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Show STATE OF THE ART Complete Unilateral Ophthalmoplegia in Herpes Zoster Ophthalmicus Srinivasan Sanjay, MBBS, MRCS( Edin), Errol Wei'en Chan, MBBS, Lekha Gopal, MBBS, FRCS( Edin), Smita Rane Hegde, MBBS, MS( Ophthal), and Benjamin Chong- Ming Chang, MB, BCh, BAO, FRCS( Irel), FRCS( Edin), FRCOphth( Lond) Abstract: Based on a review of 20 well- documented cases reported in the English literature between 1968 and 2008, herpes zoster ophthalmicus ( HZO) may rarely be associated with complete unilateral oph-thalmoplegia, defined here as impaired ocular ductions in all 4 directions within 3 months of onset of manifestations of HZO. Ophthalmoplegia occurred equally in immune- competent and immune-incompetent individuals. HZO preceded ophthalmo-plegia in 75% by a mean interval of 9.5 days and a range of 2 to 60 days, occurred simultaneously with ophthalmoplegia in 20%, and followed by 2 days the onset of ophthalmoplegia in only 5%. Concurrent conjunctival inflammation, keratitis, or anterior uveitis was present in 90%. Lumbar puncture showed features of aseptic meningitis in 88%, slightly more than the 40% 250% found in patients with HZO without ophthalmoplegia. On orbit/ brain imaging, abnormal enlargement of the extraocular muscles was present in 33%, and orbital soft tissue swelling was present in 17%. Enhancement of ocular motor cranial nerves was not reported. Complete or near- complete resolution of ophthalmoplegia occurred in 65% within a range of 2 weeks to 1.5 years ( mean 4.4 months). A single autopsy report described granulo-matous angiitis of the meninges and large vessels in the anterior cerebral circulation, as well as periaxial infarction in the optic nerve, pons, and medulla but without viral inclusion bodies or antigen. Unsettled issues are whether the pathogenesis is direct viral invasion or an immune reaction to the virus, whether the impaired ocular ductions are based on myopathic or neuropathic injury, whether there are predisposing factors to the combination of HZO and complete ophthalmoplegia, and whether treatment is effective. ( J Neuro- Ophthalmol 2009; 29: 3252337) H erpes zoster ophthalmicus ( HZO) refers to involve-ment of the ophthalmic division of the trigeminal nerve from reactivation of latent varicella zoster virus ( VZV) harbored in the trigeminal sensory ganglion. It is characterized by an acute dermatomal eruption that evolves through papular, vesiculobullous, pustular, and crusting stages over days to 3 weeks. The zoster rash is often accompanied by periocular pain and neurosensory dis-turbances in the first trigeminal division. Ocular manifestations are observed in 20% 270% of patients with HZO, with involvement of every ocular struc-ture ( 1). Postherpetic neuralgia is the most common neuro-logic sequela, but other neurologic complications, including cranial nerve palsies, stroke, myelitis, meningoencephalitis, and polyneuropathy, have also been reported ( 1,2). Ocular motor cranial nerve palsies are reported in 5% 231% of patients, but the occurrence of complete unilateral ophthalmoplegia, defined here as concurrent unilateral impairment of ocular ductions in all directions, is rarer ( 2,3). In 1948, Edgerton ( 3) summarized 40 cases of unilateral ophthalmoplegia associated with HZO reported up to 1940. A review by Chang- Godinich et al ( 4) in 1997 included 16 cases reported from 1968 to 1997 and provided a comprehensive evaluation of this condition. However, that review did not include cases reported between 1948 and 1968 or 2 cases ( 5,6) reported much later with unusual clinical features. In addition, some