Acute retinal necrosis associated optic neuropathy

Authors


Matthew T. Witmer, MD
USF Eye Institute
12901 Bruce B. Downs Blvd., MDC 21
Tampa, Florida 33612
USA
Tel: + 813 523 3215
Fax: + 813 974 5621
Email: mwitmer@health.usf.edu

Abstract

Acute retinal necrosis (ARN) syndrome is characterized by severe intraocular inflammation, occlusive vasculopathy and peripheral retinal necrosis. Vision threatening complications of this syndrome include retinal detachment, macular oedema and ischaemia and optic neuropathy. Optic nerve involvement may be the presenting sign of ARN and this condition should be included in the differential diagnosis of acute papillitis. Several mechanisms may lead to ARN associated optic neuropathy including vasculitis, optic nerve ischaemia and direct optic nerve invasion by the herpes virus. We review optic nerve involvement during ARN and present its incidence, pathogenesis, differential diagnosis and treatment.

Introduction

Acute Retinal Necrosis syndrome (ARN) is a devastating inflammatory disease of the eye. In the initial report of this syndrome, Urayama et al. described six patients with unilateral uveitis, retinal periarteritis and vitreitis, who developed rhegmatogenous retinal detachments (Urayama et al. 1971). The clinical appearance of the optic nerve was reported in four of these patients, and all demonstrated optic nerve inflammation. The patients had no systemic pathology, and no infectious aetiology for the inflammation was found.

Holland and the executive committee of the American Uveitis Society defined the diagnostic criteria for ARN (Holland 1994). In addition to the presence of intraocular inflammation, vasculitis and retinal necrosis, the authors identified several other characteristics that supported the diagnosis of ARN. These included (i) optic atrophy, (ii) scleritis and (iii) pain. This definition emphasized that ARN is an inflammatory condition that affects multiple structures of the eye besides the neurosensory retina.

Vision loss from ARN may be due to several potential complications, including retinal detachment, retinal ischaemia and oedema and optic neuropathy. Prior to the widespread use of antiviral therapy, the incidence of retinal detachment in patients with ARN was reported to be as high as 75% (Fisher et al. 1982). The importance of optic neuropathy in this disease, however, may have been overshadowed by this historical frequency of retinal detachment.

Optic neuropathy may cause significant visual loss in patients with ARN. Sergott et al. (1989) reported that patients with ARN associated optic neuropathy experienced a more severe reduction in visual acuity compared to those without optic nerve involvement. A retrospective review comparing patients who underwent an immediate vitrectomy, intravitreal lavage with acyclovir, and laser demarcation of visible necrotic areas upon the diagnosis of ARN, versus no immediate surgery, concluded that retinal ischaemia and optic nerve atrophy were the main causes of poor final visual outcomes from ARN (Hillenkamp et al. 2009). The authors concluded this because the final visual acuities were similar in both groups, despite the fact that those eyes that underwent early surgery, intravitreal lavage and laser demarcation had lower rates of secondary retinal detachment.

Optic nerve involvement in ARN has the potential to cause rapid, severe vision loss. This review discusses the history, presentation, aetiology, pathogenesis, and treatment of ARN associated optic neuropathy.

Diagnosis

Sergott et al. (1989) defined absolute and relative criteria for optic nerve involvement in ARN. The absolute criteria included (i) an afferent pupillary defect, not consistent with the retinal findings; (ii) poor correlation between retinal findings, visual acuity and visual fields; or (iii) sudden deterioration of visual acuity to 20/100 or less without corresponding retinal changes within a 24 to 36-hour interval. Relative criteria were defined as (i) optic disc oedema and (ii) enlarged optic nerves and surrounding perineural space demonstrated by CT scanning and/or B-scan ultrasonography (Sergott et al. 1989).

Optic nerve head appearance

The appearance of the optic nerve head in ARN-associated optic neuropathy is dependent on the location and duration of inflammation of the optic nerve.

