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Ophthalmic diagnoses in the ED: herpes zoster ophthalmicus
American Journal of Emergency Medicine (2008) 26, 612–617
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Diagnostics
Ophthalmic diagnoses in the ED: herpes zoster ophthalmicus William P. Carter III MD⁎, Carl A. Germann MD, Michael R. Baumann MD Emergency Medicine Department, Maine Medical Center, Portland, ME 04102, USA Received 3 August 2007; accepted 4 August 2007
Abstract The epidemiology, pathophysiology, and clinical presentation of herpes zoster ophthalmicus in the emergency department is discussed with an emphasis on the identification of the numerous potential ocular complications. Emergency physicians need to be able to recognize the clinical features of herpes zoster ophthalmicus and initiate appropriate therapy and referral. © 2008 Elsevier Inc. All rights reserved.
1. Introduction Herpes zoster (shingles) is a commonly encountered disease resulting from the reactivation of latent varicella virus in previously exposed individuals. Among the US population, more than 90% of adults are serologically positive for Varicella-zoster virus (VZV), with most having contracted the disease during childhood [1]. An estimated 10% to 20% of those individuals will experience a reactivation of the virus during their lifetime, correlating with a reported incidence of 2.2 to 3.4 cases per 1000 people per year [2,3]. The incidence of shingles increases with age, a result of declining intrinsic cell-mediated immunity, and can be expected to exceed 10 cases per 1000 people in those 75 years and older [3,4]. A recent population-based study revealed a slightly higher prevalence in women than men, conflicting with earlier studies that failed to show any sex bias [3]. Herpes zoster ophthalmicus (HZO) represents an extension of the herpes zoster infection along 1 or more ⁎ Corresponding author. Tel.: +1 207 272 9901. E-mail address: [email protected] (W.P. Carter III). 0735-6757/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2007.08.013
branches of the ophthalmic division of the fifth cranial (trigeminal) nerve. Risk factors for the development of HZO are similar to those for generalized herpes zoster and include advancing age, sex (FNM), white ethnicity, mechanical trauma, psychologic stress, immunosuppression, and exposure to infected individuals [5]. Herpes zoster ophthalmicus represents approximately 10% to 20% of all herpes zoster cases [2]. This represents a significant proportion of individuals, and the delicate nature of ophthalmic structures conveys a significant morbidity to affected individuals. In addition, patients can initially present with vague symptoms of pain, headache, and/or vision changes without the classic vesicular rash, making the diagnosis challenging to the emergency physician.
2. Case A 62-year-old woman presented to the emergency department (ED) with complaints of a 2-day history of a severe 10/10 left-sided headache with periods of blurry vision and photophobia that were unresponsive to over-thecounter pain relievers. She denied any history of
Ophthalmic diagnoses in the ED headaches, stroke, trauma, sinusitis, glaucoma, temporal arteritis, or vision problems. She does wear glasses and has seen an ophthalmologist in the previous 6 months. Results of additional review of systems were otherwise negative. Her medical history is significant only for hypertension, for which she takes atenolol. On physical examination, the patient was alert and oriented, with normal vital signs. Visual acuity was tested at 20/20 bilaterally with glasses on. Fundoscopic examination result was normal. Cranial nerves II through XII were intact; however, the patient did note some pain with light touch to the left forehead when testing cranial nerve V. Intraocular pressures were within normal limits, and there was no pain on palpation of the temporal arteries bilaterally. There was no pain with extraocular muscle movements, nor was any pain noted on palpation of the sinuses. Reflexes were 2+ throughout, with gross motor and sensation intact in all 4 extremities. Laboratory evaluation results, including erythrocyte sedimentation rate, were all within normal limits. Head computed tomography failed to reveal any acute intracranial process. After receiving morphine and compazine, the patient's pain improved, and she was discharged home with hydrocodone and instructions to follow-up with her primary care physician. Two days later, the patient returned to the ED with worsening symptoms and a new rash on her left forehead that extended down to the left tip of her nose. In addition, her left eye appeared red and swollen. The right eye appeared normal, and the rash did not appear to cross the midline. She reported that the hydrocodone did little to relieve her pain, and the rash seemed to be spreading.
2.1. Pathophysiology and clinical manifestations Varicella zoster is a DNA virus and is a member of the Herpesviridae family of viruses, which also includes herpes simplex virus, Epstein-Barr virus, and cytomegalovirus. Herpes zoster ophthalmicus occurs as a result of reactivation of latent varicella virus within the trigeminal ganglion with extension of the virus along the ophthalmic nerve (Fig. 1). This represents a direct route for spread of the virus to both ocular and extraocular structure with damage occurring secondary to perineural and intraneural inflammation of the sensory nerves [6]. Risk factors for the development of HZO are similar to those of nonophthalmic zoster infection and are primarily related to advancing age with waning cell-mediated immunity, stress, as well as any condition that predisposes to immunosuppression (ie, HIV, cancer, or being on immunosuppressive therapy) [4]. Once reactivated, the clinical progression of disease is perhaps best thought of in 3 distinct phases. During the prodromal phase, patients often report headache, malaise, photophobia, or blurry vision. During this stage, the patient
613
Fig. 1 Anatomy of the trigeminal nerve. Courtesy of Dr Anthony Kaufmann, Winnipeg Centre for Cranial Nerve Disorders, Winnipeg, Manitoba, Canada.
