Crystalline retinopathy

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Disease Entity

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Disease

Crystalline retinopathy is a term that encompasses a wide spectrum of clinical conditions characterized by refractile deposits in the retina, which have varied origin and composition.

Etiology

  • Diseases
    • Systemic
      • Metabolic
        • Cystinosis
        • Primary hyperoxaluria
        • Sjogren Larsson syndrome
      • Kjellin syndrome
      • Calciphylaxis
    • Ocular
      • Chronic retinal detachment
      • Macular telangiectasia
      • Gyrate atrophy
      • Refractile or calcified drusen
      • Neovascular AMD
      • Uveitic crystalline maculopathy
      • Radiation maculopathy
  • Drugs
    • Methoxyflurane (secondary oxalosis)
    • Nitrofurantoin
    • Tamoxifen
    • Anastrozole
    • Flupentixol
  • Toxic
    • Ingestion
      • Canthaxanthin
      • Lutein/zeaxanthin
      • Ethylene glycol (secondary oxalosis)
    • Inhalation
      • Talc (Methamphetamine abuse)
    • Intravenous
      • Talc (Methylphenidate abuse)
  • Iatrogenic
    • Retinal caratopathy
    • Intravitreal injections
      • Triamcinolone acetonide
      • Ganciclovir
  • Embolic
    • Cholesterol
  • Miscellaneous
    • West African Crystalline Maculopathy

Risk Factors

Cardiovascular disease - predisposes to embolic type of crystalline retinopathy

General Pathology

  • Cystinosis -Intracellular cystine accumulation in various tissues with kidney and eye being most susceptible. Crystal deposition occurs in conjunctiva, cornea, all the retinal layers and choroid with diffuse RPE degeneration and depigmentation. [1]
  • Primary hyperoxaluria - Birefringent crystals have been reported histopathologically from episclera, sclera, conjunctiva, cornea, ciliary body, all layers of neuroretina, RPE and choroid. [2]
  • Sjogren Larsson syndrome - Accumulation of lipid and byproducts of lipid metabolism result in Muller cell damage and dysfunction, neuronal apoptosis and photoreceptor damage. Crystals in the inner nuclear layer are a marker of Muller cell damage. With disease progress, there is subretinal deposition due to lipofuscin accumulation. [3]
  • Calciphylaxis - Basophilic calcium salts within vessel walls. It can be histopathologically differentiated from oxalosis (differential diagnosis in the scenario of renal failure) by the lack of birefringence, predilection for intravascular deposition and sparing of choriocapillaris. [4]
  • Tamoxifen - Crystals may stain positively for glycosaminoglycans [5]
  • Methoxyflurane - Birefringent crystal deposits have been found in the intravascular, intra-retinal and sub-retinal (RPE) layers. [5]

Pathophysiology

  • Cystinosis - Autosomal recessive lysosomal storage disorder. A defect in CTNS gene leads to malfunction of cystinosin protein which is a lysosomal membrane transporter for cystine. This causes intracellular cystine accumulation in lysosomes. It has been suggested that crystal formation may result in abnormal increase in cell apoptosis. [3]
  • Primary hyperoxaluria - Autosomal recessive metabolic disorder due to deficient glyoxylate metabolism in the liver. Defects in the following genes are responsible: alanine-glyoxylate aminotransferase (AGXT) in type 1 disease , glyoxylate reductase/hydroxypyruvate reductase (GRHPR) in type 2 and 4-hydroxy-2-oxoglutarate aldolase (HOGA1) in type 3. There is eventual overproduction and overexcretion of oxalate. Oxalate combines with calcium ion to form insoluble calcium oxalate salt which deposits in various tissues. [1] [3]
  • Sjogren Larsson syndrome - Autosomal recessive disorder due to deficiency in fatty aldehyde dehydrogenase enzyme (ALDH3A2 gene) leading to abnormal metabolism of essential fatty acids. Accumulation of lipids leads to Muller cell disruption, crystal formation, retinal thinning, loss of macular pigment and oxidative stress. [3]
  • Calciphylaxis - Also known as calcific uremic arteriolopathy. It is a calcific thrombogenic microangiopathy that primarily affects dialysis patients with end-stage renal disease. Vascular occlusion and thrombosis occur secondary to medial wall microcalcification, intimal proliferation, and endovascular fibrosis of small-medium blood vessels, predominantly arteries. [4]
  • Tamoxifen - Ocular findings occur in patients who have taken a high dose (120-160mg BD) for more than a year or a cumulative dose of >100g or low dosage taken for a long time (at least 2 years). The drug accumulates in lysosomes leading to oxidative stress and eventually retinal neuronal degeneration.[5]
  • Methoxyflurane - The drug is metabolized to oxalic acid and fluoride ions. At cumulative doses of >16g, this leads to deposition of calcium oxalate crystals in various tissues like kidney and retina. Oxalate deposition also occurs in other causes of secondary oxalosis like ethylene glycol ingestion. [5]

