Triads in Ophthalmology: A Comprehensive Review.

Seminars in Ophthalmology, Early Online, 1–14, 2015 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2015.1045150

REVIEW

Triads in Ophthalmology: A Comprehensive Review Koushik Tripathy, Yog Raj Sharma, Rohan Chawla, Koushik Basu, Rajpal Vohra, and Pradeep Venkatesh

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Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

ABSTRACT Ophthalmology, like any other clinical science, is constantly evolving. As our knowledge in this field expands, we enumerate and describe classical triads of symptoms or signs with relevance to ophthalmology in this article. Characteristic clinical triads for certain systemic conditions with ocular implications are also discussed. Keywords: Anterior segment, ocular physiology, oculoplasty, retina and vitreous, uveitis

Numerous classical clinical triads have been described in the literature to characterize various eye diseases. In this review, we discuss a comprehensive list of ophthalmic conditions and systemic diseases with ocular implications which are characterized by three typical findings.

occulomotor complex. In contrast, the supranuclear fibers for light reflex come from the pretectal nucleus passing through the dorsal midbrain. Thus, the lesions in the dorsal midbrain affect light reflex but spare pupillary constriction due to near response (light near dissociation). A spasm of the near reflex (accommodative spasm) is the triad of excess accommodation, excess convergence, and miosis. The optic nerve triad consists of relative afferent pupillary defect (RAPD), color vision, and brightness sense.3 In optic neuropathies, the presenting complaint is central scotoma with variable decrease in central vision. Brightness sense and color vision are more severely affected in optic nerve disease. Pain may be there on ocular movements, and refraction remains unchanged. In contrast, maculopathy causes metamorphopsia with marked dimness of central vision, no pain, and sometimes hyperopia.

OCULAR PHYSIOLOGY The near response or near synkinesis triad happens when a person focuses on a near object. The near triad includes accommodation (increased curvature of anterior surface of lens), convergence, and miosis.1 Accommodation, convergence, and pupillary constriction are co-movements, but they can occur in the absence of each other. They are controlled, synchronized, and associated with supranuclear connections, but they are not caused by one another.2 The final efferent pathway for miosis due to near response and miosis due to light reflex is the same, via Edinger Westphal nucleus to the sphincter pupillae via the third cranial nerve through ciliary ganglion. But the supranuclear control for miosis due to near response comes from cortical areas surrounding the visual cortex and from cortical areas within the frontal eye fields. They are thought to synapse at least once, before passing ventrally through the midbrain toward the visceral neurons overlying the

ANTERIOR SEGMENT The AGR triad consists of aniridia, ambiguous genitalia, and mental retardation. This triad was described in chromosome 11 short-arm interstitial deletions.4 However, the most common manifestation of de novo deletion of 11p13 is WAGR syndrome (Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation). Ocular features of aniridia are

Received 10 November 2014; accepted 12 April 2015; published online 6 July 2015 Correspondence: Dr. Koushik Tripathy, Room 489, C/O Prof. Yog Raj Sharma, Chief, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi, India. E-mail: [email protected]

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photophobia, nystagmus, strabismus, mebomian gland dysfunction, rudimentary iris, dry eyes due to limbal stem cell deficiency, cataract, subluxated or dislocated lens, optic nerve hypoplasia, foveal hypoplasia, choroidal coloboma, and glaucoma in 75% of cases. All patients with sporadic aniridia should undergo serial abdominal ultrasound to rule out Wilms’ tumor. Wilms’ tumor is named after German surgeon Dr. Max Wilms (1867–1918). Alport’s syndrome is an oculorenal syndrome characterized by ocular anomalies, progressive sensorineural hearing loss, and hemorrhagic nephropathy.5 The syndrome of hereditary congenital hemorrhagic nephritis with associated deafness was first reported in 1927 by South African physician Arthur Cecil Alport (1880–1959). There is a defect of the basement membrane (collagen IV) in this disease. Pathognomonic manifestation is anterior lenticonus, which is bilateral in 75% of cases. Other ocular manifestations are dot-and-fleck retinopathy, posterior polymorphous corneal dystrophy, and recurrent corneal erosions. Congenital rubella syndrome is characterized by the triad of cataracts, deafness, and cardiac defects. In 1941, Gregg first described this triad.6 Vaccination against mumps, measles, and rubella has been introduced among most one-year-old children as part of an immunization schedule. Rubella vaccination has also been started among females of childbearing age to prevent this syndrome. Chances of transplacental spread from mother to fetus are maximum in the first trimester. Cataract is seen in about 15% cases, which may be nuclear cataract with pearly appearance or total cataract. The live virus can persist within the lens until up to three years of age. Other ocular manifestations are microcornea, microphthalmos, glaucoma, salt and pepper retinopathy, keratitis, anterior uveitis, iris atrophy, refractive errors, nystagmus, and strabismus. Cardiac defects (patent ductus arteriosus, pulmonary stenosis) should be ruled out in all such patients before surgery under general anesthesia. Hutchinson’s triad is seen in congenital syphilis. It consists of small, widely spaced, peg-shaped, notched upper incisors with thin discolored enamel (Hutchinson’s teeth), sensory neural hearing loss, and interstitial keratitis.7 These are features of late congenital syphilis occurring in children at or older than two years of age. Hutchinson’s triad is named after the English surgeon Sir Jonathan Hutchinson (1828–1913). The ocular manifestations are limbitis with cherry-red limbal congestion with deep stromal vessels with corneal clouding (Salmon patch), granulomatous anterior uveitis, ghost vessels, and intracorneal bleed. Other manifestations include saddle nose, mulberry molars, high arched palate, prognathia, olympian brow, frontal bossing, saber shins, clutton’s joint (bilateral knee effusion), Higoumenaki’s sign

(thickening of sternal portion of clavicle), optic atrophy, and rhagades (linear scars often found around the mouth). The ICE (iridocorneal endothelial) syndrome is a spectrum of diseases including progressive (essential) iris atrophy, Chandler’s syndrome, and Cogan-Reese syndrome (iris-nevus syndrome). ICE syndrome is characterized by a ‘‘hammered silver’’ appearance to the corneal endothelium, glaucoma, and varying degrees of iris changes, such as corectopia, holes, and atrophy. Chandler’s syndrome typically has more severe corneal edema than the others. Essential iris atrophy is associated with polycoria and iris stretch holes. Cogan-Reese syndrome is characterized by numerous small pigmented nodules, iris atrophy, and pupillary distortion. Posterior polymorphous dystrophy of the cornea is considered by some to be related to the ICE syndrome. Intraoperative floppy iris syndrome (IFIS) is a triad of floppy iris that billows in response to normal irrigation in the anterior chamber, propensity for the iris to prolapse out of the main and side port incisions, and progressive pupillary constriction during surgery. This syndrome is associated with the use of systemic sympathetic alpha-1A antagonists such as tamsulosin that are prescribed to treat urinary symptoms associated with benign prostatic hypertrophy.8 The oculocerebrorenal syndrome of Lowe (OCRL) is a rare, X-linked recessive disorder affecting the central nervous system, eyes, and kidneys. The diagnostic triad includes congenital cataracts, mental retardation, and renal tubular dysfunction.9 The disease was first described in 1952 by American pediatrician Charles Upton Lowe (1921–2012) and co-workers. Other features are hypotonia, areflexia, proximal tubular acidosis, amino aciduria, phosphaturia, frontal prominence, chubby cheeks, sunken eyes, failure to thrive, and low-molecular-weight proteinuria. 50% of cases have glaucoma. This syndrome is a cause of Fanconi syndrome; it is caused by mutations in the OCRL1 gene, encoding inositol polyphosphate-5phosphatase. It is one of the rare conditions in which congenital glaucoma and congenital cataract co-exist. The cataract is seen in all cases and may be capsular, lamellar, nuclear, or total. There is microphakia (small, thin, and disc-like lens) and the cataract may show posterior lentiglobus. Female carriers manifest micropunctate cortical lens opacities without visual impact. Other ocular manifestations are miosis with poor pupillary dilation.10 Oculoglandular syndrome of Parinaud is characterized by a triad of follicular (granulomatous) conjunctivitis, regional lymphadenopathy, and fever. It is caused by Bartonella henselae (most commonly), Francisella tularensis, herpes simplex virus type 1, Paracoccidioides brasiliensis, Mycobacterium tuberculosis, Leptothrix, Sporothrix, or Treponema pallidum.11 It is named after Dr. Henri Parinaud (1844–1905), a French Seminars in Ophthalmology


