Epidemiology and Pathogenesis
Herpes zoster (zoster, shingles) is a neurocutaneous disease caused by human herpes virus 3 (HHV-3), the same virus that causes varicella (chickenpox). It is a member of the herpes virus family (Herpesviridae) and exclusively infects human or simian cells. Varicella zoster virus (VZV) is the smallest of the alphaherpes viruses and has very stable linear double-stranded DNA. It has an icosohedral capsid and lipid envelope, which contains glycoproteins for cell entry.
Herpes zoster has the highest incidence of any neurological disease, with an annual occurrence of approximately 1 million cases in the United States. . The lifetime risk is about 30%, and 50% of those living until 85 years of age will be affected. The reported incidence varies from 3.2 to 4.2 per 1000 individuals per year. Increased risk of developing zoster is associated with older age (incidence of 10 per 1000 individuals over 80 years) and immunosuppression.
In temperate climates, primary infection with this virus usually occurs before age 10 years, manifesting clinically as chickenpox (varicella). The virus then establishes a latent state in the sensory ganglia. In circumstances of diminished virus-specific and cell-mediated immunity, the virus may reactivate and spread to the corresponding dermatome along a spinal or cranial nerve to generate the characteristic unilateral vesicular exanthem. The accompanying inflammation of the sensory nerve and skin damage are purportedly responsible for the acute pain.
Physical trauma and surgery have been correlated with the development of zoster. Other reported triggers include tuberculosis, syphilis, radiation therapy, and corticosteroids.
The epidemiology of zoster ultimately is dependent on the transmission and spread of VZV in a population. The spread of primary varicella (chickenpox) infection is of primary importance, but latent and reactivated infections play an important role in maintaining VZV infections within a population. Latently infected older adults and immunosuppressed patients are important reservoirs of the virus, as these groups are more likely to experience reactivation. When zoster does occur, the virus can be transmitted to a seronegative individual during the vesicular phase of the rash and cause a primary varicella infection. A zoster exposure with a seropositive, latently infected individual may result in a subclinical reinfection and boost humoral and cellular VZV immunity but is unlikely to cause acute varicella or herpes zoster. Herpes zoster may develop in immunocompetent patients who harbor the latent virus and who are re-exposed to it by contact with someone who has active varicella or zoster infection (primary, spontaneous, or infectious zoster).
Ophthalmic Herpes Zoster
The frequency of herpes zoster ophthalmicus (HZO) is second only to thoracic dermatomal occurrence, with up to 250 000 cases occurring yearly in the United States. Of these, 50%–70% suffer visual morbidity with severity increasing in the 5th–8th decades of life. The virus most commonly establishes latency in the trigeminal sensory ganglion and reactivates in 10%–25% of the population. The ophthalmic division of the trigeminal nerve is affected 20 times more frequently than the maxillary or mandibular divisions. Ocular involvement occurs in more than 70% of patients with zoster of the first (ophthalmic) division of the trigeminal nerve. Nasociliary branch involvement with skin lesions located on the inner corner of the eye, tip of the nose (Hutchinson’s sign), and root or side of the nose is predictive (50%–85%) of ocular involvement and is strongly prognostic for ocular inflammation and corneal sensory denervation. The eye may be seriously affected in up to 50% of cases in the absence of Hutchinson’s sign.
HZO usually begins with a prodrome of influenza-like illness, which is characterized by fatigue, malaise, nausea, and mild fever; this is accompanied by progressive pain and skin hyperesthesia, which is characterized by a burning painful area along a specific dermatome, followed by a diffuse erythematous or maculopapular rash that appears 3–5 days later. These eruptions can progress to form clusters of papules and clear vesicles and evolve through stages of pustulation, vesiculation, and crusting. Patients with deeper involvement of the dermis may develop permanent scars with loss of normal pigmentation. Rarely, herpes zoster may manifest with ophthalmic symptoms in the absence of cutaneous eruptions.