Fisher et al. (1982) reported that ‘during the acute phase of ARN syndrome, swelling of the optic nerve head (Figs 1 and 2) and macular oedema (Fig. 3) were often present’. Several others have confirmed that disc oedema appears to be commonly reported in this syndrome (Margolis et al. 1988; Matsuo et al. 1988; Litoff & Catalano 1990; Kojima et al. 2004). The optic disc oedema may be either hyperaemic or pallid (Duker & Blumenkranz 1991), and peripapillary haemorrhages may accompany the swollen nerve head (Litoff & Catalano 1990; Kang & Kim 2001).

Figure 1.

 Colour photograph of the right optic nerve head from a patient with ARN, demonstrating optic disc oedema. The veins of the optic nerve are severely dilated. This patient’s vitreous biopsy was positive by polymerase chain reaction (PCR) for varicella zoster virus.

Figure 2.

 Colour photograph of the left optic nerve of a patient with ARN associated optic nerve inflammation. This patient was subsequently found to have Herpes Simplex Virus: Type 2 in the vitreous by polymerase chain reaction.

Figure 3.

 Colour photograph of the entire fundus from the same eye as Fig. 2. This eye demonstrated severe vitreitis and macular oedema, as indicated by the presence of a macular star.

Optic nerve oedema in ARN may also be associated with retinal nerve fibre layer oedema. Margolis et al. (1988) reported an ARN patient who presented with an 8-day history of decreased vision unilaterally. Upon examination, the patient displayed an afferent pupillary defect, inferior arcuate scotoma and swollen optic disc and adjacent retina, which was consistent with arcuate neuroretinitis. A fluorescein angiogram showed late hyperfluorescence of an arcuate band of nerve fibres and the optic disc.

As Holland et al. had indicated in the guidelines for the diagnosis of ARN, many patients with ARN present with optic disc pallor (Fig. 4) (Holland 1994). This atrophic appearance of the optic nerve indicates prior damage. Pallor may take several weeks to develop after the acute phase of ARN. Culbertson et al. (1982), for example, enucleated an eye within 3 weeks of presentation with ARN, which contained a pale optic nerve.

Figure 4.

 Colour fundus photograph of the right eye of an ARN patient, 4 months after presenting with ARN associated optic neuropathy. The optic nerve became white and atrophic.

The optic nerve head in ARN-associated optic neuropathy may also appear normal. In these cases, the optic nerve inflammation is retrobulbar in location (Batisse et al. 1996; Shayegani et al. 1996; Lee et al. 1998; Meenken et al. 1998; Tornerup et al. 2000). Batisse et al. (1996) reported four cases of retrobulbar optic neuritis in HIV positive patients who presented an average of 8 days prior to the diagnosis of ARN.

Optic nerve involvement in relation to retinal necrosis

Optic nerve involvement in ARN may occur before (Francis et al. 2003; Kojima et al. 2004), after, or simultaneous (Fig. 5) with the development of retinal necrosis (Fig. 6). When the optic neuropathy precedes the development of retinal necrosis, the diagnosis is particularly challenging. Optic neuropathy as a presenting sign of ARN may occur in both immunocompetent (Lewis et al. 1989; Tornerup et al. 2000; Kang & Kim 2001; Francis et al. 2003; Kojima et al. 2004) and immunocompromised patients (Winward et al. 1989; Litoff & Catalano 1990; Shayegani et al. 1996; Lee et al. 1998; Meenken et al. 1998).

Figure 5.

 Colour photograph of the same eye as Fig. 1, demonstrating ARN associated optic neuropathy coincident with peripheral retinal necrosis and vasculitis inferonasally.

Figure 6.

 Colour photograph of the retinal periphery from the same eye as Figs 2 and 3. The retinal necrosis became most prominent 1 week after the development of optic neuropathy.

Francis et al. (2003) reported three immunocompetent patients in whom optic neuritis and panuveitis were the presenting signs of ARN. In each case, the optic neuritis preceded the development of retinal necrosis by about 1 week.

Tornerup et al. (2000) reported a 34-year-old female that presented with retrobulbar optic neuritis, proptosis, and orbital inflammation. She developed retinitis 4 days later.