Triads in Ophthalmology ophthalmologist and neurologist. The eye may be involved in up to 26% of systemic Bartonella infection (cat scratch disease). The ophthalmic manifestations are neuroretinitis (disc edema and macular star), serous macular detachment, focal chorioretinitis, optic neuritis, acute multifocal inner retinitis or a characteristic retinal white spot syndrome, Bartonella retinitis, focal choroiditis, anterior uveitis, vitritis, pars planitis, focal retinal vasculitis, branch retinal arteriolar and venular occlusions, and peripapillary angiomatosis.12 Up to 7% of cases of cat scratch disease develop neurological complications like encephalitis, aseptic meningitis, seizures, transverse myelitis, cerebral vasculitis or abscess, peripheral neuropathy, polyneuritis or radiculitis, and Bell’s palsy.13 It occurs from the scratch or bite of an infected kitten or cat. The cat fleas (Ctenocephalides felis) carry Bartonella henselae in the intestinal tract and excrete the organism in their feces. Cat scratch disease usually presents as self-limiting lymphadenopathy over three to six weeks in immunocompetent individuals. Cat scratch disease is treated by systemic penicillin, cephalosporins, doxycycline, erythromycin, rifampin, azithromycin, or ciprofloxacin, Postnatally acquired measles patients exhibit a triad of cough, coryza, and follicular conjunctivitis.14 Other manifestations may be corneal epithelial keratitis, Koplick spots on conjunctiva, optic neuritis, retinal vascular occlusions and pigmentary retinopathy. Measles keratopathy is a common cause of childhood blindness in the developing world. It presents as bilateral corneal ulceration in vitamin-A-deficient children. Subacute sclerosing panencephalitis (SSPE) is a very rare (1 per 100,000 cases) and serious complication of measles infection which occurs years after measles infection. Tyrosinemia type II (Richner-Hanhart syndrome, oculocutaneous Tyrosinemia, or Oregon type tyrosinemia) is characterized by a triad of bilateral dendriform keratitis, hyperkeratotic lesions of the palms and soles, and mental retardation.15 It is an autosomal recessive disorder due to deficiency of hepatic cytosolic enzyme tyrosine amino transferase (chromosome 16q22). Children present in the first few months of life with photophobia, tearing and redness of both eyes. They are commonly misdiagnosed with herpetic keratitis. The keratitis varies from mild epithelial branching to deep ulcerations involving the anterior stroma. Nystagmus, cataract, strabismus, and thickened conjunctiva may be seen.16 Raised serum tyrosine level is confirmatory. Dietary restriction of tyrosine and phenylalanine is all that is required. Rarely, penetrating keratoplasty may be required for corneal scarring and vascularization. The syndrome gets its name from Swiss dermatologist Hermann Richner (born 1908) and Swiss internist and geneticist Ernst Hanhart (1891–1973). !

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UGH syndrome is a triad of uveitis, glaucoma, and hyphema.17 This syndrome is also called Ellingson’s syndrome in honor of American ophthalmologist F. Thomas Ellingson, who described the condition in 1978 as a complication of Mark VIII anterior chamber lens implant.18 This syndrome is seen with poorly manufactured anterior chamber intraocular lenses (ACIOL) and, rarely, posterior chamber intraocular lenses (PCIOL). This is due to mechanical trauma to the iris or angle or ciliary body by the haptic or optic of the intraocular lens (IOL). In the presence of vitreous hemorrhage, cystoid macular edema, and pseudophakic bullous keratopathy, it is called U.G.H. plus. Severe U.G.H. syndrome requires explant of the IOL.

INTRAOCULAR INFLAMMATION AND UVEITIS Acute retinal necrosis, also called Kirisawa’s uveitis,19 is a triad of an arteritis and phlebitis of the retinal and choroidal vasculature (mainly arteritis); a confluent, necrotizing retinitis, especially in peripheral retina; and a moderate to severe vitritis. It is commonly complicated by optic neuropathy and rhegmatogenous retinal detachments (75%). The other eye is involved in 36% of cases. Intravenous acyclovir is given to decrease involvement of the other eye, although it does not prevent retinal detachment. Behcet syndrome (Adamantiades Behcet disease) consists of a triple symptom complex of recurrent aphthous oral ulcers, genital ulcers, and uveitis.20 Other systemic manifestations are erythema nodosum, arthritis, and meningoencephalitis. The uveitis is classically bilateral in 80% of cases, non-granulomatous with hypopyon. Posterior segment manifestations may be occlusive retinal vasculitis with surrounding intraretinal hemorrhages, retinal edema, severe vitritis, and disc edema. Progressive damage to the sensory retina results in marked attenuation of the arterioles.21 The disease is named after Turkish dermatologist Hulusi Behcet (1889–1948) and Greek ophthalmologist Benediktos Adamantiades (1875–1962). Congenital toxoplasmosis patients have a triad of chorioretinitis (seen in 80% of patients), hydrocephalus, and intracranial calcification.22 Early firsttrimester maternal infections are less likely to result in congenital infection, but the sequelae are more severe. Transplacental passage is more common when maternal infection occurs in the latter half of pregnancy, but fetal injury is usually much less severe. The infected pregnant patients are treated with pyrimethamine-sulfonamide for cases where PCR-AF (polymerase chain reaction of amniotic fluid) testing is positive and with spiramycin where PCR-AF testing is negative.22


