Morse PH: Elschnig’s spots and hypertensive choroidopathy. Am J Ophthalmol 66:844–852, 1968.

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Tso MOM, Abrams GW, Jampol LM: Hypertensive retinopathy, choroidopathy, neuropathy. In: Singerman LJ, Jampol LM, eds: Retinal and choroidal manifestations of systemic disease. Baltimore, Williams & Wilkins, 1991:79–127.

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Walsh JB: Hypertensive retinopathy: description, classification, and prognosis. Ophthalmology 89:1127–1131, 1982.

Wolf S, et al: Quatification of retinal capillary density and flow velocity in patients with essential hypertension. Hypertension 23:464–467, 1994.

Wong TY, et al: Atherosclerosis Risk in Communities Study. Retinal arteriolar diameter and hypertension. Ann Intern Med 140:248–255, 2004.

Wong TY, et al: Retinal microvascular abnormalities and ten-year cardiovascular mortality. A population-based case-control study. Ophthalmology 110:933–940, 2003.

163 PAPILLORENAL SYNDROME

743.57, 753.0

(Renal–Coloboma Syndrome)

Cameron F. Parsa, MD

Baltimore, Maryland

normal in size, and vesicoureteral reflux can be an associated finding. Patients may be asymptomatic until renal failure is advanced. Not infrequently, both patient and physician are unaware that the ocular and renal findings are related.

Infrequently reported until recently, papillorenal syndrome remains underdiagnosed. Disk excavations may be misinterpreted as acquired due to glaucoma, or they may be thought to represent atypical bilateral morning glory anomaly or optic pit. Many are simply labeled colobomatous although they do not possess the features of true colobomas.

The syndrome is passed down in an autosomal dominant fashion with variable expressivity and de novo mutations also occur. It is important to examine family members whenever the condition is diagnosed and to provide family counseling.

Some affected families have a mutation in the homeobox gene PAX2. Often, however, no mutation can be found, implicating other genes to be involved as well.

COURSE/PROGNOSIS

The ocular course is highly variable; many patients have superonasal field defects but otherwise normal vision. Some patients develop nonrhegmatogenous serous retinal detachments, leading to severe visual loss. The propensity for retinal detachment is related to the degree of thinning of the neuroretinal rim which may allow cerebrospinal fluid (CSF) to seep into the subretinal space. Spontaneous reattachments may occur, leaving behind a characteristic pattern of retinal pigment epithelial changes. The small, or dysplastic kidneys, often lead to chronic glomerulonephropathy and proteinuria. Although some patients eventually require dialysis and renal transplantation, others remain entirely asymptomatic.

ETIOLOGY/INCIDENCE

Papillorenal syndrome (sometimes inaccurately called renalcoloboma syndrome) is an inherited condition often characterized by the association of bilateral, centrally excavated (‘vacant’) optic disks with multiple cilioretinal vessels (Figure 163.1) and dysplastic kidneys. Visual acuity is normal unless secondary serous retinal detachments develop. Kidneys may be small or

DIAGNOSIS

Laboratory findings

Diagnosis has been hampered in the past by the lack of clear nomenclature for disk anomalies. Often erroneously referred to as a coloboma, the disks in this syndrome present with characteristics distinct from actual colobomas, related to failure of

the embryonic optic fissure to close, and from other optic disk anomalies.

●The most characteristic feature is the cilioretinal blood supply of the retina compensating for an attenuation or absence of central retinal vessels. A multiplicity of peripheral arteries and veins are visible that bend and make hairpin turns over and into the neural rim of the disk, indicating their cilioretinal origin. If present, the variably attenuated central retinal vein and artery remain centrally located in the disk (Figure 163.1b). Doppler ultrasonography often reveals extensive anastomoses between such cen- trally-placed vessels and the ciliary circulation deeper within the nerve.

often are present, they are due to hypoplastic retinal development rather than to acquired nerve fiber defects.

PROPHYLAXIS

No prophylaxis is known other than the identification of affected individuals, examination of family members, and genetic counseling.

TREATMENT

tions or staphyloma.

●Superonasal field defects may be present.