Visual field defect

ARN-associated optic neuropathy may induce several types of visual field defect. These include central or arcuate scotomas and generalized constriction of the visual field (Lewis et al. 1989; Duker & Blumenkranz 1991; Culbertson & Atherton 1993). Friedlander et al. (1996) reported that altitudinal scotomas may occur from ARN-associated optic neuritis prior to the development of retinitis (Fig. 7).

Figure 7.

 Humphrey visual field from the eye whose optic nerve is pictured in Fig. 1. This demonstrates a superior altitudinal scotoma consistent with optic nerve disease.

Fluorescein angiogram

In ARN-associated optic neuritis, optic disc hyperfluorescence will often occur (Fig. 8). This is most likely to occur during the re-circulation phase (Duker & Blumenkranz 1991). An oedematous nerve will also show fluorescein staining and leakage during the later phases of the study (Friedlander et al. 1996).

Figure 8.

 Fluorescein angiogram of the optic nerve shown in Fig. 2. This image was taken 6 min after the injection of fluorescein and demonstrates optic disc staining and leakage.

Fluorescein angiography in ARN may also demonstrate delayed retinal blood flow secondary to retinal vasculitis or optic nerve compression from inflammation (Sergott et al. 1985; Kang & Kim 2001; Kojima et al. 2004). Severe compression or vasculitis may result in central retinal artery (CRAO) or vein occlusion (CRVO) associated with the optic nerve swelling (Kang & Kim 2001; Kojima et al. 2004).

Computed tomography (CT) scan

Sergott et al. (1985) were the first to describe patients with ARN that demonstrated enlarged optic nerves upon CT scan. Subsequently, this group presented eight patients with optic nerve involvement clinically (Sergott et al. 1989). The CT scan demonstrated enlarged nerves in only three of these patients. The sensitivity of this modality to diagnose optic nerve distention due to ARN-associated optic neuropathy, therefore, may be lacking.

Several case reports have shown other patients diagnosed with ARN that have demonstrated enlarged optic nerves with CT scanning. These have included both immunocompetent (Tornerup et al. 2000; Kojima et al. 2004) and immunocompromised patients (Litoff & Catalano 1990). Despite these anecdotal reports, the precise utility of CT to assist in the diagnosis and treatment of ARN-associated optic neuropathy is unknown.

Magnetic resonance imaging (MRI)

MRI of patients with ARN-associated optic neuropathy may show enhancement of different structures of the visual system posterior to the globe. This includes enhancement of the optic nerve, chiasm, tracts and lateral geniculate ganglia.

An MRI of an HIV patient with acute loss of vision to no light perception in both eyes revealed enhancement of both optic nerves. This patient later developed retinal necrosis with positive cultures for varicella zoster virus (Shayegani et al. 1996).

Greven et al. (2001) reported that the optic chiasm showed increased signal in an immunocompromised patient with ARN, and Lewis et al. (1989) demonstrated that the MRI of a patient with ARN showed high signal intensity of the optic tracts, lateral geniculate ganglia and the overlying temporal lobes and midbrain.

Despite these findings, the MRI of patients with ARN-associated optic neu-ropathy may be unremarkable (Friedlander et al. 1996; Lee et al. 1998). In two AIDS patients with retrobulbar optic neuritis associated with ARN, the optic nerve sheath was normal upon MRI (Lee et al. 1998).

B-scan ultrasound

Several cases of ARN-associated optic neuropathy have demonstrated optic nerve enlargement with B-scan. The series by Sergott et al. (1989) found that the same three patients that showed enlarged optic nerves by CT scan also demonstrated enlarged optic nerves by B-scan. Lewis et al. (1989) described one patient with bilateral optic nerve inflammation who had unilateral optic nerve enlargement by B-scan. Kojima et al. (2004) reported a patient that showed an enlarged right optic nerve with B-scan as well as with CT.

Despite these findings, however, it appears that the sensitivity with which ultrasound appears able to detect optic nerve sheath enlargement in patients with optic nerve involvement due to ARN is poor (Duker & Blumenkranz 1991).