may complain of unilateral pain, hyperesthesia, or pruritis along the ophthalmic dermatome. These symptoms typically precede the eruption of the characteristic skin lesions by a period of 1 to 5 days [2]. The vague nature of these symptoms often make diagnosis at this stage challenging. Once skin lesions develop, the disease is in the active phase. The skin lesions appear as a herpetiform cluster of erythematous vesicles and continue to form for several days, evolving through stages of pustulation, ulceration, and crusting. The lesions appear unilaterally along the ophthalmic dermatome and do not cross the midline. The presence of lesions on the tip of the nose (Hutchinson sign) represent extension of the virus along the nasociliary branch of the ophthalmic division of the trigeminal nerve (Fig. 1). Because the sensory innervation of the eye is supplied by the nasociliary branch, patients with evidence of lesions along this distribution are felt to be at greater risk for ocular complications [7,8]. Hutchinson sign is, however, variable, and patients without nasal involvement may still have intraocular complications. The chronic phase of the disease can persist for months or even years, consisting of chronic pain and hyperesthesia along the effected dermatome, cold and heat intolerance, sleep deprivation, depression, and social isolation. When the pain of HZO persists for more than 30 days or after the resolution of the cutaneous lesions, it is characterized as postherpetic neuralgia (PHN). In a retrospective population-based study on PHN performed by Ragozzino [2], the prevalence of PHN was 9% and 5% at 1-month and 2-month followup, respectively. The factors associated with increased
614
W.P. Carter III et al.
Fig. 2 Red eye in patient with anterior uveitis. Reproduced with permission from the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Sept 2002. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
risk for PHN include older age, presence of prodromal symptoms, greater severity of rash, female sex, and greater severity of pain at presentation [9].
2.2. Ocular manifestations of HZO
of the cornea) and/or uveitis (inflammation of the uveal tract, including the iris, ciliary body, and choroids) appears to occur most frequently [12]. The eyelid may appear edematous and inflamed (blepharitis), with noticeable ptosis, tearing, and/or pain. Inflammation of the conjunctiva is seen in nearly all patients with HZO with ocular involvement. The conjunctiva may appear injected and edematous with occasional petechial hemorrhages [13]. Episcleritis/scleritis, inflammation of the most superficial layers of the conjunctiva overlying the sclera, may be flat or nodular and can last for months [14]. Inflammation of the iris and ciliary body (uveitis) can sometimes be seen on slit lamp examination (Fig. 2). The resultant anterior uveitis is typically transient but can result in an increase in intraocular pressures. Although infrequent, chronic uveitis can go on to cause iris atrophy and even cataract formation [15]. The corneal manifestations of HZO are diverse and occur in approximately 50% of patients with ocular involvement of ophthalmic zoster [10]. Patients often present with varying degrees of pain, decreased vision, and/or light sensitivity. The earliest corneal finding, appearing as early as 1 to 2 days after the rash, is epithelial keratitis [10]. On slit lamp examination, this may appear as punctuate or dendritic lesions that
Herpes zoster ophthalmicus can present with extraocular symptoms (headache, malaise, fever, pain) as described, but there is also a wide variety of ocular symptoms that may occur during any of the various phases of ophthalmic zoster. The reported incidence of ocular involvement in HZO ranges from 50% to 70% [2,10,11]. Virtually any component of the eye can be involved (see Table 1), but keratitis (inflammation Table 1 Ocular complications in immunocompetent patients with ophthalmic zoster Part of eye affected
Acute Phase
Late Phase
Eyelids
Swelling, vesicular rash Conjunctivits Episclerits Scleritis Epithelial keratitis
Ptosis, eyelid retraction Self limiting Self limiting Focal sclera atrophy Neurotrophic keratopathy Corneal neovascularization Focal iris atrophy Self limiting Self limiting
Conjunctiva Episclera Sclera Cornea
Stromal keratitis Anterior chamber Rare Complications
Uveitis Ocular hypertension Extraocular muscle palsies Optic neuritis Retinal necrosis, retinitis
Optic atrophy Retinal atrophy
Reproduced with permission from BMJ Publishing Group from Opstelten and Zaal [13].
Fig. 3 Slit lamp examination in a patient with HZO. Epithelial keratitis may have a dendritic appearance mimicking herpes simplex virus keratitis (A) and stains with fluorescein dye (B). Reproduced with permission from Dr Saad Shaikh.
Ophthalmic diagnoses in the ED
615 virus-related vasculitis and hypoperfusion [17]. Involvement of the eyelid, conjunctiva, episclera/sclera, and/or anterior chamber, are most commonly self-limited complications and rarely result in permanent sequelae. However, unlike the eyelid or conjuctiva, corneal or retinal involvement (keratitis) can potentially result in significant visual impairment (Fig. 5).