Primary prevention

Yearly ophthalmological examination should preferably be done in patients receiving drugs which cause crystalline retinopathy.[5]

Diagnosis

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History

The following points should be elicited: [6][5]

  • history of breast cancer - tamoxifen, anastrozole
  • use of oral tanning agent - canthaxanthin
  • history of drug abuse - talc
  • history of prior general anesthesia - methoxyflurane
  • mental health history - flupentixol (anti-psychotic)
  • history of renal failure or dialysis - oxalosis, cystinosis, calciphylaxis
  • recurrent urinary tract infections - nitrofurantoin
  • ethylene glycol ingestion - secondary oxalosis
  • intake of kola nuts - West African Crystalline Retinopathy
  • prior retinal surgery - retinal caratopathy
  • prior intravitreal injections
  • family history - Bietti dystrophy
  • consanguinous marriage - Kjellin syndrome

Onset

  • Kjellin syndrome - onset of symptoms occurs in adolescence to adulthood and is slowly progressive

Physical examination

  • Cystinosis - Renal failure, cerebral calcification, hypothyroidism, diabetes mellitus, swallowing difficulty and distal myopathy
  • Hyperoxaluria - Urolithiasis, nephrocalcinosis
  • Sjogren Larsson syndrome - Triad of ichthyosis, cognitive impairment and spastic diplegia. Other findings include short stature, speech defects, short fingers and toes, seizures. [5]
  • Kjellin syndrome - spastic paraplegia, dementia
  • Calciphylaxis - Tender indurated skin plaques with palpable subcutaneous calcium deposits; end stage renal failure

Signs

Refractile retinal deposits are easily detected on fundoscopy. Their colour, location and pattern of distribution may give a clue towards the etiology of the crystals.

  • Cystinosis - Yellow crystals are deposited at the posterior pole with associated diffuse RPE mottling and atrophy. Older patients may show retinitis pigmentosa like picture with bone spicules. Crystals are also deposited on the conjunctiva, cornea, iris and may cause recurrent corneal erosions, band keratopathy, thickened iris and posterior synechiae [1] [3]
  • Oxalosis - There may be a hyperpigmented spot or plaque at the fovea surrounded by hypopigmentation due to concentration of crystals in the RPE. Diffuse deposition may give rise to a fundus albipunctatus or flecked retina like picture in methoxyflurane retinopathy. [1] The retinal findings can be divided into 4 grades: [2]
    1. Isolated perifoveal oxalate crystals - vision unaffected
    2. Islets or ringlets of RPE hyperplasia; may coalesce into a "charcoal like lesion" - good visual acuity
    3. Strand of subretinal fibrosis and/or fibroatrophic scarring; choroidal neovascularization may develop - dramatically reduced vision
    4. Non rhegmatogenous macular detachment

Retinal vascular disease and optic neuropathy have also been reported.

  • Sjogren Larsson syndrome - Glistening white crystals in parafoveal area; they gradually decrease in number as the disease progresses while RPE mottling increases. The macula lacks its normal dark appearance. Non retinal findings include colobomatous microphthalmos, congenital cataract and ichthyosis of the eyelid skin. [3] Interestingly, the corneas are clear, in contrast to the deep corneal opacities found in X-linked ichthyosis and ichthyosis vulgaris. [1]
  • Kjellin syndrome - Perifoveal yellow-white lesions with "flecked retina" or fundus flavimaculatus like appearance with surrounding pigment at the level of RPE. [5]
  • Calciphylaxis - Crystal deposition in the macula, within vessel walls (mainly arteries but also veins) and at arteriovenous crossings. Intravascular crystals may lead to ischemic manifestations like retinal artery occlusion. Findings include vessel wall sheathing, arteriolar attenuation and optic disc pallor. Calcific temporal artery involvement mimicking arteritic anterior ischemic optic neuropathy has also been rewgedz 4q i6k4 76lc968ported [4]
  • Chronic retinal detachment - Retinal dialysis, commonly inferotemporal in location, is the usual cause in these cases. Crystals are punctate, mainly localised in posterior pole and difficult to detect clinically. [5]
  • Tamoxifen - Golden refractile deposits usually clustered in the perifoveal area; may be associated with pigmentary changes. Macular edema is present in severe cases. [5]
  • Canthaxanthin - Golden deposits in a donut pattern concentrated in the nasal macula and peripapillary area. Macula is dry. [5]

Symptoms

Patients may often be asymptomatic with incidental detection of crystals in the retina. In other cases, they may present with the following symptoms:

  • decrease in vision
  • night blindness
  • photophobia - in those with associated corneal crystal deposition like cystinosis
  • blepharospasm - moderate to severe in Sjogren Larsson syndrome