of the reports included ( 7,9211) contained very brief clinical information on the presentation, outcomes, and underlying systemic diseases, limiting a discussion on these aspects of this condition. In this review the risk and prognostic factors, diagnostic utility of lumbar puncture and neuroimaging studies, efficacy of different treatment modalities, and the pathophysiologic basis of this condition in the light of recent neuroimaging findings will be addressed. Department of Ophthalmology and Visual Sciences ( SS, EWC, LG, SRH, BC- MC), Alexandra Hospital, Singapore; Eye Clinic ( SS, EWC, LG, SRH, BC- MC), Jurong Medical Centre, Singapore; and Department of Ophthalmology ( BC- MC), KK Women's and Children's Hospital, Singapore. Address correspondence to S. Sanjay, MBBS, MRCS( Edin), Depart-ment of Ophthalmology and Visual Sciences, Alexandra Hospital, 378 Alexandra Road, Singapore 159964; E- mail: sanjay_ s@ alexhosp. com. sg J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 325 METHODS A literature search was conducted on Medline, OVID, Cochrane Library, UpToDate, and Google Scholar data-bases using the key words: ‘‘ herpes zoster ophthalmicus,'' ‘‘ complete ophthalmoplegia,'' ‘‘ external ocular nerve palsy,'' ‘‘ oculomotor,'' ‘‘ abducens,'' and ‘‘ trochlear'' for articles published in the last 60 years ( 19482September 2008). Articles published before these databases were established were gathered from references in the more recent articles. We defined complete unilateral ophthalmoplegia as impaired ductions in all 4 directions of gaze in the eye ipsilateral to the HZO occurring simultaneously or con-secutively within 3 months of the onset of HZO. We included only cases in which the abstracts and full articles were published in the English language. We excluded cases that had inadequate documentation of the underlying systemic conditions, clinical features, treatment, or clinical course. We excluded cases with bilateral ophthalmoplegia, with extraocular motility deficits in 3 or fewer directions of gaze, with involvement of 2 or fewer ocular motor cranial nerves, and without adequate documentation of HZO. We adopted a hierarchical approach toward the selection of articles by applying the inclusion and exclusion criteria to the titles and abstracts of all articles and subsequently to the full reports. The articles were reviewed to determine the spectrum of clinical presentation, disease course, investigations, treatment modalities, and outcomes. Intraocular inflammation was present if there was evidence of corneal edema, keratitis, uveitis, vitritis, papillitis, or retinal necrosis. A successful clinical outcome was defined as complete or near- complete recovery of ophthalmoplegia with or without improvement in ptosis. Based on the application of these inclusion criteria to the titles, abstracts, and full reports, we identified 17 articles comprising a total of 20 cases published between 1948 and September 2008 ( 426,12225). Four articles comprising 8 cases, previously included in the analysis by Chang- Godinich et al ( 4) were excluded from this review based on at least 1 of the following reasons: 1) lack of clear documentation of underlying systemic conditions, clinical features, treatment, or outcome ( 7,9211); 2) development of bilateral rather than unilateral ophthalmoplegia ( 10); and 3) absence of documented HZO ( 8). Eleven of the 17 included articles, representing 11 cases, were published between 1998 and 2008 ( 12222). CLINICAL FEATURES Table 1 summarizes the clinical signs and symptoms, investigation findings, treatment, clinical course, and outcome for the 20 cases