Transcript VKH Disease
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
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Multisystem disease
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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 (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
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
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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 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).
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.
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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
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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.)
.
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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
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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% of cases (Gass: Am J Ophthalmol 1982;93:552) – 17% of cases – 28% of cases (Hakin et al: Eye 1992;6:453) (Chan et al: Arch Ophthalmol 1995;113:597) – 56% of cases (Kilmartin et al: Br J Ophthalmol 2000;84:259) – 70% of cases (Su and Chee: Graefes’ Arch Clin Exp Ophthalmol 2006;244:243) – 38% of cases (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 procedu res.
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 non necrotizing 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.