Ophthalmic Herpes Zoster
The frequency of herpes zoster ophthalmicus (HZO) is second only to thoracic dermatomal occurrence, with up to 250 000 cases occurring yearly in the United States. Of these, 50%–70% suffer visual morbidity with severity increasing in the 5th–8th decades of life. The virus most commonly establishes latency in the trigeminal sensory ganglion and reactivates in 10%–25% of the population. The ophthalmic division of the trigeminal nerve is affected 20 times more frequently than the maxillary or mandibular divisions. Ocular involvement occurs in more than 70% of patients with zoster of the first (ophthalmic) division of the trigeminal nerve. Nasociliary branch involvement with skin lesions located on the inner corner of the eye, tip of the nose (Hutchinson’s sign), and root or side of the nose is predictive (50%–85%) of ocular involvement and is strongly prognostic for ocular inflammation and corneal sensory denervation. The eye may be seriously affected in up to 50% of cases in the absence of Hutchinson’s sign.
HZO usually begins with a prodrome of influenza-like illness, which is characterized by fatigue, malaise, nausea, and mild fever; this is accompanied by progressive pain and skin hyperesthesia, which is characterized by a burning painful area along a specific dermatome, followed by a diffuse erythematous or maculopapular rash that appears 3–5 days later. These eruptions can progress to form clusters of papules and clear vesicles and evolve through stages of pustulation, vesiculation, and crusting. Patients with deeper involvement of the dermis may develop permanent scars with loss of normal pigmentation. Rarely, herpes zoster may manifest with ophthalmic symptoms in the absence of cutaneous eruptions.
Clinical Manifestations
HZO may affect all ocular and adnexal tissues and manifest with a diverse array of signs and symptoms. Ocular or extraocular involvement may occur at the time of the cutaneous eruptions or years later.
The skin of the forehead and upper eyelid is commonly affected and strictly obeys the midline with involvement of the ophthalmic division of the trigeminal nerve ( Fig. 4.5.1 ). Zoster involves the deep dermis, in contrast to herpes simplex, which is limited to the epidermis. Deep involvement may cause numerous lid complications, such as scarring, entropion, and ectropion. Conjunctival findings include hyperemia, petechial hemorrhages, papillary or follicular reaction, or, rarely, pseudo-membrane. Episcleritis and scleritis are common and tend to progress toward the limbus, causing vasculitis and sterile corneal infiltrates.
Corneal pathology tends to result from three pathophysiological mechanics: (1) active viral infection; (2) immune-mediated inflammation; and (3) chronic neurotrophic keratopathy. Active viral infections tend to affect the epithelium, leading to punctate epithelial keratitis and pseudo-dendrites ( Fig. 4.5.2 ). Pseudo-dendrites are typically smaller than typical dendrites, and lack terminal end-bulb formations. Immune-mediated stromal keratitis can take multiple forms. Nummular keratitis is the earliest finding of corneal stromal involvement and presents during the second week of the disease in 25%–30% of patients. It is characterized by multiple, fine, granular, coin-shaped infiltrates in the anterior stroma and may cause permanent scarring. Chronic interstitial keratitis may lead to deep corneal neovascularization and lipid keratopathy. Disciform keratitis is a deep stromal infiltrate that develops 3–4 months after the acute phase, characterized by a central disc-shaped area of diffuse corneal edema that results from endotheliitis and anterior chamber inflammation. Perilimbal vasculitis from immune-complex deposition can lead to sterile, peripheral, anterior cornea stromal infiltrates.
Active zoster infections travel through branches of the ophthalmic division of the cranial nerve. Each reactivation damages the corneal nerves causing progressive neurotrophic keratopathy. Late-stage HZO gives the picture of chronic epitheliopathy with filamentary keratitis and anterior stromal scars from a compromised ocular surface. The risk of secondary bacterial infection may be high in this setting.
HZO can cause nongranulomatous or granulomatous iridocyclitis (anterior uveitis) with keratic precipitates. It often has a chronic course, necessitating topical corticosteroids for control. Specific signs include elevated intraocular pressure from trabeculitis and sectoral, vasoocclusive iris atrophy. Glaucoma from HZO is often multifactorial. An early cause is from trabeculitis that resolves with corticosteroids, but chronic inflammation leads to pupillary seclusion, chronic angle-closure glaucoma, and, possibly, corticosteroid-response glaucoma.