2.3. Diagnosis
Fig. 4 Slit lamp examination of a patient with stromal keratitis as a result of herpes zoster virus infection. Subepithelial infiltrates are located in the anterior stroma below areas of previous epithelial keratitis. Reproduced with permission from Dr Saad Shaikh.
closely resemble those of herpes simplex virus keratitis (Fig. 3, A and B) [10]. The lesions form branching patterns and stain with fluorescein dye. Stromal keratitis, as characterized by granular infiltrates in the anterior corneal stroma, typically occurs later in the course of disease (2-3 weeks) and is less likely to be seen by an emergency physician (Fig. 4). The complications of corneal involvement include corneal clouding, decreased corneal sensitivity with resultant increased risk for corneal ulceration, and corneal neovascularization affecting vision quality [13]. Rare complications include extraocular muscle palsies with resultant diploplia [16], optic neuritis, as well as retinal necrosis with resultant retinal detachment secondary to
In most cases, the diagnosis of HZO is based on clinical recognition of the characteristic rash along the ophthalmic dermatome. Laboratory analysis is frequently unnecessary; however, there are a number of rapid diagnostic tests available for varicella-zoster virus (see Table 2) [11]. Diagnosis during the prodromal phase, that is, before the development of the characteristic rash, remains challenging and requires vigilance on the part of emergency physicians when presented with a clinical presentation suggestive of early HZO. Differential diagnosis includes but is not limited to temporal arteritis, migraine headache, glaucoma, contact/allergic dermatitis, cerebrovascular accident, trigeminal neuralgia, sinusitis, herpes simplex, cellulitis, erysipelas, bullous impetigo, or even necrotizing fasciitis [18].
3. Treatment: antiviral therapy Treatment of HZO infections centers around 3 major objectives: (1) treatment of the acute viral infection, (2) treatment of acute pain, and (3) prevention of PHN. This is typically achieved through the use of both antiviral and corticosteroid therapy. Before the arrival of the antiviral medications, corticosteroids were the mainstay of treatment. There exist some conflicting data regarding the utility of steroid therapy in the treatment of herpes zoster. Several recent studies have demonstrated that corticosteroids, when used in combination with antivirals, accelerate the resolution of acute pain but had no effect on long-term pain and/or PHN [19,20]. The evidence that combination therapy (prednisone and acyclovir) improves quality-of-life measures is strong; however, clearly, not all patients are good
Table 2
Rapid diagnostic test for varicella-zoster virus
Tzanck Technique Electron Microscopy Antigen detection (smear) Antigen detection (culture) DNA hybridization Fig. 5 Zoster retinitis characterized by peripheral patches of retinal necrosis. Reproduced with permission from Dr Saad Shaikh.
Rapid; poor sensitivity/specificity Rapid; poor sensitivity/specificity Several hours; good sensitivity/ specificity Few days; good sensitivity/ specificity Research tool
Reprinted with permission from American Academy of Ophthalmology n 1991 from Liesegang [11].
616 candidates for corticosteroid therapy. Therefore, the decision to use corticosteroids in the treatment regimen should be reserved for relatively healthy elderly individuals who have moderate or severe pain [20]. The mainstay of therapy is treatment with antiviral medications. Early treatment with acyclovir, preferably within 72 hours of the onset of symptoms, has been shown to reduce the percentage of ocular complications from 50% to 20% to 30% [21]. However, initiation of treatment as late as 7 days after the eruption of cutaneous lesions does appear to convey some measure of prophylactic effect in reducing the ocular complications of HZO [21]. Both valacyclovir and famcyclovir have been show to have similar efficacy in the treatment of herpes zoster and have the added benefit of a simpler dosing regimen, which may improve patient compliance [22,23]. All 3 drugs are exceptionally safe and well tolerated when taken orally; dosing adjustments are required for patients with renal insufficiency. In immunocompromised patients, intravenous acyclovir for 7 days, followed by an oral regimen to prevent recurrence, is recommended. Because of the potentially sight-threatening complications associated with HZO, all patients should be treated with antiviral therapy. Treatment will also frequently necessitate pain management with either or both narcotic and nonnarcotic analgesics.
3.1. Referral and disposition Because of the high prevalence of complications in patients diagnosed with HZO, all patients should be referred to an ophthalmologist. However, ocular complications rarely develop in the first week after onset of the rash, making immediate consultation unnecessary. Patients who present with evidence of ocular involvement and/or involvement of the nasociliary branch of the trigeminal nerve (Hutchinson sign) require prompt referral [13]. Immunocompromised patients presenting with HZO requiring intravenous antiviral therapy should be admitted to the hospital with inpatient ophthalmologic consultation.