The combined findings may sometimes create the appearance of centrally ‘vacant’ disks, which should hint to the underlying diagnosis.

●Ultrasonography may show bilateral, variably small or normal-sized, echogenic, dysplastic kidneys. In some cases, Doppler ultrasound may reveal high resistive indices to blood flow.

●Serum chemistry may indicate elevated blood urea nitrogen and creatinine levels, and urinalysis may reveal proteinuria. Microalbuminuria testing is a sensitive marker for disease.

●Blood can be drawn for PAX2 mutation analysis which is positive in some families.

Note: Unlike true or ‘typical’ colobomas, the dysplastic, vacant disks noted in this syndrome do not have central vessels displaced superiorly, nor is the area of the disk excavation greatest inferonasally. Thus, the alternative appellation for this entity, ‘renal-coloboma syndrome,’ is a misnomer and should be avoided since it implies a failure of embryonic fissure closure rather than a genetic anomaly affecting angiogenesis-mediated (as opposed to vasculogenesis) vessel formation.

Differential diagnosis

●Unlike a coloboma, there is no superodisplacement of blood vessels, nor is the disk excavation centered inferonasally in association with retinal or choroidal defects.

●Unlike morning glory anomaly, the findings are essentially bilateral and associated with good central vision (unless a serous retinal detachment occurs secondarily). The disk size is normal, and the central excavation is broad based rather than funnel shaped. Both conditions, however, do share the common feature of multiplicity of cilioretinal vessels.

●Unlike optic pits, the excavations are broad and not located toward the temporal aspect of the disc. Multiple, if not all, vessels enter and leave the disk periphery, bending or making hairpin turns over the neural rim.

●The presence of a central glial tuft and the often extensive, and frequently exclusive, cilioretinal vascular supply should help to exclude glaucoma. Although superonasal field defects

as optic nerve sheath fenestration or vitrectomy with gas bubble injection. Given the underlying etiology, lowering retrolaminar CSF pressure via sheath fenestration, or, alternatively, raising intraocular pressure, may be more effective approaches.

The most important role of the ophthalmologist in these cases is to refer the patient to a nephrologist for an evaluation and ultrasound examination of the kidneys (including Doppler scanning for resistive indices). Many individuals with ocular findings have undiagnosed chronic renal disease. Others may have normal kidney function at the time of their initial examination with abnormal anatomy, and develop premature renal failure years later. The identification of individuals at risk for renal failure may allow the timely institution of renal protective measures such as aggressive blood pressure control. Such measures are recognized to vastly improve renal potential in dysplastic kidneys and defer the need for dialysis and other procedures by many years.

COMPLICATIONS

Complications include serous retinal detachment and renal failure. Pronounced congenital disc excavations may predispose patients with otherwise ‘normal’ intraocular pressures to superimposed acquired glaucoma. Thus, careful evaluation for progressive visual field changes should be performed. Since the retina is congenitally hypoplastic, and the discs dysplastic, field changes are often atypical in form. Baseline stereo disc photos should be obtained for early detection of potential changes in disc morphology.

REFERENCES

Barroso LHL, Hoyt WF, Narahara M: Can the arterial supply of the retina in man be exclusively cilioretinal? J Neurol Ophthalmol 14:87–90, 1994.

Bron AJ, Burgess SEP, Awdry PN, et al: Papillo-renal syndrome: an inherited association of optic disc dysplasia and renal disease: report and review of the literature. Ophthalmic Paediatr Genet 10:185–198, 1989.

Chang S, Haik BG, Ellsworth RM, et al: Treatment of total retinal detachment in morning glory syndrome. Am J Ophthalmol 97:596–600, 1984.

Chen CS, Odel JG, Miller JS, Hood DC: Multifocal visual evoked potentials and multifocal electroretinograms in papillorenal syndrome. Arch Ophthalmol 120:870–871, 2002.

Dureau P, Attie-Bitach T, Salomon R, et al: Renal coloboma syndrome. Ophthalmology 108:1912–1916, 2001.

Ford B, Rupps R, Lirenman D, Van Allen MI, et al: Renal-coloboma syndrome: prenatal detection and clinical spectrum in a large family. Am J Med Genet 99:137–141, 2001.

