Neuroretinitis, Diffuse Unilateral Subacute

ntroduction
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. The ocular findings include visual loss, vitreous cells, optic disc inflammation and leakage, and transient recurrent crops of gray-white outer retinal lesions. 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.

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. In the last few years, DUSN has been reported in many other countries, including China, India, South Africa, and Spain.

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.

Clinical
History

Early stage o Mild-to-moderate visual loss o Paracentral or central scotomas o Floaters o Ocular discomfort o Conjunctival injection of affected eye Late stage o Severe unilateral visual loss o 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.

Early stage o Visual acuity - Range is from 20/30 to 20/200 or less. o Visual field - Paracentral or central scotoma may be detected. o 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. o 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 o Visual acuity - Typically less than 20/400 o Visual fields - Dense central or paracentral scotoma may be seen. o Pupils - Relative afferent pupillary defect possible o 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
o

Causes

Precise identification of the worm has not been accomplished, but two different types of worms have been recognized in endemic areas. o In the southeastern United States, Caribbean, and Latin America, a larval worm measuring about 400-700 m has been recognized. It is presumed to be Ancylostoma canium, which is a known frequent cause of cutaneous larval migrans. o In the north midwestern United States, a larger worm measuring 10002000 m 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
Papilledema Presumed Ocular Histoplasmosis Syndrome Sarcoidosis Toxoplasmosis White Dot Syndromes

Other Problems to Be Considered

Early stage Active retinal lesions include the following: Toxoplasmosis Cytomegalovirus retinitis Fungal or bacterial retinal abscesses Acute posterior multifocal placoid pigment epitheliopathy Multiple evanescent white dot syndrome Serpiginous choroiditis Behet disease Pseudopresumed ocular histoplasmosis syndrome Multifocal choroiditis Perivasculitis includes sarcoidosis Optic disc swelling includes acute neuroretinitis and papilledema Vitritis includes pars planitis Late stage Retinal pigment epithelial atrophy includes the following:

Presumed ocular histoplasmosis syndrome Unilateral retinitis pigmentosa Traumatic chorioretinopathy Chorioretinal atrophy after ophthalmic artery occlusion Optic atrophy includes the following: Secondary to optic neuritis Compressive lesions Ischemic optic neuropathy

Workup
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 is useful for monitoring the status of the inflammation. o Early stage of the disease 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 o Late stages of the syndrome Diffuse areas of focal hyperfluorescence secondary to RPE loss Leakage from choroidal neovascularization Scanning laser ophthalmoscope o 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. o 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.

Other Tests

An electroretinogram (ERG) is used to objectively evaluate the functional status of the retina and to differentiate from other retinal conditions. o In the affected eye, the ERG usually is reduced in all stages of the disease. o It is often moderately or severely reduced in the later stages of the disease. o The b-wave is affected more than the a-wave. o Rarely, the ERG may be extinguished completely. o ERG findings are normal in the unaffected eye. o 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-oculogram (EOG) findings are abnormal in approximately 50% of patients. Visual field o Paracentral and central visual field defects o 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.

Treatment
Medical Care

Laser photocoagulation of the nematode is the treatment of choice. Direct 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. Antihelminthic treatment is being used more frequently. It may be considered when the organism cannot be found.

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.

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

Anthelmintics
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.

Dosing Interactions Contraindications Precautions

Adult

22 mg/kg PO bid for 2-4 successive d in patients with moderate-to-severe vitritis; not to exceed 3 g/d More recently, 25 mg/kg/d PO qhs for 25 d has been recommended

Pediatric
Administer as in adults; in pediatric patients <30 lb, safety and effectiveness is limited

Dosing Interactions Contraindications Precautions

When used concomitantly with xanthine derivatives, it may be necessary to monitor the blood levels and/or reduce the dosage of such compounds

Dosing Interactions Contraindications Precautions

Documented hypersensitivity

Dosing Interactions Contraindications Precautions

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Frequent adverse effects include nausea, vomiting, anorexia, and mild central nervous system disturbances such as dizziness, drowsiness, or headache

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

Dosing

Interactions Contraindications Precautions

Adult
150 g/kg PO once

Pediatric
Administer as in adults; not established in pediatric patients <15 kg

Dosing Interactions Contraindications Precautions

Excreted by the liver

Dosing Interactions Contraindications Precautions

Documented hypersensitivity

Dosing Interactions Contraindications Precautions

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Frequent adverse effects include nausea, vomiting, anorexia, and mild central nervous system disturbances

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 highdose glucocorticoids.

Dosing Interactions Contraindications Precautions

Adult
400 mg PO qd for 30 d has been used

Pediatric
<15 kg: Not established >15 kg: Administer as in adults

Follow-up
Further Outpatient Care

The patients should be observed closely until the organism is identified for focal laser photocoagulation. Patients should receive follow-up evaluations every 1-2 weeks until the inflammation resolves.

Prognosis

DUSN is a condition in which prompt identification and destruction of the infecting nematode can result in the cessation of symptoms and the preservation of good visual acuity. If untreated, the disease progressively damages the retina and the optic nerve, leading to severe visual loss.

Patient Education

If the vision is reduced substantially in one eye, then emphasis should be made regarding monocular precautions and the use of protective safety glasses.

Miscellaneous
Medicolegal Pitfalls

In view of the extensive differential diagnoses and uncommon conditions that mimic DUSN, it is important to consult with a uveitis or retina specialist.