we reviewed. There were 9 men and 11 women. The mean age was 66.2 6 14.1 years with a range between 41 and 84 years. Nine patients ( 45%) were receiving medical immunosup-pression, in the form of systemic corticosteroids or chemotherapy, or had underlying hematologic or solid organ malignancy or systemic connective tissue disease, including scleroderma or rheumatoid arthritis ( 4,6,12,14, 20,23,24). Systemic treatment before the development of ophthalmoplegia included antiviral therapy ( acyclovir or valacyclovir) alone in 7 patients ( 35%), corticosteroids alone in 1 patient ( 5%), and a combination of acyclovir and corticosteroids in 1 patient ( 5%) ( 4,6,13,15,17,18,20,22). Acyclovir was administered orally in 3 patients and intra-venously in 4 patients; corticosteroids were administered orally in 1 patient and intravenously in 1 patient. Most patients ( 55%) had not received treatment before the onset of ophthalmoplegia. HZO preceded the onset of ophthalmoplegia in 15 patients ( 75%) ( 4,6,13,15218,20,22225), with a mean time interval of 9.5 days ( range 2242 days), occurred simultaneously with ophthalmoplegia in 4 patients ( 20%) ( 5,12,14,21), and occurred 2 days after the onset of ophthalmoplegia in 1 patient ( 5%) ( 19) ( Fig. 1). There was concurrent anterior segment involvement in 18 patients ( 90%) ( 4,6,12225), including conjunctival inflammation, keratitis, and anterior uveitis. The severity of anterior uveitis was mild to moderate in all patients; none demon-strated a fibrinous reaction or hypopyon. Posterior segment abnormalities were observed in 4 patients ( 20%), including vitritis, blurring of the optic disc margins, and acute retinal necrosis ( 12,16,17,24,25). The other presenting neuro- ophthalmic character-istics included complete or incomplete ptosis in all 20 patients ( Fig. 2) ( 100%) ( 426,12225), a fixed dilated pupil in 17 patients ( 85%) 426,12214,16217,20225), optic neuropathy in the context of an orbital apex syndrome in 4 patients ( 20%) ( 4,12,23,24), and proptosis in 12 patients ( 60%) ( 426,12,15,18220,23225). An ipsilateral lower motor neuron facial nerve palsy was seen in 1 patient ( 5%) ( 21). Presenting clinical signs and symptoms suggestive of meningitis or encephalitis were seen in 5 patients ( 25%) ( 426,18,24). Based on this review, complete unilateral ophthal-moplegia appears to be associated with HZO in older patients although it may occur in patients aged 50 years or younger. In the 3 patients younger than age 50, 1 had underlying scleroderma and previous treatment with peni-cillamine and plasmapheresis, which had been completed by an undocumented time interval before the presentation with HZO ( 6). The 2 remaining patients were not known to have any current or previous immune- compromising diseases or medical interventions ( 19,25). Because the number of cases with complete unilateral ophthalmoplegia is small, meaningful conclu-sions on whether associated anterior and posterior segment, 326 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Sanjay et al TABLE 1. Cases of complete unilateral ophthalmoplegia in herpes zoster ophthalmicus ( HZO) published between 1948 and September 2008 Study Age ( y)/ Sex Systemic Disease Prior Systemic Treatment Acyclovir Corticosteroids Dhingra et al, 2008 ( 12) 63/ M Multiple myeloma treated with chemotherapy 2 2 Ying et al, 2008 ( 13) 84/ M 2 1( PO) 2 Pion and Salu, 2007 ( 14) 74/ F Ovarian carcinoma stage IV 2 2 Badilla and Dolman, 2007 ( 15) 81/ F 2 1( Valacyclovir) 2 Shin et al, 2005 ( 16) 70/ M 2 2 2 Im et al, 2005 ( 17) 69/ M 2 1( IV) 2 Krasnianski et al, 2004 ( 18) 67/ F 2 1( IV) 1 ( IV) Kawasaki et al, 