Irvine AR, Crawford JB, Sullivan JH: The pathogenesis of retinal detachment with morning glory disc and optic pit. Retina 6:146–150, 1986.

Parsa CF, Cheeseman EW, Maumenee IH: Demonstration of exclusive cilioretinal vascular system supplying the retina in man: vacant discs. Trans Am Ophthalmol Soc 96:95–109, 1998.

Parsa CF, Silva ED, Sundin OH, et al: Redefining papillorenal syndrome: an underdiagnosed cause of ocular and visual morbidity. Ophthalmology 108:738–749, 2001.

Sanyanusin P, Schimmenti LA, McNoe LA, et al: Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nat Genet 9:358–363, 1995.

164VOGT–KOYANAGI–HARADA DISEASE 364.24

(Harada’s Disease; Uveomeningitis)

Russell W. Read, MD

Birmingham, Alabama

in United States studies to over 9% of uveitis cases in Japanese studies. VKH disease affects females more commonly than males. Average age of disease onset is the third to fifth decade of life, but patients as young as 4 years of age have been reported.

COURSE/PROGNOSIS

VKH disease is typically divided into four stages: prodromal, acute uveitic, convalescent, and chronic-recurrent stages. The prodromal stage manifests with predominately neurologic and auditory symptoms including headache, meningismus, tinnitus, and dysacousia. Patients may be diagnosed with aseptic meningitis if they seek medical care prior to the onset of ocular inflammation. The uveitic stage begins a variable time later, but typically within a week, with the onset of a diffuse choroiditis as the hallmark of disease. This may manifest as diffuse choroidal thickening (best demonstrated on ultrasonography), exudative retinal detachments, and papillitis. Vitreous and anterior chamber cell may be present. Fluorescein angiography reveals multiple pinpoint areas of subretinal leakage with eventual pooling in the subretinal space (Figure 164.1 and 164.2). Ciliary body edema and detachment may occur, with forward rotation of the lens-iris diaphragm and a resultant shallowed angle. As the inflammatory attack subsides, typically following

ETIOLOGY/INCIDENCE

Vogt–Koyanagi–Harada (VKH) disease is characterized by inflammation involving the eye, inner ear, skin, hair, and meninges of the central nervous system, but the exact cause remains unknown. Immunohistochemistry of ocular and skin specimens have shown an infiltration of CD4+ T-cells, epithelioid cells, and multinucleated giant cells, indicative of granulomatous inflammation. Evidence increasingly suggests that this attack is directed against an as of yet unidentified component of the melanocytes contained in the targeted tissues. This data includes studies revealing that immunization of rats or Akita dogs with tyrosinase family peptides produces a uveitis that is similar to human VKH disease. Human studies have shown that cerebrospinal fluid obtained from patients with VKH disease contains melanin-laden macrophages. This finding could be due to directed phagocytosis of melanin or to non-specific phagocytosis of melanin liberated during inflammation. However, peripheral blood lymphocytes from patients with VKH disease proliferate upon stimulation with tyrosinasefamily peptides, suggesting that melanin-related components are an immunological target. The exact inciting event that leads to the autoimmune attack against melanin is unknown, but several possibilities exist. Occult trauma of melanocytecontaining tissues could lead to a sensitization to melanin. Viral infection could likewise cause a collateral sensitization to melanin components. While not conclusive proof, Epstein–Barr virus DNA has been isolated from the vitreous of patients with VKH disease. A genetic predisposition may contribute to disease, with numerous studies showing a strong association with the human leukocyte antigen (HLA) DR4 allele and specifically with HLA-DRB1*0405 and HLA-BRB1*0410 subtypes.

VKH disease is more common in Asians, Asian Indians, Middle Easterners, Hispanics, and American Indians. The condition is rare in Africans and Caucasians. Frequency of disease varies by study clinic, ranging from 1% to 7% of uveitis cases

FIGURE 164.1. Vogt–Kayanagi–Harada syndrome (fluoroscein angiogram).

FIGURE 164.2. Vogt–Kayanagi–Harada syndrome.