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Fuch’s heterochromatic iridocyclitis is classically characterized by a triad of iris heterochromia, cataract and keratic precipitates (low-grade iritis).23 It is typically unilateral, seen in young adults of both sexes. Heterochromia may be difficult to appreciate in black patients. Usual features are stellate keratic precipitates scattered throughout the whole cornea, absence of posterior synechia, and small nodules at the pupillary border. Topical steroids are generally ineffective and mydriatics unnecessary because of the lack of posterior synechiae.10 It is named after Austrian ophthalmologist Ernst Fuchs (1851– 1930). Reactive arthritis (Reiter’s) syndrome is defined as classical triad of urethritis, polyarthritis, and conjunctival inflammation. Other ocular features include recurrent acute anterior uveitis in up to 50% of cases,24 which may be associated with spillover vitreous cells, keratitis, cystoid macular edema and, very rarely, optic disc edema. 85% patients are positive for HLA B27. Rheumatoid factor is usually not present. It develops more commonly in men after non-specific urethritis (Ureaplasma urealyticum and Chlamydia trachomatis), and in both sexes after enteric infections by Shigella, Salmonella, Campylobacter, and Yersinia. Other systemic features are circinate balanitis, keratoderma blenorrhagica involving palm and soles, prostatitis, cystitis, spondylitis, fasciitis, sacroiliitis, tendonitis, oral mucosal lesions, a recent history of diarrhea, and enthesitis. The syndrome was first described by a German physician, Hans Conrad Julius Reiter (1881– 1969), who was a military officer in 1916. As he was later convicted of war crimes for his medical experiments at the Nazi concentration camp at Buchenwald, there is controversy whether his name should further be used to denote the disease.25 Early onset sarcoid in children younger than four years of age has a distinct clinical picture characterized by the triad of rash, polyarthritis, and uveitis.26 The children typically do not present with pulmonary symptoms as seen in adults. The diagnosis of sarcoidosis is confirmed by demonstrating a typical non-caseating granuloma on a biopsy specimen. Other granulomatous diseases should be excluded. Susac syndrome (SICRET syndrome: Small Infarctions of Cochlear, Retinal, and Encephalic tissue) is characterized by encephalopathy, hearing loss, and branch retinal arterial occlusion.27 The disease predominantly affects females (female:male = 3:1) aged between 16 and 51 years. Headache is seen in almost all cases. Central fibers of corpus callosum are typically involved, sparing peripheral fibers, unlike in multiple sclerosis. Ocular features are diffuse or localized narrowing of retinal arteries with a ‘‘boxcar’’ segmentation of the blood column at the level of peripheral retinal arteries with no vitritis. Usually there is no evidence of embolic material or inflammatory reactions around the

vessel. The syndrome derives its name from American doctor John O. Susac, who described the association. Multiple areas of segmental staining away from sites of bifurcation may be appreciated on a fundus fluorescein angiogram.

GLAUCOMA Open angle glaucoma is characterized by triad of glaucomatous optic disc changes, visual field changes, and raised intraocular pressure (IOP).28 In contrast to other optic neuropathies, glaucoma progresses with time, and the visual field defects typically obey a horizontal line passing through fixation. Glaucomatous optic disc changes are characterized by irregular loss of the neuroretinal rim (NRR), retinal nerve fiber defects, deepening of the cup, and increased cup/disc ratio. Other changes of the optic disc are baring of circumlinear blood vessels, bayoneting, collaterals between veins at the optic nerve head, loss of nasal NRR, laminar dot sign, disc hemorrhages, sharpened edge or ‘‘sharpened rim’’ and peripapillary atrophy. The typical progression of visual field defect in glaucoma is superior or inferior paracentral scotoma, Siedel’s scotoma (sickle-shaped scotoma), Bjerrum’s scotoma (arcute scotoma), Roenne’s nasal step (double arcuate or ring scotoma), tubular vision, and only temporal field of vision to ultimately no light perception. Primary congenital glaucoma is clinically characterized by photophobia, blepharospasm, and tearing (epiphora).29 It affects 1 in 10,000 live births, and twothirds of patients are boys. Bilateral involvement is seen in 75% of cases, though frequently asymmetrical. Ocular features are corneal clouding, horizontal or circumferential breaks in Descemet’s membrane (Haab’s stria), increased corneal diameter, and increased optic disc cupping, which may be reversible. Surgery (goniotomy, trabeculotomy, trabeculectomy, or combined trabeculotomy and trabeculectomy) is the mainstay of management. Vogt’s triad of glaucoma may be seen in patients with post-congestive primary angle closure glaucoma and in treated cases of acute congestive glaucoma. It is characterized by glaucomflecken (anterior subcapsular lenticular opacity), patches of iris atrophy, and slightly dilated non-reacting pupil (due to sphincter atrophy).30

RETINA AND VITREOUS Aicardi syndrome is a triad consisting of widespread round or oval chorioretinal lacunae clustered around the disc, infantile spasms, and agenesis of corpus callosum.31 It is an X-linked dominant disease. In utero, it is lethal for males. It occurs only in Seminars in Ophthalmology


Triads in Ophthalmology individuals with two X chromosomes. It has also been described in boys with XXY chromosomes. Other ocular features are hypoplastic, colobomatous or pigmented optic nerve head, microphthalmos, iris colobomas, persistent pupillary membranes and cataract. Other systemic features include skeletal malformations, central nervous system malformations (microcephaly, enlarged ventricles, or porencephalic cysts), and psychomotor retardation. Death usually occurs within the first few years of life. The name is derived from Jean Aicardi (born 1926), a French doctor. Coats’ disease in advanced cases may simulate advanced exophytic retinoblastoma by the triad of retinal detachment, dilated retinal vessels, and appearance of subretinal mass.32 Differentiation of the two diagnoses is important to avoid unnecessary enucleation in Coat’s disease. Coats’ disease is histopathologically characterized by a triad of retinal vascular anomalies, sub-retinal and intraretinal cholesterol deposits, and intraretinal PAS positive deposits. It is typically seen unilaterally in males. It has a bimodal presentation, a peak in the first decade, and a small peak in young adulthood associated with hyperlipidemia. Ocular presentations are leucocoria, strabismus, telengiectatic vessels and microaneurysms especially in the temporal quadrant, and intraretinal or subretinal yellowish exudates with or without exudative detachment. Advanced cases may present with blind eyes with cataract, rubeosis iridis, glaucoma, or phthisis bulbi. In 1908, Scottish ophthalmologist George Coats (1876–1915) described the disease. Hallmarks of cone degeneration include the triad of progressive central acuity loss, color vision disturbances, and photophobia.26 Macular findings include granular mottling, metallic sheen, or foveal atrophy. In contrast to retinitis pigmentosa, disc pallor, arteriolar pigmentation and pigmentary changes are not seen. Electroretinogram at 30 Hz flicker or response to red light is severely affected. Dark adaptometry can differentiate cone and rod system abnormalities. Individuals with early presentation usually have severe disease. Visual acuity decreases progressively with age. Familial amyloidotic polyneuropathy (FAP) is characterized by peripheral neuropathy, cardiomyopathy, and vitreous opacity (amyloidosis). It is caused by mutations in the transthyretin gene (chromosome18 q11.2–q12.1), which leads to aggregation of betapleated sheet proteins in various tissues. Only FAP I and FAP II have vitreous involvement. Ocular manifestations include dimness of vision, decreased tear production, conjunctival perilimbal microaneurysms, reduction in corneal sensitivity, neurotrophic ulcers, scalloped or indented appearance of pupillary margin, multiple small dots or foot plates in the posterior lens surface (pseudopodia lentis), glaucoma, !


