Herpes Zoster Optic Neuropathy

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. 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. 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. 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.

Original Contribution Herpes Zoster Optic Neuropathy Aaron R. Kaufman, BA, Eileen M. Myers, MD, Mark L. Moster, MD, Jordan Stanley, MD, Lanning B. Kline, MD, Karl C. Golnik, MD, MEd 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 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. 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. Address correspondence to Karl C. Golnik, MD, MEd, Cincinnati Eye Institute, University of Cincinnati, 1945 CEI Drive, Cincinnati, OH 45242; E-mail: [e-mail] Kaufman et al: J Neuro-Ophthalmol 2018; 38: 179-189 HZON remains unclear and should be considered on a caseby-case basis. Journal of Neuro-Ophthalmology 2018;38:179-189 doi: 10.1097/WNO.0000000000000607 © 2017 by North American Neuro-Ophthalmology Society H erpes 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. 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 179 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 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 neuroophthalmologist. 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. 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). 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 neuroophthalmologist 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. 180 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. 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. 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 Kaufman et al: J Neuro-Ophthalmol 2018; 38: 179-189 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Kaufman et al: J Neuro-Ophthalmol 2018; 38: 179-189 Age/ Sex Days From Rash to HZON Optic Neuropathy Description BCVA at Initial Presentation for HZON Other HZO Manifestations 72/F 21 Retrobulbar ON HM Iritis Completed before HZON onset: Famciclovir 500 mg po TID (1 wk) Acyclovir 5% ung TID (1 wk) Tobramycin/ dexamethasone 0.3%/ 0.1% gtt QID (10 d) Prednisolone acetate 1% gtt QID (1 wk) Started after HZON onset: Loteprednol 0.5% gtt QID (1 wk), followed by TID (3 wk) 20/50 79/M 6 Retrobulbar ON 20/400 Iritis Started before HZON onset: Valacyclovir 1 g po TID (2 wk) Started after HZON onset: Prednisolone acetate 1% gtt QID (3 mo) Prednisolone 40 mg po daily (taper over 6 wk) 30/F 30 Retrobulbar ON 20/40 Keratoconjunctivitis Completed before HZON onset: Systemic antiviral (regimen not clarified) HZON management (not clarified if initiated before or after HZON onset): Tobramycin/ dexamethasone 0.3%/ 0.1% gtt QID (3 wk) Difluprednate 0.05% gtt daily (3 wk) Treatment (Length) Length of BCVA at Follow-up Last Follow- After up HZON (mo) Medical Comorbidity Ancillary Diagnostic Laboratories and Imaging 1 -- -- HM 4 -- -- 20/25 2 -- -- Original Contribution 181 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Clinical data of patients with herpes zoster optic neuropathy Age/ Sex Days From Rash to HZON Optic Neuropathy Description BCVA at Initial Presentation for HZON Other HZO Manifestations 63/M 6 Anterior ON 20/30 Keratoconjunctivitis 66/F 8 Retrobulbar ON NLP Treatment (Length) Length of BCVA at Follow-up Last Follow- After up HZON (mo) Started before HZON onset: CF at 2-3 feet Valacyclovir 1 g po TID (2 wk) Fluoromethalone 1% gtt QID (1 wk), followed by QHS (2 wk) Prednisone 10 mg po TID (2 wk) Keratoconjunctivitis, Started before HZON onset: Iritis Acyclovir 800 mg po 5·/d (9 d) Started after HZON onset: Acyclovir 5-10 