2004 ( 19) 47/ F 2 2 2 Yong et al, 2001 ( 20) 61/ M Chronic obstructive lung disease treated with oral corticosteroids 1 ( PO) 2 Pandey et al, 2001 ( 21) 65/ F 2 2 2 Covucci, 1999 ( 22) 54/ M 2 1( PO) 2 Chang- Godinich et al, 1997 ( 4) 82/ F Rheumatoid arthritis treated with corticosteroids, methotrexate 1 ( IV) 2 72/ F Chronic lymphocytic leukemia threated with chemotherapy 1 ( IV) 2 75/ M Previous acute myocardial infarction 2 2 Bourke and Pyle, 1994 ( 23) 63/ F History of cryptococcal meningitis 2 2 Lexa et al, 1991 ( 6) 41/ F Scleroderma treated with penicillamine, plasmapheresis 2 1( PO) Horton et al, 1991 ( 5) 82/ M Pituitary adenoma 2 2 Kattah and Kennerdell, 1978 ( 24) 72/ F 2 2 2 54/ F Hodgkin lymphoma stage IV treated with adriamycin 2 2 Pincus, 1949 ( 25) 45/ M 2 2 2 ( Continued on next page) 327 Herpes Zoster Ophthalmicus J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 TABLE 1. Continued Study Age ( y)/ Sex Clinical Features of HZO Onset of HZO Rash in Anterior Segment Posterior Segment Relation to Ophthalmoplegia Dhingra et al, 2008 ( 12) 63/ M Corneal edema, dendritic ulcer, anterior chamber reaction Optic disc swelling, nerve fiber layer hemorrhage Same time Ying et al, 2008 ( 13) 84/ M Cornea punctate epithelial erosions 2 2 wk before Pion and Salu, 2007 ( 14) 74/ F Superficial keratitis 2 Same time Badilla and Dolman, 2007 ( 15) 81/ F Anterior uveitis 2 6 wk before Shin et al, 2005 ( 16) 70/ M Corneal edema, anterior uveitis Vitritis 2 mo before Im et al, 2005 ( 17) 69/ M Corneal edema Acute retinal necrosis 7 days before Krasnianski et al, 2004 ( 18) 67/ F Eyelid edema, scleral hyperemia 2 2 days before Kawasaki et al, 2004 ( 19) 47/ F Anterior uveitis 2 2 days before Yong et al, 2001 ( 20) 61/ M Blepharoconjunctivitis 2 2 days before Pandey et al, 2001 ( 21) 65/ F Trachoma pannus 2 Same time Covucci, 1999 ( 22) 54/ M Conjunctivitis 2 2 days before Chang- Godinich et al, 1997 ( 4) 82/ F 2 2 1 wk before 72/ F Conjunctivitis 2 2 wk before 75/ M Corneal irregularity, anterior uveitis 2 0.5 wk before Bourke and Pyle, 1994 ( 23) 63/ F Corneal edema, anterior uveitis 2 5 days before Lexa et al, 1991 ( 6) 41/ F Chemosis, anterior uveitis 2 13 days before Horton et al, 1991 ( 5) 82/ M 2 2 Same time Kattah and Kennerdell, 1978 ( 24) 72/ F Anterior uveitis Vitritis, blurred optic disc margins 2 wk before 54/ F Discrete corneal lesions Blurred optic disc margins 2 days before Pincus, 1949 ( 25) 45/ M Lid edema, chemosis, subepithelial opacities, acute iridocyclitis Blurred disc margins 4 days before 328 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Sanjay et al TABLE 1. Continued Study Age ( y)/ Sex Neuro- Ophthalmic Features Pupil Dilation Residual Extra- Ocular Movements Proptosis Optic Neuropathy Dhingra et al, 2008 ( 12) 63/ M 1 2 1 1 ( relative afferent pupillary defect) Ying et al, 2008 ( 13) 84/ M 1 2 2 2 Pion and Salu, 2007 ( 14) 74/ F 1 2 2 2 Badilla and Dolman, 2007 ( 15) 81/ F 2 Central 20 all directions 1 2 Shin et al, 2005 ( 16) 70/ M 1 2 2 2 Im et al, 2005 ( 17) 69/ M 1 2 2 2 Krasnianski et al, 2004 ( 18) 67/ F 2 2 1 ( MRI) 2 Kawasaki et al, 2004 ( 19) 47/ F 2 2 1 2 Yong et al, 2001 ( 20) 61/ M 1 2 1 2 Pandey et al, 2001 ( 21) 65/ F 1 2 2 2 Covucci, 1999 ( 22) 54/ M 1 2 2 2 Chang- Godinich et al, 1997 ( 4) 82/ F 1 Minimal abduction 2 2 72/ F 1 Minimal abduction 2 1( relative afferent pupillary defect) 75/ M 1 Minimal abduction, adduction 1 2 Bourke and Pyle, 1994 ( 23) 63/ F 1 Minimal abduction 1 1( relative afferent pupillary defect, field and color vision deficit) Lexa et al, 1991 ( 6) 41/ F 1 2 1 ( MRI) 2 Horton et al, 1991 ( 5) 82/ M 1 2 1 2 Kattah and