Lumbar puncture

Optic nerve inflammation associated with ARN suggests the possibility of significant inflammation in the central nervous system. Sternberg et al. (1982) were the first to report a lymphocyte pleocytosis in the cerebrospinal fluid (CSF) in patients with ARN. The presence of inflammatory cells in the cerebrospinal fluid was subsequently demonstrated in additional patients with ARN (Fisher et al. 1982; Sergott et al. 1985; Culbertson et al. 1986; Lewis et al. 1989).

A lymphocyte pleocytosis in the CSF, however, is not sensitive or specific for detecting optic nerve involvement in ARN. Of the eight patients with optic neuropathy associated with ARN that were presented by Sergott et al. (1989), only three had lumbar punctures and only one demonstrated a lymphocyte pleocytosis. The opening pressures from the lumbar punctures of these patients were all within the normal range. They concluded that the opening pressure in ARN optic neuropathy is well within normal limits (Sergott et al. 1989).

In patients with severe infection of the central nervous system by varicella zoster virus (VZV), cerebrospinal fluid may be positive for the virus. Shayegani et al. (1996) reported an HIV patient with bilateral visual loss from retrobulbar optic neuritis that was positive for VZV in the CSF. In addition, Meenken et al. (1998) reported a patient with AIDS that presented with retrobulbar optic neuritis 3 weeks prior to a diagnosis of retinal necrosis, who also exhibited CSF that was positive for VZV by polymerase chain reaction.

Incidence

Several case series have reported the frequency of optic neuropathy during ARN. Optic nerve involvement in most series ranges from 47% to 57% of cases (Table 1) (Sergott et al. 1989; Labetoulle et al. 1995; Batisse et al. 1996; Muthiah et al. 2007); however, one study found the incidence to be much lower (Lau et al. 2007).

Table 1.   Percentage of ARN syndrome eyes with optic neuropathy.
StudyNo. of eyesNo. of patientsNo. with optic neuropathyPercentage
  1. * AIDS patients with a diagnosis of Progressive Outer Retinal Necrosis (PORN). All other reported series are ARN syndrome associated.

Sergott et al. (1989)17847.1
Labetoulle et al. (1995)14857.1
Batisse et al. (1996)231356.5
Muthiah et al. (2007)31>50
Lau et al. (2007)27311.1
Engstrom et al. (1994)*65381116.9

In 2007, Muthiah et al. reported the results from a nationwide survey in which 31 cases of ARN were diagnosed in England between March 2001 and 2002 (Muthiah et al. 2007). Over 50% of the patients presented with optic disc findings of inflammation.

The high incidence of optic neuropathy has also been reported in immunocompromised patients with ARN. Batisse et al. (1996) reported the only large series examining ARN patients with HIV. Involvement of the optic nerve occurred in 56.5% of these patients (13 of 23 patients), within a mean of 26 days and a median of 11 days (range was 0–81 days) from presentation.

Unlike prior studies, which showed a high frequency of optic nerve involvement in ARN, a retrospective review by Lau et al. (2007) reported that only 11.1% (3/27) of their patients with ARN developed optic neuropathy. This series from Moorfields Eye Hospital consisted of 22 HIV negative patients (27 eyes) during the years 1992–2004. The low rate of optic neuropathy compared with previously published series was not explained.

Histology

Histologic examination of the optic nerves has provided information that is relevant to the pathogenesis of ARN-associated optic neuropathy. Culbertson et al. (1982) reported the histology from a 67-year-old white male who was diagnosed with ARN-associated optic neuropathy. The patient had presented with a relative afferent pupillary defect and an oedematous optic disc. His visual acuity had deteriorated from 20/20 to no light perception within 2 weeks, despite maintaining an attached retina. Eighteen days after the onset of symptoms, the patient’s optic disc showed marked pallor and the eye was enucleated (Culbertson et al. 1982).

Histologically, the authors found an optic nerve that was ‘largely necrotic and heavily infiltrated with many plasma cells’ (Culbertson et al. 1982). In addition to optic nerve necrosis, cellular thrombi filled the branch arteries near the surface of the disc. These arteries contained swollen endothelial cells that occluded the artery lumen. The vasculitis involved both arteries and veins. A clear relationship was made between optic nerve oedema found during clinical examination and histologic optic nerve necrosis. The pathologic findings resembled the findings of Schwartz et al. (1976), who had performed an autopsy on a patient that had developed necrotizing retinopathy after herpes zoster ophthalmicus infection. In their patient, demyelination, necrosis, and a lymphocytic infiltrate were also found in the trigeminal ganglion (Schwartz et al. 1976).