3.2. Vaccination In May 2006, the Food and Drug Administration approved the new vaccine Zostavax (Merck, Inc.) for the prevention of herpes zoster in persons 60 years and older. Approval of the live attenuated vaccine was made on the basis of the results of the Shingles Prevention Study [24]. A randomized, double-blind, placebo-controlled study, the Shingles Prevention Study evaluated the efficacy and safety of a single dose of Zostavax in 38 546 men and women aged 60 years or older who had no history of shingles. Compared with placebo, Zostavax reduced the risk of developing shingles by 51% (P b .001) at a median follow-up period of
W.P. Carter III et al. 3.1 years. A separate analysis of those individuals who received Zostavax but still went on to develop shingles showed an overall 39% reduction in the occurrence of PHN, with the greatest reduction seen in individuals aged 70 to 79 years. Zostavax is contraindicated for persons with a history of anaphylactic/anaphylactoid reaction to vaccination, with a history of primary or acquired immunodeficiency states (HIV, leukemia, lymphoma), receiving immunosuppressive therapy, or with active untreated tuberculosis. The duration of protective effect beyond the study follow-up period of 4.0 years is unknown, as is the efficacy of vaccination in persons with a previous history of herpes zoster. Common side effects of Zostavax were headache and injection site reactions ranging from erythema, pruritis, pain/tenderness, and swelling [25].
4. Key points 1. Patients presenting during the prodromal phase of HZO may have vague nonspecific complaints, making the diagnosis difficult. 2. Patients presenting with ocular involvement, especially those with Hutchinson sign, require ophthalmic consultation. 3. Approximately 50% to 70% of patients with trigeminal Herpes Zoster will develop ocular involvement; thus, diligent examination of the eye with corneal staining should be performed. 4. Antiviral therapy is beneficial in reducing ocular complications, especially if initiated within 72 hours of the onset of symptoms. 5. The recent approval of Zostavax may lead to a reduction in the incidence/occurrence of Herpes Zoster as well as PHN.
References [1] Straus SE, et al. Varicella-zoster virus infections: biology, natural history, treatment, and prevention. Ann Intern Med 1988;108:221-37. [2] Ragozzino MW. Population-based study of herpes zoster and its sequelae. Medicine (Baltimore) 1982;61(5):310-6. [3] Insinga RP, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005;20:748-53. [4] Donahue JG, et al. The incidence of herpes zoster. Arch Intern Med 1995;155:1605-9. [5] Thomas SL, et al. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis 2004;4:26-33. [6] Naumann G, et al. Histopathology of herpes zoster ophthalmicus. Am J Ophthalmol 1968;65:533-41. [7] Zaal MJ, et al. Prognostic value of Hutchinson's sign in acute herpes zoster ophthalmicus. Graefe's Arch Clin Exp Ophthalmol 2003;241: 187-91. [8] Harding SP, et al. Natural history of herpes zoster ophthalmicus: predictors of postherpetic neuralgia and ocular involvement. Br J Ophthalmol 1987;71:353-8.
Ophthalmic diagnoses in the ED [9] Jung BF, et al. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 2004;62(9):1-12. [10] Womack LW, et al. Complications of herpes zoster ophthalmicus. Arch Ophthalmol 1983;101:42-5. [11] Liesegang TJ. Diagnosis and therapy of herpes zoster ophthalmicus. Ophthalmology 1991;98(8):1216-29. [12] Liesegang TJ. Varicella-zoster virus eye disease. Cornea 1999;18(5): 511-31. [13] Opstelten W, Zaal M. Managing ophthalmic herpes zoster in primary care. Br Med J 2005;331:147-51. [14] Pavan-Langston D. Herpes zoster ophthalmicus. Neurology 1995;45 (12):S50-1. [15] Shaikh S, et al. Evaluation and management of herpes zoster ophthalmicus. Am Fam Physician 2002;66(9):1723-30. [16] Jude E, Chakraborty A. Left sixth cranial nerve palsy with herpes zoster ophthalmicus. N Engl J Med 2005;353:16. [17] Gurwood AS, et al. Herpes zoster ophthalmicus. Optometry 2002;73 (5):295-302.
617 [18] Fitzpatrick TB, et al. Color atlas and synopsis of clinical dermatology. 5th ed. New York: McGraw-Hill; 2005. [19] Wood MJ, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisone for treatment of acute herpes zoster. N Engl J Med 1994;330:896-900. [20] Whitley RJ, et al. Acyclovir with and without prednisone for the treatment of herpes zoster: a randomized placebo-controlled trial. Ann Intern Med 1996;125(5):376-83. [21] Cobo M. Reduction of the ocular complications of herpes zoster ophthalmicus by oral acyclovir. Am J Med 1988;85:90-3. [22] Colin J, et al. Comparison of the efficacy and safety of valaciclovir and acyclovir for the treatment of herpes zoster ophthalmicus. Ophthalmology 2000;107:1507-11. [23] Tyring S, et al. Famciclovir for ophthalmic zoster: a randomised aciclovir controlled study. Br J Ophthalmol 2001;85:576-81. [24] Oxman MN, et al. A vaccine to prevent zoster and postherpetic neuralgia in older adults. N Eng J Med 2005;352(22):2271-84. [25] Gnann Jr JW, et al. Herpes zoster. N Engl J Med 2002;347(5):340-6.