Kennerdell, 1978 ( 24) 72/ F 1 2 1 2 54/ F 1 2 1 1 ( color vision deficit) Pincus, 1949 ( 25) 45/ M 1 2 1 2 ( Continued on next page) 329 Herpes Zoster Ophthalmicus J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 TABLE 1. Continued Study Age ( y)/ Sex Systemic Features Cerebrospinal Fluid Imaging Modality Dhingra et al, 2008 ( 12) 63/ M 2 N/ A CT Ying et al, 2008 ( 13) 84/ M 2 WBC 13 ( lymphocytic) CT Pion and Salu, 2007 ( 14) 74/ F 2 Mild meningoencephalitis MRI Badilla and Dolman, 2007 ( 15) 81/ F 2 N/ A CT Shin et al, 2005 ( 16) 70/ M 2 N/ A MRI Im et al, 2005 ( 17) 69/ M 2 N/ A MRI Krasnianski et al, 2004 ( 18) 67/ F Somnolent, meningitis WBC 46 ( lymphocytic) MRI Kawasaki et al, 2004 ( 19) 47/ F 2 Normal MRI Yong et al, 2001 ( 20) 61/ M 2 N/ A MRI Pandey et al, 2001 ( 21) 65/ F 2 N/ A CT Covucci, 1999 ( 22) 54/ M 2 N/ A CT Chang- Godinich et al, 1997 ( 4) 82/ F 2 WBC 10 ( lymphocytic) MRI 72/ F 2 N/ A MRI 75/ M Slurred speech N/ A CT Bourke and Pyle, 1994 ( 23) 63/ F 2 N/ A CT Lexa et al, 1991 ( 6) 41/ F Encephalopathy WBC 13 ( lymphocytic) MRI Horton et al, 1991 ( 5) 82/ M Confused N/ A CT Kattah and Kennerdell, 1978 ( 24) 72/ F Confused, meningitis WBC 87 ( lymphocytic) CT 54/ F 2 WBC 36 ( lymphocytic) N/ A Pincus, 1949 ( 25) 45/ M 2 N/ A N/ A 330 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Sanjay et al TABLE 1. Continued Study Age ( y)/ Sex Imaging Cranial Nerves Extra- Ocular Muscle Enlargement Others Findings Others Dhingra et al, 2008 ( 12) 63/ M 2 Obliques and recti 2 N/ A Ying et al, 2008 ( 13) 84/ M 2 2 2 N/ A Pion and Salu, 2007 ( 14) 74/ F 2 2 2 VEP: prolonged latency Badilla and Dolman, 2007 ( 15) 81/ F 2 Obliques and recti, tendon- sparing 2 N/ A Shin et al, 2005 ( 16) 70/ M 2 2 2 N/ A Im et al, 2005 ( 17) 69/ M 2 2 Orbital soft tissues N/ A Krasnianski et al, 2004 ( 18) 67/ F 2 All extraocular muscles Orbit and optic nerve sections VEP: reduced amplitude, prolonged latency Kawasaki et al, 2004 ( 19) 47/ F 2 Obliques and recti, tendon- sparing Orbital soft tissues N/ A Yong et al, 2001 ( 20) 61/ M 2 2 Soft tissue swelling above cavernous sinus N/ A Pandey et al, 2001 ( 21) 65/ F 2 2 2 Serum lymphocytosis, elevated ESR Covucci, 1999 ( 22) 54/ M 2 2 2 N/ A Chang- Godinich et al, 1997 ( 4) 82/ F 2 2 2 N/ A 72/ F 2 2 2 N/ A 75/ M 2 2 Soft tissue swelling anterior to globe N/ A Bourke and Pyle, 1994 ( 23) 63/ F 2 All extraocular muscles 2 N/ A Lexa et al, 1991 ( 6) 41/ F 2 Recti, non tendon- sparing Optic nerve, meningeal, and pontine enhancement Autopsy: anterior cerebral circulation granulomatous angiitis Horton et al, 1991 ( 5) 82/ M 2 2 Sellar mass invading cavernous sinus N/ A Kattah and Kennerdell, 1978 ( 24) 72/ F 2 2 2 N/ A 54/ F N/ A N/ A N/ A N/ A Pincus, 1949 ( 25) 45/ M N/ A N/ A N/ A N/ A ( Continued on next page) 331 Herpes Zoster Ophthalmicus J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 TABLE 1. Continued Study Age ( y)/ Sex Treatment of HZO Ophthalmoplegia Resolution Acyclovir/ Valacyclovir Corticosteroids Ophthalmoplegia Ptosis Dhingra et al, 2008 ( 12) 63/ M 1 ( IV) 1 ( PO) 2 2 Ying et al, 2008 ( 13) 84/ M 1 ( IV) 2 1 1 Pion and Salu, 2007 ( 14) 74/ F 1 ( IV to PO) 1 ( PO methylprednisolone) 2 2 Badilla and Dolman, 2007 ( 15) 81/ F 1 ( PO, to IV) 1 ( PO prednisone) 1 1 Shin et al, 2005 ( 16) 70/ M 1 ( IV) 1 ( IM dexamethasone, PO prednisone) 1 1 Im et al, 2005 ( 17) 69/ M 1 ( PO) 1 ( PO) 1 1 Krasnianski et al, 2004 ( 18) 67/ F 1 ( IV) 1 ( IV prednisolone) 1 1 Kawasaki et al, 2004 ( 19) 47/ F 1 ( IV) 1 ( PO prednisone) 1 1 Yong et al, 2001 ( 20) 61/ M 1 ( IV) 2 1 1 Pandey et al, 2001 ( 21) 65/ F 1 ( PO) 1 ( PO) 2 2 Covucci, 1999 ( 22) 