Clinical diagnosis

Visual acuity -

  • Mildly reduced - Kjellin syndrome
  • Reduced - Sjogren Larsson syndrome

Colour vision - Normal in Sjogren Larsson syndrome

Refraction - There is a high prevalence of myopia and astigmatism in Sjogren Larsson syndrome. [1]

Diagnostic procedures

  • Fundus autofluorescence -
    • Oxalosis - hyperautofluorescent crystals and hypoautofluorescent areas of RPE hyperplasia [3]
    • Sjogren Larsson syndrome - The normally dark fovea is hyperautofluorescent in these patients due to loss of macular pigment. [3]
  • Spectral domain OCT - It tells us precisely in which retinal layer the crystals are located.
    • Nerve fibre and inner plexiform layer - Tamoxifen
    • Intra and sub-retinal - Methoxyflurane
    • Cystinosis - all retinal layers show hyperreflective foci; foveal hyporreflectivity may be present [3]
    • Oxalosis - hyper-reflective structures throughout the retinal and subretinal tissues, including choroid [3]
    • Sjogren Larsson syndrome - Majority of crystals are localized in the inner nuclear and outer plexiform layers. Other OCT findings include foveal thinning, cystic foveal cavitations, ellipsoid zone disruptions and subretinal deposits. [3]
  • Fluorescein angiography - Can be done in selected cases to rule out
    • Macular edema - tamoxifen
    • Donut pattern of hyperfluorescence due to window defect [5]
    • Sjogren Larsson syndrome -
    • Kjellin syndrome - block choroidal fluorescence centrally with transmitted fluorescence peripherally
    • Calciphylaxis - Delayed choroidal and retinal filling, delayed AV transit and vessel wall staining in retinal artery occlusion. [4]
  • OCTA -
    • Sjogren Larsson syndrome - decreased retinal capillary density, microvascular dilation and increased flow voids in the superficial and deep capillary plexuses. [3]
  • Visual field testing - Dose dependent decrease in retinal sensitivity has been noted in canthaxanthin toxicity. [5]
  • ERG -
    • Decreased cone and rod function is seen in cystinosis [3]
    • Normal in Sjogren Larsson syndrome

Laboratory test

  • Urine analysis - increased oxalate excretion in hyperoxaluria
  • Skin biopsy - Biopsy from ulcerative lesions show characteristic histopathology in calciphylaxis including medial vessel wall calcification and necrosis of the epithelium [4]

Differential diagnosis

  • Laterality
    • Unilateral - emboli, chronic retinal detachment
    • Bilateral - toxic

Management

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General treatment

Cessation of causative agent should be considered at the first sign of retinopathy in drug induced cases like tamoxifen. [5]

Cystine-depleting agents (like cysteamine), dialysis and renal transplantation [1]

Hyperoxaluria - Plenty of fluids, oral potassium citrate, pyridoxine supplementation, dialysis, renal or liver transplant. [3]

Sjogren Larsson syndrome - Fat restriction and supplementation with medium chain triglycerides. [5]

Medical therapy

Cystinosis - Topical therapy with cysteamine eyedrops (0.5%) removes the corneal crystals [1]

Medical follow up

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Surgery

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Surgical follow up

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Complications

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Prognosis

Primary hyperoxaluria - Calcium oxalate deposits are not removed by dialysis, however regression of the retinal deposits may be noted after successful renal transplantation. [5]

In some cases like those due to methoxyflurane, the changes are irreversible.

With cessation of drug, crystalline deposits may regress in canthaxanthin and milder cases of tamoxifen retinopathy.

Additional Resources

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References

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  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Nadim F, Walid H, Adib J. The differential diagnosis of crystals in the retina. Int Ophthalmol. 2001;24(3):113–121.
  2. 2.0 2.1 Derveaux T, Delbeke P, Walraedt S, et al. Detailed clinical phenotyping of oxalate maculopathy in primary hyperoxaluria type 1 and review of the literature. Retina. 2016;36(11):2227-2235.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 Kovach JL, Isildak H, Sarraf D. Crystalline retinopathy: Unifying pathogenic pathways of disease. Surv Ophthalmol. 2019;64(1):1-29.
  4. 4.0 4.1 4.2 4.3 4.4 Naysan J, Dansingani KK, Balaratnasingam C, et al. Crystalline retinopathy and retinal vasculopathy in calcific uremic arteriolopathy (calciphylaxis). Retinal Cases & Brief Reports. 2018 Fall;12(4):331-335.
  5. 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 Drenser K, Sarraf D, Jain A, Small KW. Crystalline Retinopathies. Surv Ophthalmol. 2006;51(6):535–549.
  6. Pereira KM, Mega J, Cesaro T, Hunter A. An algorithm to identify the aetiology of crystalline retinopathy. Clin Exp Optom. 2019;102(6):551-555.