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Diagnostics
Ophthalmic diagnoses in the ED: herpes zoster ophthalmicus William P. Carter III MD⁎, Carl A. Germann MD, Michael R. Baumann MD Emergency Medicine Department, Maine Medical Center, Portland, ME 04102, USA Received 3 August 2007; accepted 4 August 2007
Abstract The epidemiology, pathophysiology, and clinical presentation of herpes zoster ophthalmicus in the emergency department is discussed with an emphasis on the identification of the numerous potential ocular complications. Emergency physicians need to be able to recognize the clinical features of herpes zoster ophthalmicus and initiate appropriate therapy and referral. © 2008 Elsevier Inc. All rights reserved.
1. Introduction Herpes zoster (shingles) is a commonly encountered disease resulting from the reactivation of latent varicella virus in previously exposed individuals. Among the US population, more than 90% of adults are serologically positive for Varicella-zoster virus (VZV), with most having contracted the disease during childhood [1]. An estimated 10% to 20% of those individuals will experience a reactivation of the virus during their lifetime, correlating with a reported incidence of 2.2 to 3.4 cases per 1000 people per year [2,3]. The incidence of shingles increases with age, a result of declining intrinsic cell-mediated immunity, and can be expected to exceed 10 cases per 1000 people in those 75 years and older [3,4]. A recent population-based study revealed a slightly higher prevalence in women than men, conflicting with earlier studies that failed to show any sex bias [3]. Herpes zoster ophthalmicus (HZO) represents an extension of the herpes zoster infection along 1 or more ⁎ Corresponding author. Tel.: +1 207 272 9901. E-mail address: [email protected] (W.P. Carter III). 0735-6757/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2007.08.013
branches of the ophthalmic division of the fifth cranial (trigeminal) nerve. Risk factors for the development of HZO are similar to those for generalized herpes zoster and include advancing age, sex (FNM), white ethnicity, mechanical trauma, psychologic stress, immunosuppression, and exposure to infected individuals [5]. Herpes zoster ophthalmicus represents approximately 10% to 20% of all herpes zoster cases [2]. This represents a significant proportion of individuals, and the delicate nature of ophthalmic structures conveys a significant morbidity to affected individuals. In addition, patients can initially present with vague symptoms of pain, headache, and/or vision changes without the classic vesicular rash, making the diagnosis challenging to the emergency physician.
2. Case A 62-year-old woman presented to the emergency department (ED) with complaints of a 2-day history of a severe 10/10 left-sided headache with periods of blurry vision and photophobia that were unresponsive to over-thecounter pain relievers. She denied any history of
Ophthalmic diagnoses in the ED headaches, stroke, trauma, sinusitis, glaucoma, temporal arteritis, or vision problems. She does wear glasses and has seen an ophthalmologist in the previous 6 months. Results of additional review of systems were otherwise negative. Her medical history is significant only for hypertension, for which she takes atenolol. On physical examination, the patient was alert and oriented, with normal vital signs. Visual acuity was tested at 20/20 bilaterally with glasses on. Fundoscopic examination result was normal. Cranial nerves II through XII were intact; however, the patient did note some pain with light touch to the left forehead when testing cranial nerve V. Intraocular pressures were within normal limits, and there was no pain on palpation of the temporal arteries bilaterally. There was no pain with extraocular muscle movements, nor was any pain noted on palpation of the sinuses. Reflexes were 2+ throughout, with gross motor and sensation intact in all 4 extremities. Laboratory evaluation results, including erythrocyte sedimentation rate, were all within normal limits. Head computed tomography failed to reveal any acute intracranial process. After receiving morphine and compazine, the patient's pain improved, and she was discharged home with hydrocodone and instructions to follow-up with her primary care physician. Two days later, the patient returned to the ED with worsening symptoms and a new rash on her left forehead that extended down to the left tip of her nose. In addition, her left eye appeared red and swollen. The right eye appeared normal, and the rash did not appear to cross the midline. She reported that the hydrocodone did little to relieve her pain, and the rash seemed to be spreading.
2.1. Pathophysiology and clinical manifestations Varicella zoster is a DNA virus and is a member of the Herpesviridae family of viruses, which also includes herpes simplex virus, Epstein-Barr virus, and cytomegalovirus. Herpes zoster ophthalmicus occurs as a result of reactivation of latent varicella virus within the trigeminal ganglion with extension of the virus along the ophthalmic nerve (Fig. 1). This represents a direct route for spread of the virus to both ocular and extraocular structure with damage occurring secondary to perineural and intraneural inflammation of the sensory nerves [6]. Risk factors for the development of HZO are similar to those of nonophthalmic zoster infection and are primarily related to advancing age with waning cell-mediated immunity, stress, as well as any condition that predisposes to immunosuppression (ie, HIV, cancer, or being on immunosuppressive therapy) [4]. Once reactivated, the clinical progression of disease is perhaps best thought of in 3 distinct phases. During the prodromal phase, patients often report headache, malaise, photophobia, or blurry vision. During this stage, the patient
613
Fig. 1 Anatomy of the trigeminal nerve. Courtesy of Dr Anthony Kaufmann, Winnipeg Centre for Cranial Nerve Disorders, Winnipeg, Manitoba, Canada.