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yellow vitreous deposits (cobweb, glass wool, or cotton wool appearance), and perivascular retinal infiltrate or sheathing.21 Systemic prognosis is poor. Familial amyloidotic polyneuropathy type IV or hereditary gelsolin amyloidosis is characterized by the triad of ‘‘corneal lattice dystrophy, progressive bilateral facial paralysis and cutis laxa.’’33 Kearns Sayre syndrome is a mitochondrial cytopathy characterized by a triad of chronic progressive external ophthalmoplegia, retinitis pigmentosa, and cardiac conduction defects (heart block).34 Onset is early, in the first or second decade, with bilateral ptosis with limitation of ocular movements. Other systemic features are ataxia, proximal muscle weakness, deafness, diabetes, and short stature. Cerebrospinal fluid (CSF) shows increased protein concentration. Biopsies of the muscles of these patients demonstrate ‘‘ragged red fibers.’’ The triad was first described in 1958 by American ophthalmologists Thomas P. Kearns (born 1922), and George Pomeroy Sayre (born 1911). Norrie’s disease (Oculoacousticocerebral degeneration) is characterized by a triad of retinal malformation or dysplasia, deafness, and mental retardation.35 It is an X-linked recessive disorder which affects males. Diseased boys become blind at birth or in early infancy. The disease is caused by mutation in the NDP gene on chromosome Xp11. Presumed ocular histoplasmosis syndrome (POHS) is a triad of multiple white atrophic scars (histo spots), peripapillary pigmentary changes, and maculopathy due to choroidal neovascularization in the absence of vitreous cells.36 It is bilateral in 60% of cases. Association with HLA B7 and HLA DR2 is known. This condition is believed to be secondary to exposure to fungus, Histoplasma capsulatum, supported by occurrence in typical geographic locations of Histoplasma (Mississippi-Missouri River Valley). The choroidal neovascularization usually develops at 20–45 years of age, in about 5% of cases, mostly associated with old macular histo spot, and occasionally within the peripapillary lesion.10 The classical triad of retinitis pigmentosa consists of pale optic discs, attenuated retinal arterioles, and bony spicule pigmentation.37 It is a group of diffuse retinal dystrophies initially predominantly affecting the rod photoreceptor cells with subsequent degeneration of cones (rod-cone dystrophy). It is the most common hereditary fundus dystrophy. Other ocular findings are posterior subcapsular cataract, myopia, astigmatism, primary open angle glaucoma, keratoconus, optic disc drusen, cystoid macular edema, epimacular membrane, vitreous cells, posterior vitreous detachment, and Coats-like disease. Schwartz Matsuo syndrome is characterized by a triad of rhegmatogenous retinal detachment, cells in anterior chamber, and elevated intraocular pressure, often in the evening.38,39 The cells in the anterior


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chamber and glaucoma resolve after retinal reattachment. Typically, patients are young males with traumatic retinal detachments with peripheral breaks (dialysis) and tears of the nonpigmented epithelium of the pars plana or plicata of the ciliary body.40 It has been shown that the rod outer segments block the trabeculum, causing glaucoma, and these outer segments mimic the anterior chamber cells. The name is derived from the American ophthalmologist A. Schwartz and the Japanese ophthalmologist N. Matsuo. Stargardt disease is a triad of a bull’s-eye maculopathy, fundus flavimaculatus fleks, and a silent or dark choroid on fluorescein angiography.41 It is the most common macular dystrophy. The ABCA4 gene (chromosome 1p22) is implicated in its causation, causing diffuse deposition of lipofuscin within retinal pigment epithelium. The disease is transmitted in an autosomal recessive manner. Children present at the first or second decade with decrease in central vision which may be out of proportion to macular disease. The macula may show non-specific mottling, beaten bronze or snail slime appearance, and geographic atrophy, which may have a bull’s-eye configuration. Optical coherence tomography shows thinning at the fovea. Visual prognosis is usually poor. The disease was discovered in 1909 by Karl Stargardt (1875–1927), a German ophthalmologist.

NEURO-OPHTHALMOLOGY Balint’s syndrome is a disorder of visuospacial relationships resulting from bilateral occipitoparietal lesions. It is characterized by the triad of simultanagnosia, optic ataxia, and acquired oculomotor apraxia.42 Simultanagnosia is the failure to integrate multiple elements of a scene to form the total picture. In optic ataxia or misreaching, the patients reach for an object as if they were blind; there is a disconnection between visual input and the motor system. Acquired ocular motor apraxia (‘‘spasm of ftxation’’ or ‘‘psychic paralysis of gaze’’) involves the loss of voluntary movement of the eyes while fixating on a target. Hungarian neurologist Reszo¨ (Rudolf) Balint (1874– 1929) first described this triple symptom complex. Gordon Holmes (1876–1965) described spatial disorientation associated with this syndrome. The syndrome is also sometimes called Balint-Holmes syndrome. Charles Bonnet syndrome is a triad of complex visual hallucinations, ocular pathology causing bilateral visual deterioration, and preserved cognitive status.43 However, some patients may have simple unformed hallucinations which later evolve into complex ones. Patients with Charles Bonnet syndrome have a clear sensorium and are aware that the visions are not real. Although most commonly it

involves direct damage to the visual system (e.g., agerelated macular degeneration, glaucoma), it may also result from cerebral pathology interrupting connections between the eye and the occipital cortex (deafferentation of visual cortex).44 Charles Bonnet (1720– 1793), a Genevan naturalist and philosophical writer, described the syndrome in his 87-year-old grandfather, who was nearly blind from bilateral cataracts but perceived men, women, birds, carriages, buildings, tapestries, and scaffolding patterns. The Foster Kennedy syndrome (Gowers-PatonKennedy syndrome, Kennedy’s phenomenon, or Kennedy’s syndrome) consists of the triad of optic atrophy, contralateral papilledema, and anosmia (or hyposmia). The syndrome occurs due to lesions in the olfactory groove area, sphenoid ridge or, in rare cases, the frontal lobes.45 This syndrome is due to optic nerve compression, olfactory nerve compression, and increased intracranial pressure (ICP) secondary to a mass. The syndrome gets its name from IrishAmerican neurologist Robert Foster Kennedy (1884– 1952) and Sir William Richard Gowers (1845–1915), a British neurologist. Absence of the septum pellucidum and corpus callosum can be found as part of DeMorsier’s syndrome (septo-optic dysplasia), along with bilateral optic nerve hypoplasia and pituitary abnormalities. These patients should have pituitary hormone studies because they may require supplementation. In Horner’s syndrome (Horner syndrome, BernardHorner syndrome, Claude Bernard-Horner syndrome, or oculosympathetic palsy) there is a classical triad of mild (1–2 mm) ptosis, miosis, and anhidrosis.46 Von Passow syndrome is a form of Horner syndrome with iris heterochromia (heterochromia iridis). Horner’s syndrome results from a lesion to the sympathetic pathways that supply the head and neck, including the oculosympathetic fibers. Patients have a mild (less than 2 mm) ptosis of the upper lid and inverse ptosis of the lower lid due to palsy of the Muller muscle in the upper and lower lids, causing a decreased palpebral aperture. There is miosis in the involved side, as the sympathetic system along with the dilator pupillae is involved. For the same reason, the pupil takes longer time to dilate at dark (’’dilation lag‘‘) resulting in more prominent anisocoria at dark. The lesion of sympathetic pathways may be in first-order neurons or the central Horner (between the hypothalamus and ciliospinal center of Budge at spinal cord level C8-T2); in the second-order neurons or preganglionic Horner (from the spinal cord to superior cervical ganglion, travelling in the cervical sympathetic chain through the brachial plexus, over the pulmonary apex); or may involve third-order neurons or postganglionic Horner (from the superior cervical ganglion, travelling through the adventitia of the internal carotid artery to the ophthalmic nerve, supplying the Muller muscle and dilator pupillae Seminars in Ophthalmology


