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Herpes Zoster Optic Neuropathy

Kaufman, Aaron, R., BA; Myers, Eileen, M., MD; Moster, Mark, L., MD; Stanley, Jordan, MD; Kline, Lanning, B., MD; Golnik, Karl, C., MD, MEd

Journal of Neuro-Ophthalmology: June 2018 - Volume 38 - Issue 2 - p 179–189
doi: 10.1097/WNO.0000000000000607
Original Contribution
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Background: Herpes zoster optic neuropathy (HZON) is a rare manifestation of herpes zoster ophthalmicus (HZO). The aim of our study was to better characterize the clinical features, therapeutic choices, and visual outcomes in HZON.

Methods: A retrospective chart review was performed at multiple academic eye centers with the inclusion criteria of all eyes presenting with optic neuropathy within 1 month of cutaneous zoster of the ipsilateral trigeminal dermatome. Data were collected regarding presenting features, treatment regimen, and visual acuity outcomes.

Results: Six patients meeting the HZON inclusion criteria were identified. Mean follow-up was 2.75 months (range 0.5–4 months). Herpes zoster optic neuropathy developed at a mean of 14.1 days after initial rash (range 6–30 days). Optic neuropathy was anterior in 2 eyes and retrobulbar in 4 eyes. Other manifestations of HZO included keratoconjunctivitis (3 eyes) and iritis (4 eyes). All patients were treated with systemic antiviral therapy in addition to topical and/or systemic corticosteroids. At the last follow-up, visual acuity in 3 eyes had improved relative to presentation, 2 eyes had worsened, and 1 eye remained the same. The 2 eyes that did not receive systemic corticosteroids had the best observed final visual acuity.

Conclusion: Herpes zoster optic neuropathy is an unusual but distinctive complication of HZO. Visual recovery after HZON is variable. Identification of an optimal treatment regiment for HZON could not be identified from our patient cohort. Systemic antiviral agents are a component of HZON treatment regimens. Efficacy of systemic corticosteroids for HZON remains unclear and should be considered on a case-by-case basis.

Boston University School of Medicine (ARK), Boston, Massachusetts; Department of Ophthalmology (EMM, KCG), University of Cincinnati, Cincinnati Eye Institute, Cincinnati, Ohio; Neuro-Ophthalmology Service (MLM), Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania; and Department of Ophthalmology (JS, LBK), University of Alabama School of Medicine, Birmingham, Alabama.

Address correspondence to Karl C. Golnik, MD, MEd, Cincinnati Eye Institute, University of Cincinnati, 1945 CEI Drive, Cincinnati, OH 45242; E-mail: golnikkarl@gmail.com

Presented as poster “Herpes Zoster Optic Neuropathy in Patients With Herpes Zoster Ophthalmicus” at the 2016 American Academy of Ophthalmology Annual Meeting, October 15–18, 2016; Chicago, IL.

The authors report no conflicts of interest.

Herpes zoster ophthalmicus (HZO) has a diverse spectrum of presentations that can include both anterior and posterior segment pathology (1). Herpes zoster optic neuropathy (HZON) is a rare manifestation that has been reported to occur in 0.4% of eyes with HZO (2). This optic neuropathy develops after the cutaneous appearance of the herpes zoster rash within the ophthalmic branch of the trigeminal nerve (V1). Previous reports of HZON have only included clinical descriptions of 1 or 2 eyes. The aim of this case series is to better characterize the clinical features, therapeutic choices, and visual outcomes in HZON.

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METHODS

Institutional review board approval was acquired from all sites, and study design was consistent with both the Declaration of Helsinki and the Health Insurance Portability and Accountability Act. A multicenter retrospective review of medical records was performed at University of Cincinnati/Cincinnati Eye Institute, Wills Eye Hospital, and University of Alabama Department of Ophthalmology. The inclusion criteria used were patients with optic neuropathy occurring within 1 month of cutaneous zoster of the ophthalmic division of the ipsilateral trigeminal dermatome. A 1-month time interval was chosen to decrease the possibility of coincidental causes of optic neuropathy such as nonarteritic anterior ischemic optic neuropathy or optic neuritis and to identify cases with strong temporal association between the rash and optic neuropathy. Cases of optic neuropathy occurring in the setting of an orbital apex syndrome due to HZO were specifically excluded because this was believed to represent a distinct HZO manifestation. After initial evaluation and initiation of treatment by a general ophthalmologist or optometrist, patients were referred to a neuro-ophthalmologist (K.C.G., M.L.M., L.B.K.) for further evaluation, and the clinical diagnosis of optic neuropathy was established by the neuro-ophthalmologist. Snellen visual acuities at each visit, other HZO manifestations, and treatment regimens were reviewed. Chart review was performed to last follow-up with the neuro-ophthalmologist.