54/ M 1 ( PO) 2 2 2 Chang- Godinich et al, 1997 ( 4) 82/ F 1 ( IV) 1 ( IV methylprednisolone) 1 1 72/ F 1 ( PO) 1 ( PO prednisone) 1 1 75/ M 2 2 1 1 Bourke and Pyle, 1994 ( 23) 63/ F 1 ( PO) 1 ( IV methylprednisolone) 1 1 Lexa et al, 1991 ( 6) 41/ F 1 ( IV) 1 ( IV to unknown) 2 2 Horton et al, 1991 ( 5) 82/ M 1 ( unknown route) 1 ( unknown) N/ A N/ A Kattah and Kennerdell, 1978 ( 24) 72/ F 2 1( PO prednisone) 1 2 54/ F 2 1( PO prednisone) 2 2 Pincus, 1949 ( 25) 45/ M 2 2 1 2 332 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Sanjay et al TABLE 1. Continued Study Age ( y)/ Sex Complete Resolution Time to Resolution of Ophthalmoplegia Pupil Optic Neuropathy or Last Follow- up Visit Dhingra et al, 2008 ( 12) 63/ M 2 2 8 mo Ying et al, 2008 ( 13) 84/ M N/ A N/ A 2 mo Pion and Salu, 2007 ( 14) 74/ F N/ A N/ A 2 mo Badilla and Dolman, 2007 ( 15) 81/ F N/ A N/ A 1 mo Shin et al, 2005 ( 16) 70/ M 1 N/ A 6 mo Im et al, 2005 ( 17) 69/ M N/ A N/ A 5 mo Krasnianski et al, 2004 ( 18) 67/ F N/ A N/ A 2 wk Kawasaki et al, 2004 ( 19) 47/ F N/ A N/ A 2 mo Yong et al, 2001 ( 20) 61/ M N/ A N/ A 5 mo Pandey et al, 2001 ( 21) 65/ F N/ A N/ A 3 y Covucci, 1999 ( 22) 54/ M 2 N/ A 5 wk Chang- Godinich et al, 1997 ( 4) 82/ F N/ A N/ A 1 mo 72/ F 2 1 2 mo 75/ M N/ A N/ A 5 wk Bourke and Pyle, 1994 ( 23) 63/ F N/ A 1 1 yr Lexa et al, 1991 ( 6) 41/ F 2 N/ A N/ A Horton et al, 1991 ( 5) 82/ M N/ A N/ A N/ A Kattah and Kennerdell, 1978 ( 24) 72/ F 2 N/ A 2 mo 54/ F 2 1 N/ A Pincus, 1949 ( 25) 45/ M 2 N/ A 1.5 yr 333 Herpes Zoster Ophthalmicus J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 neuro- ophthalmic, or intracranial manifestations may be more frequent in this condition is difficult to establish. However, because adverse neurologic sequelae have been identified with this condition, a general recommendation can be made for an active neurologic assessment directed toward identifying signs of meningoencephalitis. PREDISPOSING FACTORS There is insufficient evidence to implicate any disease or treatment factors associated with the develop-ment of complete unilateral ophthalmoplegia in HZO. The association between disseminated zoster and systemic corticosteroid therapy, hematologic malignancy, and HIV infection is well- recognized ( 26229). In addition, progressive outer retinal necrosis ( PORN) in HZO is strongly associated with HIV positivity ( 30). In contrast, there is no evidence that a reduction in immune status correlates with development of post- HZO neurologic sequelae such as stroke, meningoencephalitis, myelitis, or cranial neuropathy ( 31,32). In a recent study of neurologic complications in HZO, all patients were immunocompetent ( 33). In our review of complete ophthalmoplegia associated with HZO, there were 4 patients ( 20%) with lymphopro-liferative disease or taking corticosteroids at the time of presentation. Because of the paucity of comparative evidence, it is difficult to conclude that an immunocom-promised state predisposes to unilateral ophthalmoplegia. A significant association between HZO- associated ophthalmoplegia and rash severity, iritis, and iris atrophy was reported by Marsh et al ( 11). However, this study did not account for possible confounding effects of each factor through multivariate analysis. There is insufficient evidence to determine whether treatment of HZO with acyclovir or corticosteroid reduces the incidence of unilateral ophthalmoplegia. In this review, 40% of patients were managed with at least 1 type of antiviral agent ( acyclovir or valacyclovir), and 10% were managed with systemic corticosteroids. In a recent case series of 4 patients who developed ophthalmoplegia