mg/kg iv q8h (5 d) Methylprednisolone 1 g iv daily (5 d), followed by prednisone 80 mg po daily (tapered over 10 d) NLP 4 0.5 Medical Comorbidity HZON developed while on prednisone for unknown jaw pathology Patient had 15-yr history of multiple sclerosis Ancillary Diagnostic Laboratories and Imaging -- Kaufman et al: J Neuro-Ophthalmol 2018; 38: 179-189 MRI (with contrast and fat suppression) at 1 wk after HZON onset showed no optic nerve enhancement; contrast-enhanced brain sections showed stable white matter changes Serum laboratories: ESR 35, CRP 0.85, WBC 8.2 CSF laboratories (with 1 wk trend): RBC 499 due to hemorrhagic tap, 8 nucleated cells (75% lymphs, 18% monocytes, 1% bands) (1-5), glucose 134 (40-70), protein 45 (12-60), HSV PCR 1/2 neg, CMV PCR neg, EBV PCR neg, VZV PCR neg, cultures neg Original Contribution 182 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Kaufman et al: J Neuro-Ophthalmol 2018; 38: 179-189 Age/ Sex Days From Rash to HZON Optic Neuropathy Description BCVA at Initial Presentation for HZON Other HZO Manifestations 76/F 14 Anterior ON 20/400 Iritis Treatment (Length) Length of BCVA at Follow-up Last Follow- After up HZON (mo) Started before HZON onset: 20/300 Valacyclovir 1 g po TID (10 d) Started after HZON onset: Prednisone 60 mg daily (tapered over 4 wk) 5 Medical Comorbidity -- Ancillary Diagnostic Laboratories and Imaging MRI with contrast after HZON onset showed no nerve enhancement nor evidence of lesion on brain sections Serum laboratories: ESR 4, CRP ,0.5, ANA 1:40, Lyme Ab neg, HIV Ab neg, ACE neg, RPR neg, FTA neg, ANCA neg CSF laboratories: WBC 2, Protein 32, OCB neg, IgG neg, HSV neg, Lyme neg, VDRL neg, VZV PCR neg, MBP neg, ACE neg, cultures neg Treatment modalities designated "Started before HZON onset" refer to drugs that were initiated before and continued after the onset of optic neuropathy. ACE, angiotensin converting enzyme; ANA, anti-nuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; BCVA, best-corrected visual acuity; CF, count fingers; CMV, cytomegalovirus; CRP, C-reactive protein; EBV, Epstein-Barr virus; ESR, erythrocyte sedimentation rate; F, female; FTA, fluorescent treponemal antibody; HM, hand motion; HSV, herpes simplex virus; HZON, herpes zoster optic neuropathy; M, male; MBP, myelin basic protein; NLP, no light perception; OCB, oligoclonal bands; ON, optic neuropathy; PCR, polymerase chain reaction; RBC, red blood cell count; RPR, rapid plasma reagin; VDRL, venereal disease research laboratory test; VZV, varicella zoster virus; WBC, white blood cell count. Original Contribution 183 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) BCVA at Optic Initial Neuropathy Presentation Description for HZON Age/Sex Time From Rash to HZON Atmaca and Ozmert (3) 58/M 9d Anterior ON CF at 1.5 meter -- Started after HZON onset: oral corticosteroids, periocular steroid injections NLP 3 Serum laboratories: CRAO occurred after ESR wnl, WBC wnl HZON X-ray of skull and sella turcica: wnl Freitas-Neto et al (4) 58/F Rash present at HZON onset Anterior ON 20/200 Iritis Started after HZON onset: topical corticosteroid, oral prednisone, oral valacyclovir 20/20 1 FA: hyperfluorescence with late dye leakage in optic nerve OCT: thickening of retinal fiber layers around nerve head Gündüz and Özdemir (5) 48/M 5d 20/50 12 Serum laboratories: WBC wnl, ESR wnl CSF: lymphocytic pleiocytosis Hong and Yang (6) 6/F 1 wk Anterior ON 20/50 Completed before HZON 20/25 onset: oral acyclovir Started before HZON onset: topical prednisolone Started after HZON onset: oral acyclovir, oral prednisolone 12 FA: hyperfluorescence in optic