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RESULTS

Seven eyes that met the inclusion criteria were identified. However, 1 eye was excluded because the patient had a history of polymyalgia rheumatica and was not evaluated by a neuro-ophthalmologist until 3 months after onset of optic neuropathy, making the diagnosis of HZON uncertain. The remaining 6 eyes were included in this analysis (Table 1). The criteria for diagnosis of optic neuropathy included the presence of relative afferent pupillary defect accompanied by decreased vision and new visual field defect and/or impaired identification of Ishihara plates. Treatment regimens, described in more detail later in this section, included local and systemic treatment with antiviral and corticosteroid agents. Mean patient age was 64 years (range: 30–79 years). Mean follow-up time with a neuro-ophthalmologist was 2.75 months (range: 0.5–4 months).

TABLE 1-a

TABLE 1-a

TABLE 1-b

TABLE 1-b

TABLE 1-c

TABLE 1-c

Herpes zoster optic neuropathy presentation developed at a mean of 14.1 days after initial appearance of a skin rash (range: 6–30 days). Four eyes developed retrobulbar optic neuropathy, and 2 eyes had an anterior optic neuropathy with optic disc edema. Other HZO manifestations included iritis (4 eyes) and keratoconjunctivitis (3 eyes). No patient developed vitritis or posterior segment manifestations such as retinitis or retinal necrosis, and none developed central nervous system zoster infection.

All patients had ancillary testing by either the neuro-ophthalmologist or the referring physician. However, given the retrospective nature of the study, the detailed testing results were only available for 2 patients. Both had brain MRI with contrast, and neither showed enhancement or other abnormality of the optic nerve. White matter changes were detected in the patient with multiple sclerosis, but in the other patient, the brain was normal in appearance. The erythrocyte sedimentation rate and C-reactive protein (CRP) assays were normal in both patients. Cerebrospinal fluid (CSF) analysis in the patient with a history of multiple sclerosis showed mild lymphocytic pleiocytosis but was unremarkable in the other patient. Varicella zoster virus (VZV) polymerase chain reaction CSF analysis was negative in both patients. Investigations of other infectious etiologies for the optic neuropathy by serum and/or CSF laboratories were negative in both patients.

Treatment modalities for all eyes included systemic antiviral therapy in addition to topical and/or systemic corticosteroids. Antiviral therapy had been completed in 2 patients before HZON onset, whereas HZON developed during ongoing antiviral therapy in the remaining 4 eyes. Of the 4 patients who received systemic corticosteroids, 1 was already on corticosteroid therapy for an unrelated medical condition. Thus, this patient developed HZON in the setting of the ongoing corticosteroid therapy.

Visual acuity in 3 eyes had improved compared with vision at presentation, and 2 eyes worsened. One patient who presented with no light perception vision showed no change in visual acuity at last follow-up. Both eyes that did not receive systemic corticosteroids showed visual acuity improvement and experienced the best visual acuity at final follow-up. One of the 4 eyes receiving systemic corticosteroids improved relative to initial presentation.

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DISCUSSION

Our study demonstrated that HZON has a spectrum of disease manifestations that may lead to varying treatment approaches. In addition, visual prognosis in HZON is highly variable because HZON may completely resolve in some patients or may cause severe visual loss even with treatments that are efficacious for other manifestations of HZO.

Previous reports satisfying the inclusion criteria of our study were identified for comparison with the current series (Table 2) (3–18). Reports of HZON developing more than 1 month after HZO (19–23), occurring before development of a skin rash (24), after nontrigeminal zoster rash (25), developing contralateral to the rash (26), and bilaterally occurring optic neuropathy (5,19) also have been published. In both this and previous series, HZON presented as either an anterior (3,4,6–11,16–18) or retrobulbar optic neuropathy (5,12–16). The retrobulbar form was more common in our patient cohort, although the anterior variant has been more frequently reported in the literature. The variable presentation of the optic neuropathy also was seen in its appearance on imaging. Two of our patients had brain MRI that was unremarkable, and previous reports have documented cases both with (16,18) and without (6) optic nerve enhancement. In addition, posterior scleritis has been documented with HZON (2), but this was not observed in our series.