Posterior segment manifestations of HZO include retinal perivasculitis, ischemic optic neuropathy, and forms of necrotizing retinopathy. These complications are uncommon but vision threatening. Two forms of retinitis are worth noting: acute retinal necrosis (ARN), which tends to occur mainly in immunocompetent patients, and progressive outer retinal necrosis (PORN), which occurs mainly in immunocompromised patients. ARN tends to present with severe ocular inflammation, whereas PORN appears less inflamed but has a much faster and vision-threatening clinical course. PORN is characterized by multifocal, deep retinal lesions that rapidly progress to confluence with minimal or no intraocular inflammation, an absence of vascular inflammation, and perivenular clearing of retinal opacification.
External ocular motor palsies frequently occur in acute HZO. Infections may affect the third, fourth, and sixth cranial nerves. These complications are thought to be from vasculitis within the orbital apex and frequently resolve within a year.
Postherpetic Neuralgia
Pain that continues following rash healing has been termed postherpetic neuralgia (PHN). Pain in HZO has three phases: (1) acute pain—first 30 days during and after rash onset; (2) subacute herpetic neuralgia—between 30 and 120 days; and (3) PHN when greater than 120 days.
PHN can occur in any patient with HZO; however, it usually is not seen in patients less than 50 years of age, and its frequency increases until age 70 years. It afflicts about one half of all patients with herpes zoster who are older than 70 years and appears to be more severe in older patients. The pain may occasionally be so extreme and persistent that some patients consider suicide. Risk factors for PHN include greater acute pain severity, greater rash severity, and presence of a painful prodrome preceding the rash. Additional risk factors for PHN include older age and female gender.
Postherpetic Neuralgia
Pain that continues following rash healing has been termed postherpetic neuralgia (PHN). Pain in HZO has three phases: (1) acute pain—first 30 days during and after rash onset; (2) subacute herpetic neuralgia—between 30 and 120 days; and (3) PHN when greater than 120 days.
PHN can occur in any patient with HZO; however, it usually is not seen in patients less than 50 years of age, and its frequency increases until age 70 years. It afflicts about one half of all patients with herpes zoster who are older than 70 years and appears to be more severe in older patients. The pain may occasionally be so extreme and persistent that some patients consider suicide. Risk factors for PHN include greater acute pain severity, greater rash severity, and presence of a painful prodrome preceding the rash. Additional risk factors for PHN include older age and female gender.
Herpes Zoster Ophthalmicus in Acquired Immune Deficiency Syndrome
HZO is an important early clinical marker for acquired immunodeficiency syndrome (AIDS), especially in high-risk younger patients. Immunocompromised patients have a higher incidence, greater severity, and more prolonged course of ocular involvement, as well as PHN, compared with immunocompetent patients with HZO. All nonpregnant, young patients with HZO should be tested for human immunodeficiency virus (HIV). PORN is reported with increasing frequency in patients with AIDS. Following cytomegalovirus retinopathy, PORN is the second most frequent opportunistic retinal infection in patients with AIDS in North America.
Diagnosis
The diagnosis of herpes zoster disease generally is based on clinical findings, although in recent decades, the clinical manifestations and spread of VZV have shifted. This change may confound clinical impressions (e.g., HSV lesions may appear to be zosteriform and be difficult to differentiate from zoster). Differential diagnosis includes eczema herpeticum, eczema vaccinatum, impetigo contagiosum, enterovirus-associated exanthema, contact dermatitis, drug eruptions, and insect bites.
Cytological examination of cutaneous vesicular scrapings reveals multiple eosinophilic intranuclear inclusions (Lipschutz’s bodies) and multinucleated giant cells (Tzanck’s preparation). Specimens (cutaneous vesicular scraping or conjunctival swab) must be transported to the laboratory as quickly as possible under low temperature conditions (4 °C). Immune electron microscopy techniques using specific peroxidase-labeled monoclonal antibodies against specific virus antigens can directly detect VZV. VZV-DNA can be obtained via anterior chamber paracentesis or vitreous tap and analyzed using real-time polymerase chain reaction. Fluorescent antibody techniques, cytospin direct immunofluorescence staining, and rapid direct immunofluorescence assays (SimulFluor direct fluorescent antibody) are additional methods for detecting VZV.
Serological tests to detect herpes zoster antibodies are of limited use because cross-reactivation between VZV and HSV can occur. Following zoster infection, a booster of IgG is detected for 2 weeks and then falls to lower levels and could persist at that level for years.