may complain of unilateral pain, hyperesthesia, or pruritis along the ophthalmic dermatome. These symptoms typically precede the eruption of the characteristic skin lesions by a period of 1 to 5 days [2]. The vague nature of these symptoms often make diagnosis at this stage challenging. Once skin lesions develop, the disease is in the active phase. The skin lesions appear as a herpetiform cluster of erythematous vesicles and continue to form for several days, evolving through stages of pustulation, ulceration, and crusting. The lesions appear unilaterally along the ophthalmic dermatome and do not cross the midline. The presence of lesions on the tip of the nose (Hutchinson sign) represent extension of the virus along the nasociliary branch of the ophthalmic division of the trigeminal nerve (Fig. 1). Because the sensory innervation of the eye is supplied by the nasociliary branch, patients with evidence of lesions along this distribution are felt to be at greater risk for ocular complications [7,8]. Hutchinson sign is, however, variable, and patients without nasal involvement may still have intraocular complications. The chronic phase of the disease can persist for months or even years, consisting of chronic pain and hyperesthesia along the effected dermatome, cold and heat intolerance, sleep deprivation, depression, and social isolation. When the pain of HZO persists for more than 30 days or after the resolution of the cutaneous lesions, it is characterized as postherpetic neuralgia (PHN). In a retrospective population-based study on PHN performed by Ragozzino [2], the prevalence of PHN was 9% and 5% at 1-month and 2-month followup, respectively. The factors associated with increased
614
W.P. Carter III et al.
Fig. 2 Red eye in patient with anterior uveitis. Reproduced with permission from the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Sept 2002. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
risk for PHN include older age, presence of prodromal symptoms, greater severity of rash, female sex, and greater severity of pain at presentation [9].
2.2. Ocular manifestations of HZO
of the cornea) and/or uveitis (inflammation of the uveal tract, including the iris, ciliary body, and choroids) appears to occur most frequently [12]. The eyelid may appear edematous and inflamed (blepharitis), with noticeable ptosis, tearing, and/or pain. Inflammation of the conjunctiva is seen in nearly all patients with HZO with ocular involvement. The conjunctiva may appear injected and edematous with occasional petechial hemorrhages [13]. Episcleritis/scleritis, inflammation of the most superficial layers of the conjunctiva overlying the sclera, may be flat or nodular and can last for months [14]. Inflammation of the iris and ciliary body (uveitis) can sometimes be seen on slit lamp examination (Fig. 2). The resultant anterior uveitis is typically transient but can result in an increase in intraocular pressures. Although infrequent, chronic uveitis can go on to cause iris atrophy and even cataract formation [15]. The corneal manifestations of HZO are diverse and occur in approximately 50% of patients with ocular involvement of ophthalmic zoster [10]. Patients often present with varying degrees of pain, decreased vision, and/or light sensitivity. The earliest corneal finding, appearing as early as 1 to 2 days after the rash, is epithelial keratitis [10]. On slit lamp examination, this may appear as punctuate or dendritic lesions that
Herpes zoster ophthalmicus can present with extraocular symptoms (headache, malaise, fever, pain) as described, but there is also a wide variety of ocular symptoms that may occur during any of the various phases of ophthalmic zoster. The reported incidence of ocular involvement in HZO ranges from 50% to 70% [2,10,11]. Virtually any component of the eye can be involved (see Table 1), but keratitis (inflammation Table 1 Ocular complications in immunocompetent patients with ophthalmic zoster Part of eye affected
Acute Phase
Late Phase
Eyelids
Swelling, vesicular rash Conjunctivits Episclerits Scleritis Epithelial keratitis
Ptosis, eyelid retraction Self limiting Self limiting Focal sclera atrophy Neurotrophic keratopathy Corneal neovascularization Focal iris atrophy Self limiting Self limiting
Conjunctiva Episclera Sclera Cornea
Stromal keratitis Anterior chamber Rare Complications
Uveitis Ocular hypertension Extraocular muscle palsies Optic neuritis Retinal necrosis, retinitis
Optic atrophy Retinal atrophy
Reproduced with permission from BMJ Publishing Group from Opstelten and Zaal [13].
Fig. 3 Slit lamp examination in a patient with HZO. Epithelial keratitis may have a dendritic appearance mimicking herpes simplex virus keratitis (A) and stains with fluorescein dye (B). Reproduced with permission from Dr Saad Shaikh.
Ophthalmic diagnoses in the ED
615 virus-related vasculitis and hypoperfusion [17]. Involvement of the eyelid, conjunctiva, episclera/sclera, and/or anterior chamber, are most commonly self-limited complications and rarely result in permanent sequelae. However, unlike the eyelid or conjuctiva, corneal or retinal involvement (keratitis) can potentially result in significant visual impairment (Fig. 5).
