Diffuse Unilateral Subacute Neuroretinitis


Background

Diffuse unilateral subacute neuroretinitis (DUSN) is a progressive parasitic disease affecting the outer retina and retinal pigment epithelium (RPE). This syndrome is primarily unilateral, although bilateral cases have occurred. [1DUSN has been reported to develop in association with other infectious processes such as catscratch disease caused by Bartonella henselae [2and herpes simplex virus type 2 infection [3. The ocular findings of DUSN include visual loss, vitreous cells, optic disc inflammation and leakage, and transient recurrent crops of gray-white outer retinal lesions. [456]

Stationary or migrating nematodes have been identified deep in the retina or in the subretinal space. Later in the course of the disease, slowly progressive RPE changes and optic atrophy may be observed, as well as narrowing of the retinal vessels.

Pathophysiology

The exact pathophysiology is uncertain, but the local inflammatory changes may be related to toxic effects or immunologic stimulation from excretory products of the larva or from release of unknown soluble tissue toxins. The fleeting gray-white lesions in the outer retina appear to be a local reaction to noxious stimulation. The loss of vision and progressive optic atrophy secondary to death of ganglion cells and neural fibers may be a remote reaction to soluble toxins.

Epidemiology

Frequency

United States

The southeast and the upper Midwest are known endemic areas for the disease.

International

DUSN has been reported initially in the Caribbean islands, Brazil, Ghana, and Germany. [78In the last few years, DUSN has been reported in many other countries, including China, [9India, [10South Africa, Spain, and Korea [11.

Mortality/Morbidity

No cases of mortality have been reported. Four cases of severe neurologic degeneration with DUSN have been reported in children.

The natural history of untreated DUSN involves multiple recurrent episodes of diffuse and focal inflammation of the retina and RPE with secondary progressive visual loss and optic atrophy in the affected eye.

It rarely affects the fellow eye. Only 2 cases with bilateral involvement have been reported.

Race

DUSN does not show any particular racial preference.

Sex

This condition occurs more frequently in males than in females.

Age

It occurs most frequently in the second and third decades. Young children and older adults also may be affected.


History

Early-stage history may include the following:

  • Mild-to-moderate visual loss

  • Paracentral or central scotomas

  • Floaters

  • Ocular discomfort

  • Conjunctival injection of affected eye

Late-stage history may include the following:

  • Severe unilateral visual loss

  • Paracentral or central scotomas

In some patients, the disease may be asymptomatic with the characteristic changes found only on routine eye examination.

Physical

Patients should undergo a complete eye examination, including visual acuity, pupillary reactions, visual fields, slit lamp examination of the anterior and posterior segments, indirect ophthalmoscopy, and detailed examination of the retina using a fundus contact lens. [1213]

Early stage

Visual acuity - Range is from 20/30 to 20/200 or less.

Visual field - Paracentral or central scotoma may be detected.

Pupils - A relative afferent pupillary defect may be noted.

Anterior segment findings reveal normal conjunctiva or conjunctival injection, ciliary flush, anterior chamber cells and flare, fine keratic precipitates, and small hypopyon.

Posterior segment examination findings reveal mild-to-moderate vitritis, optic disc swelling, narrowing of the retinal arterioles, retinitis, and nematodes.

Retinitis is the most characteristic feature of this syndrome. Transient, multiple, focal, gray-white lesions of the deep retina or RPE vary in size from 0.25-1 disc diameter and tend to develop in clusters over wide areas of the retina at various time periods. The active evanescent gray-white lesions fade within a period of 7-10 days as the nematode moves elsewhere in the eye, only to recur in an adjacent area or distant site over the ensuing weeks. Lesions typically resolve without any ophthalmoscopic or angiographic evidence of damage.

Nematode: Identification of the subretinal worm is the pathognomonic finding in DUSN. To localize the worm, careful and repeated examination with a fundus contact lens is required. The worm can be present in all layers of the retina, but it most frequently is found in the subretinal or outer retinal layers. The motile worm is more likely to be observed in the neighborhood of the active grayish-white retinal lesions. The worms appear smooth in outline, tapered on both ends, and often assume an S-shaped, coiled, or figure "8" configuration. These organisms propel themselves by a coiling and uncoiling motion and sometimes move in a snakelike fashion in the subretinal space. They may be noted to move under direct observation in an apparent aversion to bright light, and a white glistening sheen may be noted over the region.

Other less frequently encountered clinical signs include the following: focal retinal and subretinal hemorrhages, perivenous exudates and vascular sheathing, localized serous detachments of the neurosensory retina, cystoid macular edema, retinal striae, and choroidal neovascularization.

Late stage

Visual acuity - This ranges from 20/20 to 20/400 or less.

Visual fields - Dense central or paracentral scotoma may be seen.

Pupils - Relative afferent pupillary defect possible

Posterior segment examination reveals the following findings:

  • Focal and diffuse loss or mottling of the RPE, most typically seen in the paramacular region, sparing the center of the macula in most patients

  • Generalized narrowing of the retinal arterioles

  • Marked optic disc pallor

  • Choroidal neovascularization and/or disciform scarring

  • Peripapillary arteriolar sheathing

Causes

Precise identification of the worm has not been accomplished, but two different types of worms have been recognized in endemic areas.

In the southeastern United States, Caribbean, and Latin America, a larval worm measuring about 400-700 µm has been recognized. It is presumed to be Ancylostoma canium, which is a known frequent cause of cutaneous larval migrans.

In the north midwestern United States, a larger worm measuring 1000-2000 µm has been observed. It is proposed by some authors to be Baylisascaris procyonis and is a rare cause of visceral and ocular larval migrans.