Management
HZO is treated with oral antivirals: acyclovir, famciclovir, or valacyclovir. Acyclovir (800 mg, five times daily for 7–10 days), reduces viral shedding and the chance of systemic dissemination, and reduces the incidence and severity of ocular complications, particularly if used within 72 hours of onset of symptoms. Acyclovir also can shorten the duration of pain if taken within the first 3 days of onset of symptoms. Intravenous acyclovir is recommended in immunocompromised patients.
Famciclovir (500 mg, three times daily for 7 days) is a prodrug of penciclovir and has a much higher bioavailability (77%) compared with acyclovir (18%). It has been shown to be well tolerated and safe with similar efficacy to acyclovir.
Valacyclovir (1000 mg three times daily for 7 days) is the l -valine ester of acyclovir and has higher bioavailability (80%) compared with acyclovir (18%). It has similar activity to acyclovir in the prevention of the sequelae of herpes zoster and has been shown to be as effective in preventing ocular complications of HZO. Comparative analysis also has shown that tolerability of the two drugs was similar. Valacyclovir has been shown to significantly accelerate the resolution of pain compared with acyclovir. Comparisons between valacyclovir and famciclovir treatment in HZO have not shown significant difference in resolution of pain or rash.
Of note, acute renal failure rarely has been reported with these medications, especially intravenous administration. As a result, kidney function should be monitored closely and renal dosing guidelines followed when appropriate. Dosing for children should be executed with reference to appropriate dosing guidelines. Acyclovir and valacyclovir are thought to be safe for use during pregnancy.
Management of Ocular Manifestation
Palliative therapy, including Burow’s solution, cool compresses, mechanical cleansing of the involved skin, and topical antibiotic ointment without corticosteroid, are helpful in treating skin lesions.
Oral acyclovir has been shown to be effective for the punctate, pseudo-dendritic, and delayed corneal mucous plaque forms of herpes zoster epithelial keratitis. Debridement may be helpful.
Neurotrophic keratitis or epithelial defects associated with herpes zoster keratitis may be treated with nonpreserved artificial tears, eye ointments, punctal occlusion, pressure patching, or therapeutic soft contact lenses. If these measures are unsuccessful, tarsorrhaphy, conjunctival flap, or autologous conjunctival transplantation should be considered. Studies have shown that good results can be achieved with corneal transplantation in patients with a history of HZO.
Topical corticosteroids are useful in the management of sclerokeratitis, keratouveitis, interstitial keratitis, anterior stromal infiltrates, and disciform keratitis. Corticosteroids generally should not be used in cases of exposure or neurotrophic keratitis because of the possibility of keratolysis. Topical cycloplegics prevent ciliary spasm associated with herpes zoster inflammatory disease. Aqueous suppressants and topical corticosteroids should be used to treat HZO glaucoma. Herpes zoster vitritis, vitreous hemorrhage, and vitreous debris may respond to topical, periocular, or systemic corticosteroids. Herpes zoster infections affecting the cranial nerves are best treated with a combination of systemic corticosteroids and intravenous acyclovir. Retinitis (ARN and PORN) is best treated with a combination of intravitreal injections and valacyclovir.
Postherpetic Neuralgia
Postherpetic neuralgia is challenging to control and may be treated with analgesics, tricyclic antidepressants (nortriptyline, amitriptyline, desipramine, clomipramine), and anticonvulsants (carbamazepine and phenytoin), often in combination. Newer medications (e.g., gabapentin—ranging from 300 mg three times daily to 1200 mg three times daily; and pregabalin) are more effective than tricyclic antidepressants against treating allodynia, another subtype of neuralgia. Capsaicin cream (0.025%) is effective when applied to the involved skin three to four times daily, although 2 weeks of treatment is often required for pain relief. PHN may be severe, intractable, and permanent, with some patients requiring psychiatric and pain clinic care, and occasionally trigeminal rhizotomy or stellate ganglion block may occur.
Findings of a meta-analysis reveal that famciclovir and valacyclovir significantly reduce the duration but not the incidence of PHN. Studies have shown corticosteroids to have no beneficial effect in the treatment of PHN. Amitriptyline for 90 days reduced the incidence of pain at 6 months. Finally, a single trial of percutaneous electrical nerve stimulation (PENS) in 50 patients reported decrease in pain incidence at 3 and 6 months compared with famciclovir.
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