after HZO ( 33), all had been treated with acyclovir before the development of this complication. The relatively low frequency of corticosteroid administration in 10% of patients probably reflects caution exercised in patients with known or suspected immune- compromising diseases or medical therapy. As with acyclovir, the efficacy of corti-costeroid treatment in preventing unilateral ophthalmoplegia remains unsettled. INVESTIGATIONS In the 8 patients who had a lumbar puncture, the cerebrospinal fluid ( CSF) profile was consistent with aseptic meningitis in 7 patients ( 88%) ( 4,6,13,14,18, 19,24), comparatively higher than the 40% 250% found in HZO without ophthalmoplegia ( 34). Only 1 patient was tested for CSF varicella- zoster immune globulin, which FIG. 1. A. Fifteen days after onset of herpes zoster ophthalmicus ( HZO) in a patient, complete ophthalmoplegia of the left eye has developed. The patient was treated with intravenous acyclovir. B. At 10 weeks after onset, the ophthalmoplegia has lessened. 334 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Sanjay et al was elevated at 38.5 U/ ml ( 18). However, CSF varicella zoster virus ( VZV)- specific DNA analysis was not per-formed in the series reviewed. These CSF viral assays may be useful diagnostically in the small group of patients with HZO in whom ophthalmoplegia and meningeal symptoms present before the rash ( 19,35). In the 9 patients who underwent CT and the 9 who underwent MRI intracranial and orbital imaging, the findings included abnormal enlargement of the oblique or rectus muscles ( with and without tendon- sparing) in 6 patients ( 33%) ( 6,12,15,18,19,23), orbital soft tissue swelling in 3 patients ( 17%) ( 17219), optic nerve enhancement in 2 patients ( 12%) ( 6,18), and meningeal and pontine trigeminal nucleus enhancement in 1 patient ( 6%) ( 6). Imaging also detected a pituitary adenoma in 1 patient ( 5), a cavernous sinus mass of uncertain diagnosis in 1 patient ( 20), and soft tissue swelling anterior to the globe in 1 patient ( 4). None of the scans showed ocular motor cranial nerve enhancement. Eight patients ( 44%) demon-strated normal imaging studies ( 4,13,14,16,21,22,24). Visual evoked potentials, performed in 2 patients, showed reduced amplitude and delayed latency in 1 patient ( 18). A single autopsy report ( 6) revealed granulomatous angiitis of the meninges, bilateral vasculitis of the large vessels in the anterior cerebral circulation, areas of subacute infarction in the pons and medulla, and periaxial infarction in the optic nerve. No viral inclusion bodies or antigens were detected. TREATMENT AND OUTCOME Therapy for HZO- associated ophthalmoplegia was initiated in 18 patients ( 90%), 3 patients having been treated with acyclovir alone ( 15%), 2 patients with systemic corticosteroids alone ( 10%), and 13 patients with FIG. 2. A. Fifteen days after onset of herpes zoster ophthalmicus ( HZO) in a patient, complete left upper lid ptosis has developed. B. Two weeks later, the ptosis has lessened. C. Ten weeks later, it has almost resolved. 335 Herpes Zoster Ophthalmicus J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 a combination of acyclovir ( or valacyclovir) and systemic corticosteroids ( 65%) ( 426,12224). Agents were admin-istered orally and intravenously. At the end of the follow- up period, complete or near-complete resolution of ophthalmoplegia was observed in 13 patients ( 65%) ( 4,13,15220,23,25), the time interval to resolution having a range of 2 weeks to 1.5 years and a mean of 4.4 months. Four patients ( 20%) were followed for periods of 5 weeks, 2 months, 8 months, and 3 years