Differential Diagnoses


Laboratory Studies

Serologic studies for parasites, analysis of stool for ova and parasites, and hematologic evaluation for eosinophilia are of limited value in establishing the diagnosis of DUSN.

Some serological tests may be indicated to exclude other diseases.

Imaging Studies

Fluorescein angiography

Fluorescein angiography is useful for monitoring the status of the inflammation.

In early stages, fluorescein angiography may show the following:

  • Leakage from the optic nerve head capillaries and some generalized paravenous leakage

  • Window defects indicating minimal changes in the RPE

  • Staining of the clinically apparent gray-white lesions during the later phases of the angiogram, which are nonfluorescent in the early phase

  • Cystoid macular edema in some patients

In late stages, fluorescein angiography may show the following:

  • Diffuse areas of focal hyperfluorescence secondary to RPE loss

  • Leakage from choroidal neovascularization

Scanning laser ophthalmoscope

Although an examination with a fundus contact lens by a skilled ophthalmologist is the method of choice, the scanning laser ophthalmoscope (SLO) provides a new examination modality with distinct advantages for identifying live worms in young patients with DUSN. The infrared laser is safe and comfortable for a prolonged examination. [15]

Using blue illumination, the ocular fundus appears dark and provides a high-contrast background for the white image of the worm. The red perimetry laser stimulus can be used to stimulate the worm's movement and to pinpoint its location.

Spectral domain optical coherence tomography

In the early stage, when worms can be localized, spectral domain optical coherence tomography (SD-OCT) may display a hyper-reflective object of irregular shape that affects all layers of the retina. This is associated with thinning of the nerve fiber layer and inner retinal layers and with diffuse disruption of the outer retinal architecture.

In late stages, thinning of the nerve fiber layer and inner nuclear layers persists and does not change with treatment or even in patients with improved vision. Some patients may have progressive restoration of the inner segment/outer segment junction and outer retinal architecture following treatment. [161718]

Other Tests

An electroretinogram (ERG) is used to objectively evaluate the functional status of the retina and to differentiate from other retinal conditions, as follows:

  • In the affected eye, the ERG usually is reduced in all stages of the disease.

  • It is often moderately or severely reduced in the later stages of the disease.

  • The b-wave is affected more than the a-wave.

  • Rarely, the ERG may be extinguished completely.

  • ERG findings are normal in the unaffected eye.

  • ERG performed before and after laser photocoagulation appears to be useful in monitoring the retinal findings. After laser photocoagulation, recovery of ERG findings may be documented.

Electro-oculography (EOG) findings are abnormal in approximately 50% of patients.

Visual field testing may show the following:

  • Paracentral and central visual field defects

  • Useful to monitor the visual field over a period of time and to differentiate from other conditions

Histologic Findings

The only histologic findings are from an enucleated eye presumed to have DUSN. Histopathology showed nongranulomatous vitritis, retinitis, and retinal and optic nerve perivasculitis. RPE and low-grade, patchy nongranulomatous choroiditis were observed. There was no evidence of a worm.


Medical Care

Laser photocoagulation of the nematode is the treatment of choice. [1920Direct laser photocoagulation has been effective in destroying the worm. In early stages of DUSN, prompt localization and destruction of the worm by photocoagulation may improve the vision of patients, and, in other situations, the progression of the disease is halted. No significant intraocular inflammation has been associated with this treatment. If worms cannot be localized, application of laser along the edges of active lesions may decrease the morbidity and improve vision. [21]

Antihelminthic treatment is being used more frequently. It may be considered when the organism cannot be found.

Combination therapy (eg, laser treatment, systemic steroids, anthelminthics) is also used. [22]

Surgical Care

Although direct laser photocoagulation of the nematode is the treatment of choice for DUSN, surgical transvitreal removal of the nematode may be indicated in selected cases. [23]

Pars plana vitrectomy and removal of an intact parasite by various vitrectomy instrumentation allow removal of the nematode for parasitologic identification. [24]

In addition, the inflammation may completely subside with recovery of function.

Consultations

Consultation with a uveitis or retinal specialist is often useful for patients with suspected DUSN.


Medication Summary

Antihelminthic treatment is for patients with moderate-to-severe vitreous inflammation or when it is not possible to locate and treat the nematode with photocoagulation. However, it is not effective in destroying the organism in all patients, especially in those with minimal vitreous inflammation where the drug has low ocular penetration. [25]

Thiabendazole is the drug of choice for initial medical therapy. Successful treatment is characterized by the development of a localized area of intense retinitis and fading of the grayish-white retinal lesions within 10 days after completion of therapy.

Ivermectin may be considered if thiabendazole is not effective or cannot be tolerated.

High-dose oral albendazole seems to be safe and beneficial for patients with active DUSN in the early or late clinical stage. [26]

Anthelmintics

Class Summary

Vermicidal drugs that kill the organism by various antihelminthic actions.

Thiabendazole (Mintezol)

An antihelminthic agent. Probably acts by inhibiting the helminth-specific enzyme fumarate reductase. Vermicidal and/or vermifugal.

Ivermectin (Stromectol)

A semisynthetic, anthelmintic agent mainly used for filarial worms. Effectiveness in the treatment of DUSN is unclear.

Albendazole (Albenza)

A benzimidazole carbamate drug that inhibits tubulin polymerization, resulting in degeneration of cytoplasmic microtubules. Decreases ATP production in the worm, causing energy depletion, immobilization, and finally death. Converted in the liver to its primary metabolite, albendazole sulfoxide. Less than 1% of the primary metabolite is excreted in the urine. Plasma level is noted to rise significantly (as much as 5-fold) when ingested after high-fat meal. Experience with patients < 6 y is limited. To avoid inflammatory response in CNS, patient must also be started on anticonvulsants and high-dose glucocorticoids.



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