Electron microscopy of the specimen from Culbertson et al. (1982) found herpes virus in all layers of the retina. The report did not include the electron microscopy findings of the optic nerve. Consequently, it was unknown at that time whether the herpes viral particles observed in the retina were also present in the optic nerve.

Rungger-Brandle et al. (1984) also histologically examined an eye with ARN-associated optic neuropathy. They concluded that the herpes virus was only affecting cells of neuronal origin within the retina, while sparing retinal glial cells. Because the optic nerve is a continuation of retinal neuronal elements (i.e. ganglion cells), this suggested that the optic nerve itself could be directly infected with the viral agent that was causing ARN.

Evidence of varicella zoster virus within the optic nerve tissue of patients with ARN was eventually detected using immunofluorescence techniques (Batisse et al. 1996; Greven et al. 2001). Greven et al. (2001) described the case of an immunosuppressed patient with acute vision loss in both eyes and increased signal on the MRI in the area of the posterior optic nerve and chiasm. The patient’s pathology specimen of his optic nerve and retina revealed intranuclear inclusions suggestive of herpes infection. Focal areas of demyelination were present in the nerve with infiltration of the nerve by macrophages. Immunostains of the anterior nerve were positive for VZV (Greven et al. 2001).

Pathogenesis

Several mechanisms have been proposed to explain the optic neuropathy associated with ARN. (i) Intraneural vasculitis, (ii) loculated exudates within the optic nerve sheath causing compressive ischaemia, and (iii) inflammation and necrosis due to direct herpes virus infection of the optic nerve have all been implicated in the pathogenesis.

Culbertson et al. (1982) noted severe vasculitis that affected both arteries and veins and suggested that sudden vision loss in many patients with ARN may be the result of an arteritic optic neuropathy. These authors, however, claimed that failure to see virus in the choroid, retinal vascular endothelium or optic nerve on pathologic examination suggested that the virus did not propagate in these tissues and that the pathology in these tissues was not due to direct viral cytopathologic effects. Rather, these authors believed that the optic neuropathy associated with ARN was a form of ischaemic optic neuropathy (Culbertson et al. 1986).

In contrast to this theory, Sergott et al. hypothesized that intraneural optic nerve inflammation may cause a transudate and exudate within the subdural space surrounding the optic nerve. They suggested that inflammatory fluid was loculated within the closed and limited subdural space and compressing the optic nerve vasculature destined to supply the retina (Sergott et al. 1985). They believed that the poor retinal blood flow seen upon fluorescein angiography was from both retinal vasculitis and optic nerve compression (Sergott et al. 1985). The presence of a CRAO or CRVO, in connection with acute optic disc oedema and distention of the optic nerve sheath in some patients with ARN, is consistent with this compressive mechanism (Kojima et al. 2004). This proposed mechanism provided rationale for optic nerve sheath decompressions to treat this condition (Sergott et al. 1989).

Direct infection of the optic nerve by herpes virus is another potential mechanism that explains optic neuropathy during ARN. Many of the initial histologic specimens from patients with ARN failed to demonstrate herpes virus within optic nerve tissue (Culbertson et al. 1982, 1986). However, direct infection of the optic nerve by VZV was later shown using immunohistochemical methods (Batisse et al. 1996; Greven et al. 2001). Culbertson et al. (1986) had stated that the abrupt border between affected and nonaffected retina in the ARN syndrome suggested cell-to-cell viral transfer. Two mechanisms of viral transfer have been suggested; the first is local (nonsynaptic) viral transfer from infected to noninfected optic nerve axons and the second is transneuronal (transsynaptic) transfer along the visual pathways (Labetoulle et al. 2000).

Several cases have reported HSV encephalitis in association with retinitis (Ganatra et al. 2000). It was assumed that the virus spreads from the brain to the retina via the optic nerve. Lewis et al. (1989) postulated that HSV travelled posteriorly along the optic nerves into the optic chiasm and the brain. The mechanism by which the herpes virus spreads locally and systemically in ARN, however, is controversial.