TABLE 2-a

TABLE 2-a

TABLE 2-b

TABLE 2-b

TABLE 2-c

TABLE 2-c

TABLE 2-d

TABLE 2-d

Anterior segment complications of HZO were common in our patients, as a majority had keratoconjunctivitis and/or iritis. The association of anterior segment HZO with HZON is well characterized by previous studies (4–8,10–14,16,17). Herpes zoster ophthalmicus intermediate and posterior segment complications other than the optic neuropathy were not observed in our series, although vitiris (7,17) choroidal involvement (9), acute retinal necrosis (ARN) (27,28), and progressive outer retinal necrosis (PORN) (24,29) previously have been described. Also, it has been reported that retrobulbar optic neuropathy may precede development of ARN (27,28) and PORN (24,29) in immunocompromised individuals.

The close temporal relationship of optic neuropathy after the development of cutaneous zoster provided the basis for diagnosing HZON. Although ophthalmic manifestations of herpes zoster may be delayed by up to 6 months or more (19,20,30), our case series used a relatively narrow timeframe of 1 month between trigeminal rash and onset of optic neuropathy to confirm attribution of the optic neuropathy to VZV (3–18). The mean time from rash to HZON in our series was 14.1 days (range: 6–30 days).

In addition to a clear temporal association between the cutaneous zoster and optic neuropathy, ancillary testing may be used in diagnosing HZON, particularly in excluding other potential causes. Brain MRI is helpful in excluding demyelinative optic results. Erythrocyte sedimentation rate and CRP may be useful in excluding giant cell arteritis. Levels of these nonspecific inflammatory markers previously have been reported as normal in HZON (3,5,11,13,14). Excluding other infectious causes of optic neuropathy may require additional serum and CSF studies (7,13,14,16,17). CSF analysis in HZON may show a mild lymphocytic pleocytosis (5,9,12,14), although this was not observed in 1 patient in our series. Varicella zoster virus PCR of CSF was normal in our patients and in a previous report (9) and, thus, did not aid in the diagnosis of HZON. High levels of VZV antibody in CSF were reported in 1 case of HZON (9) and elevated serum VZV antibody titers also have been reported (9,12,16,17). Thus, there may be a role for CSF and/or serum antibody studies in diagnosing HZON.

While the precise pathophysiologic mechanism of HZON is unknown, it seems that it is likely multifactorial given the diversity of HZON presentation (18). Gündüz and Özdemir (5) first proposed a unifying 3-component mechanism attributing optic nerve involvement to direct viral invasion of the optic nerve (via trans-synaptic [31–33] and hematogenous routes [34]), extension of local inflammation from adjacent meningeal and brain tissue (35,36) and/or generalized ocular ischemia (37). Perineuritis, a common pathologic finding in HZO, also could play a role in vision loss in HZON (35).

Although treatment regiments of our patients were diverse, all received systemic antiviral therapy in addition to topical and/or systemic corticosteroids. In all our patients, treatment with systemic antiviral agents (acyclovir, valacyclovir, and famciclovir) was started before the onset of HZON due to cutaneous and/or ophthalmic disease manifestations. However, HZON may progress despite aggressive systemic antiviral therapy. Previous reports and our study have yet to define the role for systemic corticosteroids in treatment of HZON. Based on the previously reported cases which satisfy our study's inclusion criteria (Table 2), corticosteroids seem to improve the visual outcome. Of the prior reports, 9 of 12 patients (75%) receiving systemic corticosteroids showed improved final acuity (3,4,6,7,9,11–14,16,18), whereas 3 of 5 patients (60%) who did not receive corticosteroids showed improved final visual acuity (5,8,10,15,17). In contrast, in our patient cohort, only 1 of the 4 patients treated with corticosteroids showed visual acuity improvement, whereas both eyes that did not receive systemic corticosteroids had the best final acuity (20/25 and 20/50).

Conclusions regarding treatment of HZON based on our case series are subject to several limitations. Treatment regimens were diverse due to patient management by different clinicians. In addition, involvement of different providers at different institutions introduced a selection bias. Different medical comorbidities also may have affected treatment outcomes. Finally, the retrospective nature of our study and relatively small number of patients also limit our conclusions.

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