2.3. Diagnosis
Fig. 4 Slit lamp examination of a patient with stromal keratitis as a result of herpes zoster virus infection. Subepithelial infiltrates are located in the anterior stroma below areas of previous epithelial keratitis. Reproduced with permission from Dr Saad Shaikh.
closely resemble those of herpes simplex virus keratitis (Fig. 3, A and B) [10]. The lesions form branching patterns and stain with fluorescein dye. Stromal keratitis, as characterized by granular infiltrates in the anterior corneal stroma, typically occurs later in the course of disease (2-3 weeks) and is less likely to be seen by an emergency physician (Fig. 4). The complications of corneal involvement include corneal clouding, decreased corneal sensitivity with resultant increased risk for corneal ulceration, and corneal neovascularization affecting vision quality [13]. Rare complications include extraocular muscle palsies with resultant diploplia [16], optic neuritis, as well as retinal necrosis with resultant retinal detachment secondary to
In most cases, the diagnosis of HZO is based on clinical recognition of the characteristic rash along the ophthalmic dermatome. Laboratory analysis is frequently unnecessary; however, there are a number of rapid diagnostic tests available for varicella-zoster virus (see Table 2) [11]. Diagnosis during the prodromal phase, that is, before the development of the characteristic rash, remains challenging and requires vigilance on the part of emergency physicians when presented with a clinical presentation suggestive of early HZO. Differential diagnosis includes but is not limited to temporal arteritis, migraine headache, glaucoma, contact/allergic dermatitis, cerebrovascular accident, trigeminal neuralgia, sinusitis, herpes simplex, cellulitis, erysipelas, bullous impetigo, or even necrotizing fasciitis [18].
3. Treatment: antiviral therapy Treatment of HZO infections centers around 3 major objectives: (1) treatment of the acute viral infection, (2) treatment of acute pain, and (3) prevention of PHN. This is typically achieved through the use of both antiviral and corticosteroid therapy. Before the arrival of the antiviral medications, corticosteroids were the mainstay of treatment. There exist some conflicting data regarding the utility of steroid therapy in the treatment of herpes zoster. Several recent studies have demonstrated that corticosteroids, when used in combination with antivirals, accelerate the resolution of acute pain but had no effect on long-term pain and/or PHN [19,20]. The evidence that combination therapy (prednisone and acyclovir) improves quality-of-life measures is strong; however, clearly, not all patients are good
Table 2
Rapid diagnostic test for varicella-zoster virus
Tzanck Technique Electron Microscopy Antigen detection (smear) Antigen detection (culture) DNA hybridization Fig. 5 Zoster retinitis characterized by peripheral patches of retinal necrosis. Reproduced with permission from Dr Saad Shaikh.
Rapid; poor sensitivity/specificity Rapid; poor sensitivity/specificity Several hours; good sensitivity/ specificity Few days; good sensitivity/ specificity Research tool
Reprinted with permission from American Academy of Ophthalmology n 1991 from Liesegang [11].
616 candidates for corticosteroid therapy. Therefore, the decision to use corticosteroids in the treatment regimen should be reserved for relatively healthy elderly individuals who have moderate or severe pain [20]. The mainstay of therapy is treatment with antiviral medications. Early treatment with acyclovir, preferably within 72 hours of the onset of symptoms, has been shown to reduce the percentage of ocular complications from 50% to 20% to 30% [21]. However, initiation of treatment as late as 7 days after the eruption of cutaneous lesions does appear to convey some measure of prophylactic effect in reducing the ocular complications of HZO [21]. Both valacyclovir and famcyclovir have been show to have similar efficacy in the treatment of herpes zoster and have the added benefit of a simpler dosing regimen, which may improve patient compliance [22,23]. All 3 drugs are exceptionally safe and well tolerated when taken orally; dosing adjustments are required for patients with renal insufficiency. In immunocompromised patients, intravenous acyclovir for 7 days, followed by an oral regimen to prevent recurrence, is recommended. Because of the potentially sight-threatening complications associated with HZO, all patients should be treated with antiviral therapy. Treatment will also frequently necessitate pain management with either or both narcotic and nonnarcotic analgesics.
3.1. Referral and disposition Because of the high prevalence of complications in patients diagnosed with HZO, all patients should be referred to an ophthalmologist. However, ocular complications rarely develop in the first week after onset of the rash, making immediate consultation unnecessary. Patients who present with evidence of ocular involvement and/or involvement of the nasociliary branch of the trigeminal nerve (Hutchinson sign) require prompt referral [13]. Immunocompromised patients presenting with HZO requiring intravenous antiviral therapy should be admitted to the hospital with inpatient ophthalmologic consultation.