Triads in Ophthalmology via a long ciliary nerve). The vasomotor and sudomotor fibers to the face exit the superior cervical ganglion and ascend along the external carotid artery. Thus, anhidrosis or decreased sweating in the ipsilateral side of the face is seen in the preganglionic or central Horner only. Impaired hemi-facial (or hemibody) flushing seen in children with sympathetic denervation to the face is called Harlequin sign. Cocaine, 4–10% solution in both eyes, dilates the normal pupil but not the Horner’s pupil. A postcocaine anisocoria of more than 0.8 mm is sufficient to diagnose Horner’s syndrome. Cocaine blocks reuptake of the neurotransmitter norepinephrine from the synaptic cleft. The absence of endogenous norepinephrine in the synapse in Horner’s leads to poor dilation with cocaine. Apraclonidine (0.5% or 1%), a weak alpha1-agonist and a strong alpha2agonist dilates Horner pupils due to upregulation of alpha1 receptors. However, upregulation of the alpha receptor needs 5–8 days, so the apraclonidine test may be false negative in an acute setting.47 Hydroxyamphetamine 1% stimulates the release of stored endogenous norepinephrine from the postganglionic axon terminals into the neuromuscular junction at the iris dilator muscles. In postganglionic thirdorder neuron lesions, it fails to dilate as there is no presynaptic store of norepinephrine in the neuromuscular junction, in contrast to lesions of first- or secondorder neurons. Ischemic optic neuropathy was described classically as a triad of vision loss, afferent pupillary defect, and a swollen optic nerve.48,49 Non-arteritic anterior ischaemic optic neuropathy is caused by occlusion of the short posterior ciliary arteries, resulting in partial or total infarction of the optic nerve head. It presents in the sixth to seventh decades with sudden, painless, monocular visual loss, frequently discovered on awakening, suggesting that nocturnal hypotension may play an important role. Visual acuity is normal or only slightly reduced in about 30% of patients.10 The remainder have moderate to severe impairment. Visual field defects are typically inferior altitudinal but central, paracentral, quadrantic, and arcuate defects may also be seen. Dyschromatopsia is usually proportional to the level of visual impairment, in contrast with optic neuritis, in which color vision may be severely impaired when visual acuity is reasonably good. The pathognomonic triad of Leber’s hereditary optic neuropathy is circumpapillary telangiectatic microangiopathy, swelling of the nerve fiber layer around the disc (pseudoedema), and absence of leakage from the disc or papillary region on fluorescein angiography.50 It is due to mutations in maternally inherited mitochondrial DNA. It is seen typically in males of 15–35 years of age, although females of 10–60 years age may also be affected. The pupillary light reactions may remain fairly brisk. Visual prognosis is poor. !


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Most patients suffer severe visual loss due to optic atrophy with a final visual acuity of 6/60 or less. The 11778 mutation carries the worst prognosis. Neuroretinitis due to cat scratch disease is a triad of abrupt vision loss, unilateral optic disc swelling, and macular edema (macular star).51 About 25% of neuroretinitis cases are idiopathic (Leber idiopathic stellate neuroretinitis). Cat-scratch fever is responsible for 60% of cases. Other causes include syphilis, Lyme disease, mumps, and leptospirosis. Signs of optic nerve dysfunction are usually mild or absent because visual loss is largely due to macular involvement.10 A macular star typically develops as the disc swelling gradually resolves. The macular star takes 6–12 months to resolve, resulting in near-normal visual acuity commonly. Ocular tilt reaction (OTR) is the triad of skew deviation with ocular torsion and a head tilt.52 This triad of signs is typically observed with lesions of the lateral pontomedullary junction or the paramedian thalamic-mesencephalic region. Skew deviation is a vertical misalignment of the visual axes caused by a disturbance of prenuclear vestibular inputs to the oculomotor nuclei. The hypertropia may be the same (comitant) in all positions of gaze, or it may vary and even alternate. When skew deviation is incomitant, it may mimic an isolated oblique palsy by the Bielschowsky three-step test. Assessment of ocular torsion in both eyes may help to distinguish the two.3 The OTR is usually caused by an imbalance in otolithocular and otolith-collic reflexes. Optic neuritis (ON) is the most common cause of acute unilateral visual loss in young adults, having an incidence of 1–5 in 100,000 per year. Women are more often affected than men, with a peak manifestation between the ages of 15 and 49.53,54 Typical triad of optic neuritis is subacute unilateral loss of vision, periocular pain, and impaired color vision.55 There is pain on ocular movements, especially on elevation; RAPD is present, and contrast sensitivity and brightness sense are severely affected. The symptoms usually worsen over the course of a few days to two weeks, but spontaneously recover in 490% of cases after 2–3 weeks, regardless of steroid treatment. Response to intravenous steroid may be dramatic. Orbital apex syndrome (OAS) is characterized by a triad of ophthalmoplegia due to paresis of the third, fourth, and sixth cranial nerves; anesthesia in the region of supply of ophthalmic division of the fifth nerve; and amaurosis due to involvement of the optic nerve.56 The cause is a lesion in orbit involving the optic canal and superior orbital fissure. The cavernous sinus syndrome (CSS) may include the features of an OAS with involvement of the maxillary branch of the trigeminal nerve (V2) and oculosympathetic fibers.57 Superior orbital fissure syndrome (SOFS) or Rochon– Duvigneaud syndrome is due to lesions immediately anterior to the orbital apex, including the structures


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exiting the annulus of Zinn and often those external to the annulus, causing multiple cranial nerve palsies in the absence of optic nerve pathology.56 Ross syndrome is a rare focal dysautonomia. It is characterized by the triad of tonic pupil, absent muscle stretch reflexes, and progressive segmental impairment of sweating.3 Ross described this syndrome in 1958.58 Tonic pupil with absent muscle stretch reflex without anhidrosis is called Adie (or Holmes Adie) syndrome. Some patients have compensatory hyperhidrosis in the early stages of Ross syndrome. In the late stage, most patients have generalized anhidrosis. Sympathetic nervous system abnormalities like postganglionic Horner syndrome and mild postganglionic sympathetic denervation of the heart have been described. However, its benign and slowly progressive nature differentiates it from other dysautonomias. Spasmus nutans is a triad of nystagmus (unilateral or bilateral asymmetric, high frequency, horizontal), head nodding, and torticollis.59 It is frequently asymmetrical with increased amplitude in abduction. It typically presents between three and 18 months of age. Idiopathic variety resolves spontaneously by three years of age. Other causes are glioma of the anterior visual pathway, empty sella syndrome, and porencephalic cyst. Glioma of the optic chiasma must be ruled out in every patient with monocular nystagmus.