with minimal or no improvement in ophthalmoplegia or ptosis ( 12,14,21,22). The follow- up interval of 5 weeks and 2 months in 2 of these patients may have been too short to determine outcome. In the remaining 3 ( 15%) patients with ophthalmoplegia, its outcome could not be determined because of inadequate documentation in 1 patient ( 5) or other adverse events in 2 patients ( 6,24). One patient ( 24) developed Staphylococcus aureus endophthalmitis requir-ing evisceration of the eye. The second patient ( 6) had scleroderma and developed ophthalmoplegia concurrent with meningoencephalitis 2 weeks after onset of HZO, at which time MRI demonstrated hyperintensities in the cerebral hemispheres and pons. The patient became comatose and died of sepsis. If these 3 patients are excluded from the analysis of outcome, the frequency of complete or near- complete resolution of ophthalmoplegia would be 76.5%. Among the 13 patients who sustained near- complete or complete recovery of ophthalmoplegia, 11 also achieved full or near- complete recovery of ptosis, representing 55% of the 20 patients reviewed ( 4,13,15220,23). There were no patients who achieved resolution of ptosis without concurrent resolution or improvement in ophthalmoplegia. Among the 17 patients described as having an ipsilateral fixed dilated pupil as an initial presenting sign, the outcome was described for only 8 patients ( 4,6,12,16,22225), only 1 of which showed improvement in sphincter function ( 16). Resolution in optic neuropathy was seen in 3 of the 4 patients who manifested this sign at presentation ( 75%) ( 4,12,23,24). Postherpetic neuralgia was observed in 2 patients ( 10%) ( 4,15). Based on this review, one cannot determine whether the clinical outcome was influenced by treatment. One cautionary note concerns the patient whose HZO was initially managed for up to 2 weeks with oral and topical steroids ( 6). Acyclovir was started only at the point when complete ophthalmoplegia and encepha-lopathy had developed, the only patient in the review in whom systemic steroids were initiated without systemic acyclovir cover. Orbital and intracranial MRI had demon-strated features of orbital pseudotumor syndrome and meningoencephalitis. The meningoencephalitis continued to progress over the next 2 weeks and eventually led to death of sepsis. PATHOPHYSIOLOGY The proposed mechanisms of ophthalmoplegia in HZO are a direct viral cytopathic effect and a reactive immunologic response to the virus ( 6,36). Support for a primary viral cause is suggested by the marked clinical response in 1 patient to an increased acyclovir dose and reduction of the prednisone dose ( 23). An immune mechanism would produce perineuritis, peripheral nerve demyelination, contiguous orbital inflammation, cranial vasculitis, myositis, brainstem encephalitis, and meningitis ( 4,6,12,15219,36). Notably, granulomatous angiitis was the histopathologic lesion noted in the leptomeninges and carotid vessels in the patient with scleroderma described by Lexa et al ( 6). Although MRI findings support perineuritis as a pathophysiologic mechanism, none of the patients in this review demonstrated ocular motor nerve enhancement on neuroimaging. Instead, extraocular muscle enlargement ( 33%) and orbital soft tissue swelling ( 17%) were found on imaging. The high incidence of mydriasis ( 85%) and complete ptosis ( 70%) favors a neurogenic mechanism. HZO- associated ophthalmoplegia may thus involve multi-ple mechanisms. REFERENCES 1. Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity. Ophthalmology 2008; 115( 2 Suppl): S32S12. 2. 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