3.2. Vaccination In May 2006, the Food and Drug Administration approved the new vaccine Zostavax (Merck, Inc.) for the prevention of herpes zoster in persons 60 years and older. Approval of the live attenuated vaccine was made on the basis of the results of the Shingles Prevention Study [24]. A randomized, double-blind, placebo-controlled study, the Shingles Prevention Study evaluated the efficacy and safety of a single dose of Zostavax in 38 546 men and women aged 60 years or older who had no history of shingles. Compared with placebo, Zostavax reduced the risk of developing shingles by 51% (P b .001) at a median follow-up period of
W.P. Carter III et al. 3.1 years. A separate analysis of those individuals who received Zostavax but still went on to develop shingles showed an overall 39% reduction in the occurrence of PHN, with the greatest reduction seen in individuals aged 70 to 79 years. Zostavax is contraindicated for persons with a history of anaphylactic/anaphylactoid reaction to vaccination, with a history of primary or acquired immunodeficiency states (HIV, leukemia, lymphoma), receiving immunosuppressive therapy, or with active untreated tuberculosis. The duration of protective effect beyond the study follow-up period of 4.0 years is unknown, as is the efficacy of vaccination in persons with a previous history of herpes zoster. Common side effects of Zostavax were headache and injection site reactions ranging from erythema, pruritis, pain/tenderness, and swelling [25].
4. Key points 1. Patients presenting during the prodromal phase of HZO may have vague nonspecific complaints, making the diagnosis difficult. 2. Patients presenting with ocular involvement, especially those with Hutchinson sign, require ophthalmic consultation. 3. Approximately 50% to 70% of patients with trigeminal Herpes Zoster will develop ocular involvement; thus, diligent examination of the eye with corneal staining should be performed. 4. Antiviral therapy is beneficial in reducing ocular complications, especially if initiated within 72 hours of the onset of symptoms. 5. The recent approval of Zostavax may lead to a reduction in the incidence/occurrence of Herpes Zoster as well as PHN.
References [1] Straus SE, et al. Varicella-zoster virus infections: biology, natural history, treatment, and prevention. Ann Intern Med 1988;108:221-37. [2] Ragozzino MW. Population-based study of herpes zoster and its sequelae. Medicine (Baltimore) 1982;61(5):310-6. [3] Insinga RP, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005;20:748-53. [4] Donahue JG, et al. The incidence of herpes zoster. Arch Intern Med 1995;155:1605-9. [5] Thomas SL, et al. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis 2004;4:26-33. [6] Naumann G, et al. Histopathology of herpes zoster ophthalmicus. Am J Ophthalmol 1968;65:533-41. [7] Zaal MJ, et al. Prognostic value of Hutchinson's sign in acute herpes zoster ophthalmicus. Graefe's Arch Clin Exp Ophthalmol 2003;241: 187-91. [8] Harding SP, et al. Natural history of herpes zoster ophthalmicus: predictors of postherpetic neuralgia and ocular involvement. Br J Ophthalmol 1987;71:353-8.
Ophthalmic diagnoses in the ED [9] Jung BF, et al. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 2004;62(9):1-12. [10] Womack LW, et al. Complications of herpes zoster ophthalmicus. Arch Ophthalmol 1983;101:42-5. [11] Liesegang TJ. Diagnosis and therapy of herpes zoster ophthalmicus. Ophthalmology 1991;98(8):1216-29. [12] Liesegang TJ. Varicella-zoster virus eye disease. Cornea 1999;18(5): 511-31. [13] Opstelten W, Zaal M. Managing ophthalmic herpes zoster in primary care. Br Med J 2005;331:147-51. [14] Pavan-Langston D. Herpes zoster ophthalmicus. Neurology 1995;45 (12):S50-1. [15] Shaikh S, et al. Evaluation and management of herpes zoster ophthalmicus. Am Fam Physician 2002;66(9):1723-30. [16] Jude E, Chakraborty A. Left sixth cranial nerve palsy with herpes zoster ophthalmicus. N Engl J Med 2005;353:16. [17] Gurwood AS, et al. Herpes zoster ophthalmicus. Optometry 2002;73 (5):295-302.
617 [18] Fitzpatrick TB, et al. Color atlas and synopsis of clinical dermatology. 5th ed. New York: McGraw-Hill; 2005. [19] Wood MJ, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisone for treatment of acute herpes zoster. N Engl J Med 1994;330:896-900. [20] Whitley RJ, et al. Acyclovir with and without prednisone for the treatment of herpes zoster: a randomized placebo-controlled trial. Ann Intern Med 1996;125(5):376-83. [21] Cobo M. Reduction of the ocular complications of herpes zoster ophthalmicus by oral acyclovir. Am J Med 1988;85:90-3. [22] Colin J, et al. Comparison of the efficacy and safety of valaciclovir and acyclovir for the treatment of herpes zoster ophthalmicus. Ophthalmology 2000;107:1507-11. [23] Tyring S, et al. Famciclovir for ophthalmic zoster: a randomised aciclovir controlled study. Br J Ophthalmol 2001;85:576-81. [24] Oxman MN, et al. A vaccine to prevent zoster and postherpetic neuralgia in older adults. N Eng J Med 2005;352(22):2271-84. [25] Gnann Jr JW, et al. Herpes zoster. N Engl J Med 2002;347(5):340-6.