disk, increased in later phase OCT: swelling of optic disc MRI: wnl Litoff and Catalano (7) 40/F Rash present at HZON onset Anterior ON LP 2 Serum laboratories: Patient was HIV+ FTA neg, VDRL neg, toxoplasma Ab wnl, CMV culture neg CSF laboratories: cryptococcal Ag neg Urine: CMV culture neg CT: diffusely enlarged optic nerve Study Retrobulbar ON 20/200 Other HZO Manifestations Length of BCVA at Follow-up Last After HZON Follow-up (mo) Treatment Stromal keratitis, iritis, Started after HZON onset: topical dexamethasone, topical acyclovir Iritis Kaufman et al: J Neuro-Ophthalmol 2018; 38: 179-189 Dendritic keratitis, iritis, vitritis, peripheral retinitis Used for contralateral HZO 3 wk before ipsilateral HZO, but completed before HZON onset: IV Acyclovir Started after HZON onset: IV acyclovir, IV methylprednisolone, oral acyclovir, topical fluoromethalone NLP Ancillary Testing Results Additional Comment -- Contralateral eye also developed retrobulbar HZON (presenting at 20/50 3 wk after rash, improving to 20/25) -- Original Contribution 184 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Previous reports of herpes zoster optic neuropathy Kaufman et al: J Neuro-Ophthalmol 2018; 38: 179-189 BCVA at Optic Initial Neuropathy Presentation Description for HZON Age/Sex Time From Rash to HZON 9/M ,2 wk Anterior ON CF at 29 Iritis, retinitis Started after HZON onset: topical steroid Nakazawa et al 62/M (9) 2 wk Anterior ON 20/200 Conjunctivitis, choroidal involvement Ramsell (10) 78/F 2 wk Anterior ON LP Scharf et al (11) 73/M 10 d Anterior ON Schmidt (12) 73/F 4 wk Retrobulbar ON Study Monroe (8) Other HZO Manifestations Length of BCVA at Follow-up Last After HZON Follow-up (mo) Ancillary Testing Results Additional Comment 1 -- -- Completed before HZON 20/20 onset: IV acyclovir Started after HZON onset: IV acyclovir, IV prednisolone followed by oral prednisolone 12 Serum laboratories: VZV IgG high titer, CF Ab high titer CSF laboratories: lymphocytic pleocytosis, protein wnl, glucose wnl, VZV IgG pos, VZV PCR neg FA: hyperfluorescence in optic nerve in late phase CT: optic nerve wnl -- Punctate keratitis, iritis, complete ophthalmoplegia After HZON onset: topical prednisolone 20/60 3 -- -- CF Conjunctivitis, subepithelial keratitis Completed before HZON onset: systemic antiviral therapy After HZON onset: systemic corticosterioid NLP 12 Serum laboratories: CRAO occurred ESR wnl, mild after HZON leukocytosis (differential wnl) X-ray of skull and sella turcica: wnl LP Epithelial keratitis Completed before HZON 20/600 onset: topical vidaribine After HZON onset: oral prednisone 8 Serum laboratories: no leukocytosis, elevated VZV titer CSF laboratories: lymphocytic pleocytosis CT: thickening of the optic nerve Treatment CF -- Original Contribution 185 Copyright © North American Neuro-Ophthalmology Society. 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(Continued ) Study Age/Sex Time From Rash to HZON BCVA at Optic Initial Neuropathy Presentation Description for HZON Other HZO Manifestations Treatment Length of BCVA at Follow-up Last After HZON Follow-up (mo) Ancillary Testing Results Additional Comment Singh et al (13) 58/M #4 d Retrobulbar ON 20/120 Conjunctivitis, iritis Started before identification of HZON: oral acyclovir, topical acyclovir, topical steroid Started after HZON onset: oral prednisolone 20/20 8 Serum laboratories: ESR wnl, HIV 1/2 neg -- Tunis and Tapert (14) 19/M 27 d Retrobulbar ON NLP Conjunctivitis, dendritic keratitis After HZON onset: oral prednisone CF at 2 feet 3 Serum laboratories: ESR wnl, syphilis neg CSF laboratories: mild lymphocytic