The Von Szily (1924) model of HSV-1 transmission suggests that HSV-1 spreads to the brain via the optic nerve and from the brain to the contralateral eye via the contralateral nerve. This model was based on experiments using rabbits, in which unilateral intraocular inoculation of HSV produced disease in the contralateral eye (Szily 1924). Whittum et al. (1984) duplicated Von Szily’s experiments using the eyes of mice. When eyes were injected with HSV-1, 70–100% of contralateral eyes developed inflammation in all layers of the retina. Viral infection of the anterior segment of the contralateral eye did not occur. In the injected eye, the opposite reaction occurred, with severe anterior segment inflammation and mild vitreous inflammation, but no retinal involvement by necrosis.

Olson et al. (1987) performed several experiments on rabbits by injecting HSV-1 into the anterior chamber or vitreous of one eye and transecting the ipsilateral or contralateral optic nerve. Early signs of HSV retinopathy were noted in the area of the optic nerve head. These findings included disc swelling and hyperaemia, vascular congestion of the retinal vessels, peripapillary haemorrhage and retinal opacification. They concluded that invasion of the optic nerve is a pathway by which HSV-1 may spread to the brain and cause encephalitis (Olson et al. 1987). Their results suggested that HSV-1 can exit the eye through multiple pathways, but it reaches the retina of the contralateral eye primarily by the optic nerve. Bosem et al. (1990) also showed that the optic nerve is the way that HSV is transmitted to the retina of the contralateral eye. For the transmission of virus along the optic nerve, direct infection of the optic nerve by herpes virus must occur.

Various immunologic factors may be influential in an individual’s response to new or chronic infection with herpes viruses. Margolis et al. (1988) suggested that the presentation of papillitis and arcuate retinitis in one of their patients might be an immune response to infected ganglion cell bodies and their axons. Zaltas et al. (1992) showed that the ability of the eye to resist invasion from HSV is determined by its immunologic background.

The three major theories to explain optic nerve disease in ARN syndrome have not been reconciled in the literature. It is possible that each of these mechanisms may occur in different clinical settings. It is also possible that a combination of mechanisms may be responsible for optic nerve compromise in a single patient. Kang & Kim (2001) presumed there was direct optic nerve viral infection causing inflammation and necrosis as well as intraneural vasculitis causing ischaemic necrosis in the same patient.

Relationship of ARN to PORN

In 1990, Forster et al. were the first to describe the condition that is now known as progressive outer retinal necrosis syndrome (PORN) (Forster et al. 1990). They reported two patients with HIV who developed rapidly progressive retinal necrosis associated with systemic cutaneous varicella zoster infection.

A distinction between ARN and PORN has been made on a clinical basis despite the fact that the primary infectious aetiologic agents of the two syndromes are the same. Holland and the executive committee of the American Uveitis Society proposed that ARN and PORN be viewed as two distinct disorders that were specific clinical variants of herpetic retinopathy (Holland 1994). It was their contention that patients with AIDS can develop either syndrome, with the specific manifestations possibly being dependent on the level of immune function.

In addition, Holland et al. believed that the use of the term “ARN” should not be limited to otherwise healthy patients, because it is unnecessarily restrictive (Holland 1994). In fact, ARN had previously been reported in patients with HIV (Neetens et al. 1985). The use of the terms, ARN and PORN, appears to be useful as clinical diagnoses to describe disease phenotype and likely represents different manifestations of the same infectious process.

PORN Optic Neuropathy

Optic nerve involvement has been frequently reported in patients with PORN. In Forster et al.’s initial report, they described a patient that presented with declining visual acuity in the right eye to hand motion vision within 4 days. Both optic discs appeared hyperaemic and swollen on exam (Forster et al. 1990).

Margolis et al. (1991) described five patients with HIV and retinal necrosis in a presentation consistent with PORN. Optic nerve involvement occurred in all patients. Histologic examination revealed necrosis and a marked lymphocytic infiltrate observed in both optic nerve specimens. Clinical and laboratory evidence showed that varicella zoster virus was the causative agent. This was the first pathologic evidence that PORN caused an optic neuropathy similar to the findings seen with ARN.