OCULOPLASTY AND OCULAR ADNEXA Blepharophimosis syndrome (BPES) is a triad of horizontal shortening of the palpebral fissures (blepharophimosis), congenital ptosis, and epicanthus inversus (epicanthic fold more prominent in the lower lid).60 BPES has three types: either autosomal dominant with or without premature ovarian failure, and sporadic. It is caused by mutation of the FOXL2 gene at 3q23. Other associated ocular anomalies are telecanthus, tarsal plate hypoplasia, generalized tightness of the lid skin (often causing lower eyelid ectropion), prominent vertical brow hair—often extending across the nasal bridge, flat brow, laterally displaced lower punctum, refractive error, and strabismus. Y–V plasty or Mustarde´ Z-plasty followed by bilateral ptosis surgery is usually required. Direct carotid-cavernous fistula is clinically characterized by Dandy’s triad (pulsatile proptosis, conjunctival chemosis, and ocular bruit).61 Direct fistulae are high-flow shunts in which carotid artery blood goes directly into the cavernous sinus through a defect in the wall of the intracavernous portion of the internal carotid artery, mostly after trauma. Other ocular features are dilated corkscrew scleral or episcleral vessels, conjunctival injection and chemosis, elevated

IOP on the involved side, dilated tortuous retinal veins, ischemic maculopathy or retinal artery occlusion, enlarged cup-to-disc ratio, ophthalmoplegia (often cranial nerve 6), anterior segment ischemia, and blood in Schlemm’s canal. Orbital bruit is classically abolished by ipsilateral carotid compression. Management is by endovascular embolization with coils or balloons, which may be transvenous or transarterial. Crouzon syndrome consists of a triad of premature synostosis, midfacial hypoplasia, and exophthalmos.62–64 It is caused by premature fusion of the coronal and sagittal sutures. Most patients have exotropia with a V pattern and vision loss due to optic atrophy. Other ocular features are hypertelorism, exposure keratopathy, luxation of globe beyond the lids, ametropia, amblyopia and optic atrophy, due to chronic papilloedema and cerebral hypoperfusion secondary to sleep apnoea. Mutation in the fibroblast growth factor receptor (FGFR) gene is implicated as the cause. Mutation involves chromosome 10q25-26, involving fibroblast growth factor receptor (FGFR2) as well as the FGFR3 gene when associated with acanthosis nigricans.65 Systemic features include short anteroposterior diameter of head, wide cranium, parrot beak nose, frog-like facies, prognathism, and inverted V-shaped palate. Ocular associations include blue sclera, cataract, ectopia lentis, glaucoma, coloboma, megalocornea, and optic nerve hypoplasia.10 Meningioma (of the optic nerve sheath) is denoted by a triad of optic atrophy, optocilliary shunt vessels, and painless, slowly progressive monocular vision loss.66 Meningiomas have proliferation of benign meningothelial cells in whorls. Calcified psammoma bodies are commonly found. They cause damage by compression of adjacent structures. Spencer’s triad is optociliary shunts, optic atrophy, and optic nerve meningioma.67 Meningioma produces the railroadtrack sign on CT, due to the hyperdense meningioma of the optic nerve sheath and normal or atrophic optic nerve inside the optic nerve sheath. They typically affect middle-aged women. Histological types are meningothelial and psammomatous. Removal is usually not required in middle-aged patients with slow-growing tumors due to good prognosis. Surgical excision is required in young patients with aggressive tumors, especially in a blind eye. Prognosis for life is good in adults, although the tumor may be more aggressive in children.

SYSTEMIC DISEASES WITH OCULAR INVOLVEMENT The ‘‘allergic triad’’ of symptoms for atopy consists of eczema (atopic dermatitis), hay fever (seasonal allergic rhinitis), and asthma.68 They also have a tendency to have food allergies. Very commonly, they are Seminars in Ophthalmology


Triads in Ophthalmology associated with allergic conjunctivitis characterized by watering and itching sensation in the eye, conjunctival congestion, papillary reaction, chemosis, and lid edema. This is a type-1 hypersensitivity mediated by IgE. The triad of unilateral deafness, corneal anesthesia, and a mild lower motor neuron facial nerve paresis is virtually pathognomonic of cerebellopontine angle mass, usually a vestibular schwannoma. Unsteadiness of gait caused by compression of the vestibular nerve often is present in stage 2. Ocular manifestations are exposure keratopathy, lagophthalmos, and Bruns nystagmus (ipsilateral coarse cerebellar horizontal jerk nystagmus and fine high-frequency vestibular nystagmus in the other eye). Churg strauss syndrome is a rare disorder characterized by the triad of severe asthma, eosinophilia, and systemic vasculitis. Churg and Strauss, in their original 1956 article, outlined a triad of pathologic features associated with the disease: an eosinophilic tissue infiltration, granuloma formation, and a necrotizing vasculitis involving small- and medium-sized vessels.69 Ocular manifestations are diffuse orbital inflammation, myositis, lacrimal gland inflammation, eyelid inflammation, conjunctival inflammation and granulomas, marginal ulcerative keratitis, anterior uveitis, episcleritis, ischemic optic neuropathy, retinal vasculitis, central or branch retinal arterial occlusion (CRAO and BRAO), central retinal venous occlusion (CRVO), anterior ischaemic optic neuropathy (AION), posterior scleritis, cranial nerve palsies, and amaurosis fugax. Cushing’s triad is a feature of raised intracranial pressure leading to cerebral herniation and fatal brainstem compression.70 It consists of bradycardia, hypertension, and irregular respiration (respiratory depression).71 Ophthalmic features include papilloedema, bilateral sixth cranial nerve palsy, and pupillary disturbances. Cushing’s triad is named after American neurosurgeon Harvey Williams Cushing (1869–1939). Felty syndrome is a triad of rheumatoid arthritis (RA), splenomegaly, and neutropenia.72 Ocular findings are secondary sjogren syndrome (dry eye) and episcleritis. This syndrome is seen in less than 1% of patients with seropositive rheumatoid arthritis, commonly in females. Classic Felty syndrome has high RA factor titres and it usually occurs after 12 years or more of rheumatoid arthritis. Infections related to granulocytopenia are the major cause of death. It is named for American physician Augustus Roi Felty (1895–1964). Systemic features include fever, anaemia and thrombocytopenia and, in some cases, anorexia, general malaise, weight loss, recurrent infections, brown pigmentation of exposed skin surfaces, peripheral neuropathy, carpal tunnel syndrome, arteritis, pain in the upper left quadrant of the abdomen, and Raynaud’s syndrome. !


