
–
–
–
–
45%
17%
28%
56%
70%
of
of
of
of
of
cases
cases
cases
cases
cases
– 38% of cases
(Gass: Am J Ophthalmol 1982;93:552)
(Hakin et al: Eye 1992;6:453)
(Chan et al: Arch Ophthalmol 1995;113:597)
(Kilmartin et al: Br J Ophthalmol 2000;84:259)
(Su and Chee: Graefes’ Arch Clin Exp Ophthalmol
2006;244:243)
(Galor et al: Am J Ophthalmol 2009;148:704)
Sympathetic Ophthalmia
Incidence
Role of ocular surgery

Ocular surgery, particularly retinal surgery, is
now a greater risk than accidental trauma.
Kilmartin et al: Br J Ophthalmol 2000;84:259
Su and Chee: Graefe’s Arch Clin Exp Ophthalmol 2006;244:243

Risk of one in 1152 retinal surgical procedures.
Kilmartin et al: Br J Ophthalmol 2000;84:448
Sympathetic Ophthalmia
Incidence
Role of vitrectomy
 In 0.06% of cases
 In 0.01% when vitrectomy was the only
operative procedure and penetrating
wound.
Gass: Am J Ophthalmol 1982;93:552

A prospective surveillance for SO in UK
and Ireland showed risk of one in 799
vitrectomies.
Kilmartin et al: Br J Ophthalmol 2000;84:448
Sympathetic Ophthalmia
Incidence
Role of vitrectomy


Vitreoretinal surgery is an important risk
factor.
It may be appropriate to counsel patients
about risk of SO before performing
vitrectomy
Kilmartin et al: Br J Ophthalmol 2000;84:448

Any bilateral uveitis following vitreoretinal
surgery should alert the surgeon to the
possibility of SO.
Sympathetic Ophthalmia
Incidence
Evisceration 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.
Sympathetic Ophthalmia
Incidence
Evisceration versus enucleation

Four cases of SO following evisceration
Green et al: Trans Am Acad Ophthalmol Otolaryngol 1972; 76:625

Six cases of SO after evisceration.
Ikui et al: Nippon Ganka Kiyo1965; 16:458

A case of SO following evisceration of a blind,
painful, post-traumatic, glaucomatous eye.
Griepentrog et al: Ophthal Plast Reconstr Surg 2005; 21:316
Sympathetic Ophthalmia
Incidence
Evisceration versus enucleation

Evisceration is safe with little risk of SO.
Levine et al: Ophthal Plast Reconstr Surg 1999; 15:4.
Toit et al: Br J Ophthalmol 2008;92:61.

High degree of clinical suspicion is required.
Sympathetic Ophthalmia
Clinical Manifestations



Interval between injury and onset of
inflammation ranges from 5 days to 66
years.
70 to 80% occur within 3 months and
90% within 1 year of injury.
Peak incidence occurs at 4 to 8 weeks
following injury.
Lubin et al: Ophthalmology 1980;87:109
Zaharia et al: Can J Ophthalmol 1984;19:240
Manak: Surv Ophthalmol 1979;24:141
Sympathetic Ophthalmia
After successful retinal reattachment
surgery with vitrectomy





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.
Sympathetic Ophthalmia
After retinal reattachment surgery
with silicone oil tamponade





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.
Sympathetic Ophthalmia
After complicated cataract surgery
and IOL implantation




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.
Sympathetic Ophthalmia
After penetrating trauma




28-year-old man.
Developed SO 12 weeks after sustaining
penetrating trauma.
Treatment: Oral steroids + cyclosporin A.
Control of inflammation and good visual
outcome.
Sympathetic Ophthalmia
After cyclophotocoagulation



38-year-old lady.
Lt. eye blind since childhood with no
known clear cause.
Developed SO 9 weeks after left eye
cyclophotocoagulation that was done
prior to referral.
Sympathetic Ophthalmia
After cyclophotocoagulation
Sympathetic Ophthalmia
Differential Diagnosis
Vogt-Koyanagi-Harada disease
(No previous ocular trauma or surgery)
Sympathetic Ophthalmia
Pathogenesis
Immunogenetics
−Genetics predisposition which is very similar
to VKH disease.
−Increased frequency of HLA-A11 antigen in
patients with SO.
Reynard et al: Am J Ophthalmol 1983;95:216
−Associated with HLA-DRB1*04, DQA1*03,
DQB1*04 among Japanese, British, Irish
patients.
Shindo et al; Tissue Antigens 1997;49:111
Kilmartin et al: Br J Ophthalmol 2001;85:281.
Sympathetic Ophthalmia
Pathological Features
−
Similar in both exciting and sympathizing
eyes.
−
Classic description is that of a diffuse nonnecrotizing granulomatous choroidal
inflammation with Dalen-Fuchs nodules.
−
Relative sparing of the choriocapillaris or
retina (uncharacteristic feature).
Sympathetic Ophthalmia
Management
Prevention
− Careful microsurgical management
of the wound with prompt closure
of all penetrating injuries.
Sympathetic Ophthalmia
Management
Prevention
−
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.
Sympathetic Ophthalmia
Management
Controversy regarding any advantage
of enucleating the exciting eye once
SO has started in the sympathizing
eye.
Sympathetic Ophthalmia
Management
−
Enucleation within 2 weeks of onset is
associated with a relatively benign clinical
course and improves visual outcome.
Lubin et al: Ophthalmology 1980;87:109
Reynard et al: Am J Ophthalmol 1983;96:290
−
−
Enucleation is valueless and should not be
performed.
Enucleation of the exciting eye did not
result in improved visual function in the
sympathizing eye.
Winter: Am J Ophthalmol 1955;39:340
Sympathetic Ophthalmia
Management
−
Exciting eye may eventually have the
better vision, or diagnosis may be
incorrect.
−
Enucleation should be considered only
in eyes with nil visual prognosis.
Sympathetic Ophthalmia
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.
Sympathetic Ophthalmia
Management
- Early diagnosis.
- Prompt and effective treatment with
systemic immunosuppressive agents
has improved the prognosis.
Sympathetic Ophthalmia
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.
Sympathetic Ophthalmia
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.
- 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
Sympathetic Ophthalmia
Conclusions
−
−
−
−
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.
Sympathetic Ophthalmia
Conclusions
−
Diagnosis is made clinically, histological
proof is not required.
−
Injured eyes which have potential vision
should not be enucleated in an attempt
to prevent or lessen SO or to provide
confirmatory pathology.
Sympathetic Ophthalmia
Conclusions
−
Prognosis was considered poor prior to
the use of systemic immunosuppression.
−
Today, it should no longer be regarded
as a blinding disease.
−
Prompt and adequate systemic
immunosuppressive therapy with
systemic steroids and steroid-sparing
agents has improved prognosis.