Optic nerve involvement may precede the development of PORN in immunosuppressed patients. In many of these cases, the optic neuritis was retrobulbar in location and the vision did not improve (Friedlander et al. 1996; Shayegani et al. 1996; Meenken et al. 1998). Shayegani et al. (1996) described one case of bilateral retrobulbar optic neuritis that preceded the development of PORN in a patient with HIV. The patient rapidly developed no light perception in both eyes prior to the development of retinitis. Three weeks after the initial presentation of vision loss from optic neuritis, the patient developed retinal infiltrates. Similarly, Friedlander et al. (1996) reported three cases (six eyes) of patients with AIDS who presented with optic neuropathy prior to manifesting ARN. Although the authors preferred to use the term ARN, they described features consistent with a diagnosis of PORN. Two of these patients presented with optic nerve swelling, while one patient presented with normal optic nerves and was diagnosed with retrobulbar optic neuropathy.

The largest case series of AIDS patients with a diagnosis of PORN consists of 38 patients (65 eyes) (Engstrom et al. 1994). The authors found optic nerve abnormalities in 17% of eyes (Table 1). Manifestations of optic nerve involvement included disc swelling, hyperaemia and optic atrophy. A relative afferent pupillary defect was noted in 38% of patients (11/29), although it was attributed to optic neuropathy in only five of these cases.

Treatment

No randomized controlled trials documenting the efficacy or safety of any treatment for ARN/PORN-associated optic neuropathy exist. Consequently, the current treatment of this complication is based on anecdotal experience. The most appropriate treatment remains controversial.

Optic nerve sheath decompression

Sergott et al. performed optic nerve sheath decompressions (ONSD) in eight eyes that were diagnosed with ARN-associated optic neuropathy. They reported six of the eight eyes demonstrated visual acuity improvement to >20/400 after the procedure, while one eye worsened and one stayed the same (Sergott et al. 1985, 1989). They believed that optic nerve sheath decompression had the greatest effect if performed within 12 days of onset of ARN optic neuropathy. The authors could not explain why ONSD improved vision in some patients but suggested that it released loculated fluid within the optic nerve sheath that may have caused vascular compromise to the nerve and retina. The results of the series by Sergott et al. have been criticized because of the lack of a control group (Duker & Blumenkranz 1991).

Antivirals

Immediate treatment of the underlying cause of retinal necrosis and inflammation is recommended for patients with ARN or PORN. Palay et al. (1991) showed in a retrospective, multicenter study that acyclovir in patients with unilateral ARN decreases the risk of infection to the fellow eye. Twenty five percent of patients treated with acyclovir had the fellow eye affected within 2 years, whereas 65% of the group without treatment developed ARN in the fellow eye during the same length of follow-up (Palay et al. 1991). Although this study did not examine optic neuropathy specifically, these results suggest that acyclovir prevents the spread of virus within the visual system.

In cases where VZV optic neuropathy precedes retinitis, intravenous acyclovir has been reported to improve visual outcomes (Winward et al. 1989; Lee et al. 1998). Winward et al. reported a case of HIV-associated VZV optic neuropathy that improved with intravenous acyclovir. This patient, however, was taking PO acyclovir when the neuritis developed (Winward et al. 1989).

Acyclovir also appears to be efficacious in the treatment of ARN optic neuritis, although no randomized controlled trial has been performed to demonstrate this (Duker & Blumenkranz 1991).

Steroids

Once initiation of antiviral therapy has begun, many physicians suggest administering high doses of systemic steroids to patients with ARN/PORN. The use of steroids in the treatment of ARN/PORN, however, remains controversial (Lau et al. 2007).

Many believe that steroids may worsen or even induce ARN and should be used with caution (Satoh et al. 1998; Browning 2003; Francis et al. 2003; Cardine et al. 2004). It is known that steroids suppress the host’s immune response. There have been reports of patients who seemed to have had their disease worsened by steroids (Litoff & Catalano 1990; Friedlander et al. 1996). Litoff et al. described a case of VZV optic neuritis in an HIV patient who developed peripheral retinitis 6 weeks after treatment with high-dose steroids (Litoff & Catalano 1990).