9

Gardner’s syndrome is characterized by a triad of multiple polyps of the colon, multiple osteomas (of the skull, mandible, and long bones), and soft tissue tumors (epidermoid cysts, lipomas and fibromas).73 Gardner’s syndrome is a variant of familial adenomatous polyposis (FAP), which is an autosomal dominant disorder. Adenomatous polyposis coli (APC) gene at chromosome 5q is involved in the disease. The ocular feature is congenital hyperplasia of the retinal pigment epithelium (CHRPE). Singular lesions are not pathognomonic of FAP, but the presence of four or more lesions is highly specific for the diagnosis of familial polyposis of the colon. Bilateral, multiple, widely separated, frequently oval or spindle-shaped lesions of variable size are associated with hypopigmentation at one margin. They are usually located in the midperiphery of the fundus. Malignant changes in the form of adenocarcinomas have been reported, but are rare. The syndrome is named for Eldon J. Gardner (1909–1989), an American geneticist who first described it in 1951.74 In type 2 Gaucher disease (acute infantile neuropathic Gaucher’s disease), a triad of trismus, strabismus, and retroflexion of the head is seen.75,76 Gaucher disease type 2 is caused by mutations in the GBA gene (betaglucocerebrosidase, chromosome 1q21). It is inherited in an autosomal recessive pattern. Usually, patients present within six months of age with hepatomegaly. Most patients show signs of involvement of the cranial nerve nuclei and extrapyramidal tracts. Features include enlarged liver and spleen, severe and progressive brain damage, eye movement disorders, spasticity, seizures, rigidity of neck and limbs (hypertonia), failure to thrive, and a poor ability to swallow. Affected children usually die by the age of two years. The disease is named after the French doctor Philippe Gaucher (1854–1918), who described it in 1882. In Goldenhar syndrome (Oculoauriculovertebral dysplasia or Branchial arch syndrome), the classical triad includes ocular dermoid cyst, preauricular skin tags, and vertebral dysplasia (cervical hemivertebra).77 It has also been described as a triad of craniofacial microsomia, ocular dermoid cysts, and spinal anomalies.78 It is associated with anomalous development of the first and second branchial arches. It is named after Belgian-American ophthalmologist Maurice Goldenhar (1924–2001). Other ocular features are upper lid coloboma, microphthalmos, disc coloboma, and Duane retraction syndrome. Mental handicap is seen, especially in association with microphthalmos. Gradenigo’s syndrome (Gradenigo-Lannois syndrome) is a manifestation of inflammation of the petrous apex (petrous apicitis) due to otitis media and mastoiditis involving the apex of the petrous temporal bone.79 The classical triad consists of periorbital unilateral pain due to trigeminal nerve involvement, diplopia due to sixth nerve palsy, and persistent otorrhea.


10 K. Tripathy et al. However, the classical syndrome due to otitis media is very rare in current era of antibiotics. It was first described by Giuseppe Gradenigo in 1904. Graves disease is clinically defined by a triad of exophthalmos, pretibial myxedema, and hyperthyroidism.80 The classical symptom triad of exophthalmos, goiter, and tachycardia (Merseburger triad) was described by German physician Karl Adolph von Basedow (1799–1854) and Irish surgeon Robert James Graves (1796–1853), so the disease is also known as Basedow-Graves disease.81,82 Thyroid eye disease consists of soft tissue changes, exophthalmos, myopathy, optic neuropathy, and eyelid changes. Pretibial myxoedema is an infiltrative dermopathy characterized by waxy discolored induration of skin on the anterior aspect of the legs, extending onto the dorsum of the foot. Risk factors for thyroid eye disease are smoking, female sex, and radioiodine therapy. Systemic control of thyroid status has no effect on exophthalmos. Hemochromatosis is characterized by the classic triad of bronze complexion, hepatomegaly, and diabetes mellitus. Other features are hypogonadism, cardiomyopathy, arthropathy, and cirrhosis. Ocular features are dry eye, rusty-brown perilimbal conjunctival, and scleral discoloration. Hand-Schuller-Christian disease is a chronic disseminated form of histiocytosis involving both soft tissues and bones in children of 2–5 years or older children and adults of either sex. It is characterized by a triad of proptosis, diabetes insipidus (from involvement of posterior pituitary), and osteolytic defects in the skull.83 The proptosis usually appears later than bone lesions, and may be unilateral or bilateral.84 Other rare ocular manifestations include strabismus due to involvement of extraocular muscles and vision loss due to optic nerve involvement. Systemic features are involvement of the flat bones of the skull, ribs, pelvis, scapula; tooth loss caused by apical and gingival infiltration in older patients; chronic otitis media and otitis externa; short height; hyperprolactinemia; and hypogonadism. It is named after American pediatrician Alfred Hand (1868–1949), Austrian neurologist and radiologist Artur Schu¨ller (1874–1957), and American physician Henry Asbury Christian (1876–1951). The classic triad of Henoch-Scho¨nlein purpura consists of purpuric rash occurring on the lower extremities, abdominal pain or renal involvement, and arthritis.85 Patients with Henoch-Scho¨nlein purpura may develop neurologic or visual dysfunction. The neurologic symptoms and signs may be caused by accompanying hypertension or cerebral arteritis. Some patients develop visual loss from intraorbital or intraocular hemorrhage. In these cases, one or both eyes may be lost from intractable glaucoma. Hyperviscosity syndrome typically presents with a triad of bleeding diathesis (gingival, epistaxis,

gastrointestinal, intraretinal, or postsurgical bleeding), visual disturbances (from retinal vein vascular abnormalities, retinal vein thrombosis, diplopia, or optic nerve edema), or focal neurologic findings (headache, vertigo, deafness, syncope, ataxia, diplopia, or even coma, cerebral hemorrhage, seizures and chorea).86 Causes for hyperviscosity syndrome are circulating serum immunoglobulins (Waldenstro¨m macroglobulinemia and multiple myeloma), increased cellular blood components in leukemias, polycythemia, and the myeloproliferative disorders. Other ocular features are conjunctival telangiectasia and intraretinal hemorrhages. Klippel–Trenaunay syndrome (KTS, Angiosteohypertrophy) is a sporadic disease characterized by a triad of cutaneous hemangiomata, especially of an extremity, hemihypertrophy of bone and soft tissue of the affected limb, and varicosities (naevus variqueux osteohypertrophique). The eye ipsilateral to the affected limb is generally affected. Ocular features are orbital varices and retinal varicosities, glaucoma, cataracts, heterochromia, and Marcus-Gunn pupil. Lambert Eaton myasthenic syndrome (LEMS) presents with classic triad of proximal muscle weakness, areflexia, and dysautonomia.87 It is due to autoantibodies against presynaptic voltage gated calcium channels (VGCC). In contrast, myasthenia gravis (MG) is due to autoantibodies against post-synaptic acetyl choline receptors. LEMS starts with mild upper leg weakness, in contrast to MG, which is characterized by ptosis and diplopia. Paresis of ocular muscles, diplopia, and ptosis are relatively uncommon in LEMS. Pupillary light reflex may be sluggish. The triad of a central Horner syndrome, ipsilateral ataxia, and contralateral hypalgesia clinically identifies as lateral medullary infarction (Wallenberg’s lateral medullary syndrome).88 They are caused by involvement of descending sympathetic fibers (first-order neurons), inferior cerebellar peduncle, and lateral spinothalamic tract, respectively. This is due to occlusion of posterior inferior cerebellar artery or vertebral artery. The syndrome gets its name from German neurologist Adolf Wallenberg (1862–1949). Classic miller fisher syndrome (MFS) is a rare form of Guillain–Barre´ syndrome (GBS), characterized by descending paralysis. Eyes are involved early and a characteristic triad of bilateral ophthalmoplegia, ataxia, and areflexia develops.89 Anti-GQ1b ganglioside antibodies are present in 90% of cases. MFS may mimic as ocular myasthenia. Typically, ophthalmoplegia starts as a symmetric paresis of upgaze; horizontal gaze is later involved and downgaze is not involved or involved last. Ptosis is not a feature and pupillary involvement is variable. Bell’s phenomenon is often preserved. Atypical MFS is not uncommon with asymmetries between the eyes, abduction or adduction palsies, and occulomotor nerve palsies. Atypical MFS may also present with Seminars in Ophthalmology