pleiocytosis CT of head and orbits: wnl -- z40/F 7d Retrobulbar ON NLP No antiviral or corticosteroid agents NLP 13 -- -- 2 wk Anterior ON 20/600 20/28.7 3 Serum laboratories: VZV IgG pos, VZV IgM pos, syphilis neg, HIV neg FA: late staining of optic disc CT: swelling of optic nerve without contrast enhancement MRI: optic nerve sheath enhancement on T1-weight -- Veasey (15) Wang et al 72/M (16); Case 1 -- Punctate keratitis, complete ophthalmoplegia Kaufman et al: J Neuro-Ophthalmol 2018; 38: 179-189 Completed before HZON onset: IV acyclovir Started after HZON onset: IV acyclovir followed by oral acyclovir, oral prednisolone Original Contribution 186 Copyright © North American Neuro-Ophthalmology Society. 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(Continued ) Kaufman et al: J Neuro-Ophthalmol 2018; 38: 179-189 Study Age/Sex Time From Rash to HZON Wang et al 69/M (16); Case 2 12 d Winward et al (17) 22/M 1 wk Yalcinbayir et al (18) 48/M BCVA at Optic Initial Neuropathy Presentation Description for HZON Retrobulbar ON Anterior ON .1 wk but rash Anterior ON present at HZON onset 20/50 HM 20/200 Other HZO Manifestations Conjunctivitis, punctate keratitis Treatment Completed before HZON onset: IV acyclovir followed by oral acyclovir Started after HZON onset: IV acyclovir followed by oral acyclovir, oral prednisolone Conjunctivitis, iritis, Completed before vitritis, acute retinal HZON: topical necrosis corticosteroid, oral acyclovir Started after HZON onset: IV acyclovir -- Completed before HZON: oral acyclovir Started after HZON onset: IV acyclovir followed by oral acyclovir, oral prednisolone Length of BCVA at Follow-up Last After HZON Follow-up (mo) Ancillary Testing Results Additional Comment 20/22.3 1 Serum laboratories: VZV IgG pos, VZV IgM neg, RPR neg FA: normal MRI: ring-shaped optic nerve enhancement on T1-weight -- 20/60 1.5 Serum laboratories: leukopenia, elevated VZV titer, minimally reactive FTA, RPR neg, VDRL neg, toxoplasma neg Patient was HIV+ 20/40 12 Serum laboratories: WBC wnl, extensive workup for primary and acquired immunodeficiency neg MRI: optic nerve thickening and contrast enhancement -- Original Contribution Previous literature reports of herpes zoster optic neuropathy cases satisfying the inclusion criteria for our study (optic neuropathy occurring within 1 month of ipsilateral cutaneous zoster of trigeminal dermatome). Visual acuities have been converted to Snellen 20-foot notation to facilitate comparison. Treatment regimens list only antiviral and steroid agents and exclude other agents such as cycloplegics and antibiotics. Treatment modalities designated "Started before HZON onset" refer to drugs that were initiated before and continued after the onset of optic neuropathy. BCVA, best-corrected visual acuity; CF, count fingers; CMV, cytomegalovirus; CRAO, central retinal artery occlusion; CSF, cerebrospinal fluid; ESR, erythrocyte sedimentation rate; F, female; FA, fluorescein angiography; FTA, fluorescent treponemal assay; HIV, human immunodeficiency virus; HM, hand motion; HZO, herpes zoster ophthalmicus; HZON, herpes zoster optic neuropathy; LP, light perception; M, male; NLP, no light perception; OCT, optical coherence tomography; RPR, rapid plasma reagin; VDRL, veneral disease research laboratory test; VZV, varicella zoster virus; WBC, white blood cell count; wnl, within normal limits. 187 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Original Contribution (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 188 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. 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