In other cases of ARN, however, the use of steroids has been shown to lead to favourable outcomes (Barondes et al. 1992; Kalman et al. 1994). Kojima et al. reported the case of a patient with ARN whose contralateral eye developed disc swelling, suggestive of bilateral ARN. The patient was treated with IV steroids and IV acyclovir and the visual acuity improved (Kojima et al. 2004).

Because of the destructive nature of the inflammation in eyes with ARN, many clinicians treat patients with steroids (Culbertson & Atherton 1993; Lau et al. 2007). It is important to ensure, however, that patients with ARN are treated with antiviral medication prior to initiating steroid therapy. No randomized controlled trial of patients with ARN-associated optic neuropathy treated with steroids is currently available.

Treatment duration

Many clinicians treat ARN with intravenous antiviral medication for about 2 weeks followed by oral medication for 6–8 additional weeks (Duker & Blumenkranz 1991). Once antiviral therapy has been initiated, a high-dose steroid taper is commonly begun using the degree of inflammation as a clinical indicator of response.

The decision whether to treat patients whose vision has deteriorated to no light perception remains controversial. Some vision may be recovered with high-dose steroids even if vision declines to no light perception from ARN-associated optic neuropathy (Culbertson & Atherton 1993). Lee et al. (1998) described two patients with AIDS and bilateral VZV optic neuritis that preceded retinitis. With treatment, these patients experienced recovery of vision in eyes which previously had no light perception. The treatment of patients with visual acuity of no light perception also may decrease the risk to the contralateral eye (Palay et al. 1991).

Differential Diagnosis

Optic nerve disease associated with ARN or PORN must be differentiated from optic nerve disease due to other aetiologies. This may be particularly challenging because optic neuropathy may be the presenting sign of ARN or PORN. ARN and PORN, therefore, should be included in the differential diagnosis of acute optic nerve swelling. Other causes of optic nerve swelling such as autoimmune optic neuritis, increased intracranial pressure, nonarteritic anterior ischaemic optic neuropathy (NA-ION) (Friedlander et al. 1996), or other infectious aetiologies may present in a similar manner. If ARN/PORN is suspected, inquiring about the immunologic status and any recent history of cutaneous herpesvirus infection is prudent.

Laboratory analysis using polymerase chain reaction (PCR) may help differentiate causes of ocular inflammation. Tran et al. (2003) showed that an anterior chamber (AC) tap with PCR analysis is highly sensitive for diagnosing herpetic retinitis. Sims et al. (2009) reviewed the outcomes of 23 eyes with ARN. In every patient (100%, 10/10) that underwent an AC tap, there was identification of the viral agent by PCR. AC tap was recommended as the first laboratory investigative method for ARN (Sims et al. 2009).

Conclusion

Optic neuropathy in ARN may have a sudden onset and devastating visual outcome. While advances in retinal detachment prevention and repair have continued to develop, the treatment of the optic nerve component of this disease has not evolved to any appreciable degree. Currently, it appears that the most important parameter for preserving vision is early diagnosis and treatment of this disease with antiviral medication. Accurate and timely diagnosis, however, may be difficult given the appearance of the optic nerve in this disease, which mimics other causes of optic nerve pathology.

Future studies should evaluate the potential risk factors for optic nerve involvement in this syndrome. It may be particularly useful to delineate the reasons why certain patients with optic nerve inflammation associated with ARN are able to improve with therapy and retain useful vision, while other patients have a rapid deterioration of visual acuity. In addition, controlled studies that examine the efficacy and safety of potential treatments for the optic nerve component of the disease are needed.

Acknowledgements

As the corresponding author, I take responsibility for the integrity of the data and the accuracy of the analysis as well as the decision to submit for publication. Contributions of Authors: Design of the review (MW, PP, GL); Research for the review (MW, GL); Writing of the review (MW, PP, BF, GL); Proofreading of the review (MW, PP, GL). Prior Submissions of Manuscript: None. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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