Triads in Ophthalmology bilateral ptosis with preserved ocular motility (‘‘inverse’’ Miller-Fisher syndrome). An association triad of neurofibromatosis type 1, pheochromocytoma, and somatostatin-rich carcinoid tumor at ampulla is now known.90 Thus, the duodenum should be carefully examined in any patient with neurofibromatosis who undergoes laparotomy for pheochromocytoma. The ophthalmic features of neurofibroma type 1 are optic nerve glioma, spheno-orbital encephalocele, eyelid neurofibromas, prominent corneal nerves, mammillations of iris, congenital ectropion uvae, Lisch nodule, choroidal nevi, and retinal astrocytoma. Progressive multifocal leukoencephalopathy (PML) is characterized pathologically by a triad of multifocal demyelination, hyper-chromatic enlarged oligodendroglial nuclei, and enlarged bizarre astrocytes with lobulated hyperchromatic nuclei.91 PML presents insidiously with homonymous hemianopia, cortical blindness, language disturbances, motor weakness, sensory loss, incoordination, conjugate gaze palsy, and dementia. Sampter’s triad is characterized by asthma, nasal polyps, and allergy to aspirin or non-steroidal antiinflammatory drugs (NSAIDs). A 44-year-old lady with Sampter’s triad has been reported to develop an acute attack of asthma after a single dose of topical ketorolac drop.92 Sjogren’s syndrome (SS) consists of a triad of symptoms including dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and rheumatoid arthritis.93 Dry eye is due to deficiency of the aqueous layer of tear film. Rarely, Adie’s pupil has been reported. Systemic features are enlargement of salivary glands, and occasionally of lacrimal glands, dry nasal passage, diminished vaginal secretions, Raynaud phenomenon, and cutaneous vasculitis. It was first described in 1933 by Swedish ophthalmologist Henrik Sjo¨gren. Sturge–Weber syndrome (encephalotrigeminal angiomatosis) is characterized by the triad of skin [nevus flammeus (cutaneous hemifacial hemangioma)], central nervous system (leptomeningeal angiomatosis, cerebral gyriform calcifications), and ocular findings (choroidal hemangioma and glaucoma). It is a sporadic disorder. Glaucoma develops ipsilateral to the facial haemangioma, especially if the lesion affects the upper eyelid. Isolated trabeculodysgenesis and raised episcleral venous pressure are causative factors in early- and late-presenting glaucoma, respectively. Diffuse choroidal hemangioma presents at the second decade, and fundus has typical diffuse tomato ketchup appearance of the retina, especially at the posterior pole. Secondary retinal cystoids degeneration, exudative retinal detachment, and neovascular glaucoma may complicate diffuse choroidal hemangioma. Suprasellar germ cell tumors (ectopic pinealomas or atypical teratomas) have the symptom triad of !


11

diabetes insipidus, visual disturbances, and panhypopituitarism.94 They are germ cell tumors in children. Diabetes insipidus due to involvement of the neurohypophysis is seen in almost all patients. Visual diminution with bitemporal hemianopia is seen in 85–90% cases. Tuberous sclerosis (Bourneville disease or epiloia) is a triad of epilepsy, low intelligence quotient (mental retardation), and adenoma sebaceum or facial angiofibroma. This is called Vogt’s triad of tuberous sclerosis in honor of German neurologist Heinrich Vogt, who described this in 1908.95 Ocular involvement is in the form of retinal or optic nerve astrocytic hamartoma (or phacoma) in 50% of patients and adenoma sebaceum of the lids.96 The retinal lesions generally do not require treatment, as they do not grow. Astrocytic hamartomas, found in the retina or brain, are often calcified. Other findings include cafeáu-lait spots, ash leaf depigmentation (shagreen patches), and periungual fibromas. Virchow’s triad consists of hypercoagulability of blood, abnormality of blood flow, and endothelial injury.97 They predispose to thrombus formation and therefore retinal vascular occlusions. The name is linked to famous German scientist Rudolf Carl Virchow (1821–1902), though he did not describe the triad. Wegner’s granulomatosis is a histological triad of necrotizing vasculitis (granulomatous and disseminated small vessels), granulomatous inflammation, and tissue necrosis.98 Ocular involvement, mostly orbital, occurs in up to 50% of cases. Ocular manifestations are painful proptosis, reduced ocular motility, chemosis, uveitis, scleritis, keratitis, optic nerve edema, nasolacrimal duct obstruction, dacryocystitis, and occlusive retinal periarteritis. The classic clinical triad of this systemic inflammatory condition includes necrotizing granulomas of the upper and lower respiratory tract, necrotizing vasculitis of the lung, and glomerulonephritis.76 Biopsies of orbital tissues may not show the classic triad of vasculitis, tissue necrosis, and granulomatous inflammation. Wernicke’s encephalopathy is a triad of nystagmus and ophthalmoplegia, unsteadiness of stance and gait (ataxia), and mental status change.99 Mental status changes include confusion, apathy, inability to concentrate and, if left untreated, coma and death. The typical triad is seen in only 16% of cases. It is seen due to thiamine (vitamin B1) deficiency. In particular, this disease is seen in adults misusing alcohol or those having acquired immune deficiency syndrome (AIDS). Ocular involvement is seen in 29% of cases. Ocular manifestations include symmetrical or asymmetrical palsies of lateral recti or other ocular muscles, and conjugate-gaze palsies due to involvement of the pontine tegmentum and of the sixth and third cranial nerve nuclei. Patients may present with sluggish reaction of the pupils to light, light-near dissociation,

12 K. Tripathy et al. bilateral visual disturbances with optic disc edema, with retinal hemorrhages.

CONCLUSION


Multiple ocular conditions, along with systemic diseases, have been associated with three typical clinical signs or symptoms in the literature. Thorough knowledge about these clinical signs can be helpful in correlating ocular and systemic signs and symptoms and can aid in establishing a comprehensive diagnosis.

METHOD OF LITERATURE SEARCH We searched PubMed, Google scholar, and Google books using the phrases triads, triad in ophthalmology, triad and systemic diseases, and ‘‘constellation of three signs’’ or constellations of three symptoms. Articles in English were reviewed; in addition, articles in other languages were reviewed using their English abstracts.

ACKNOWLEDGMENTS The authors sincerely acknowledge technical support and proofreading by Trina Sengupta Tripathy, without which this manuscript would not have materialized.

DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

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