Herpes Zoster Uveitis

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Disease Entity

Varicella zoster virus (VZV)-associated uveitis is a common cause of unilateral hypertensive uveitis. Anterior uveitis is the most frequent presentation although posterior uveitis can be observed as well.

Etiology

Herpes zoster (HZ) uveitis is caused by the reactivation of the varicella zoster virus (VZV), a double-stranded DNA virus of the Herpesviridae family. Following primary infection, VZV remains dormant within the dorsal root ganglia and may reactivate along the first division of the trigeminal nerve, resulting in ophthalmic manifestations. In this context, HZ uveitis can occur with or without cutaneous manifestation, known as Herpes Zoster Ophthalmicus (HZO) or varicella- zoster sine herpete, respectively.

Epidemiology

Anterior uveitis is the most common presentation of VZV-associated uveitis and occurs in 40 to 60% of HZO.[1] Patients are typically older than 50 years at presentation and both genders are equally affected. Studies from North Carolina and the United Kingdom have shown an increased risk in the white race compared with the black race.[2][3]

Although most patients are immunocompetent, immunocompromised patients are at greater risk of HZ uveitis and systemic involvement.[4]

Risk factors

The development of HZ uveitis is primary dependent on the virulence of VZV and the immune status of the host. Hence, triggers of the VZV reactivation encompass increasing age (especially after 60 years of age), exposure to affected individuals, immunosuppression (including HIV and immunosuppressive drugs), psychological stress, or direct trauma.

General pathology

Following reactivation, patient may experience symptoms of the prodromal phase including mild fever, nausea, malaise, skin hyperesthesia, tingling and progressive pain. Subsequently, a dermatomal rash may appear along the ophthalmic division of the trigeminal nerve, without crossing the midline, within three to five days. The presence of the eruption on the tip of the nose, known as Hutchinson’s sign, is a predictor for ocular inflammation. HZ uveitis occurs most often two to four weeks after the onset of HZO.

VZV-associated anterior uveitis tends to be mild and self-limited, however bilateral and severe disease can occur in the context of posterior uveitis and immunosuppression. Furthermore, the course of HZ uveitis tends to be chronic, in contrast to the acute and recurrent course in HSV-related uveitis.

Primary prevention

Prophylactic varicella-zoster vaccination in adults over 50 years of age is recommended and was shown to decrease the incidence of herpes zoster by 50 percent and the burden of illness due to herpes zoster by 60 percent.[5]

Symptoms

Patients with VZV-associated anterior uveitis usually describe a foreign body sensation, blurred vision, eye pain, and/or intense photophobia. When the posterior segment is solely involved, patients may experience an acute painless vision loss and floaters.

Clinical findings / Signs

HZ uveitis can involve both the anterior and the posterior segments of the eye, and manifest with the following clinical signs:

  • Skin lesions, including Hutchinson’s sign
  • Decreased visual acuity
  • Increased intraocular pressure
  • Ciliary injection
  • Chemosis
  • Conjunctivitis
  • Scleritis, episcleritis
  • Corneal involvement: decreased corneal sensitivity, punctate keratic precipitates, corneal edema, pseudodendrites, anterior stromal infiltrates, sclerokeratitis, keratouveitis/endothelitis, serpiginous ulceration, delayed corneal mucous plaques, disciform keratitis, neurotrophic keratitis, and exposure keratitis.
  • Miosis
  • Inflammatory anterior chamber cells and proteinaceous flare
  • Patchy or sectoral iris atrophy
  • Vitritis
  • Acute retinal necrosis (ARN): peripheral areas of white or yellow retinal necrosis that extend centrally
  • Progressive outer retinal necrosis (PORN): multifocal deep retinal opacities in the posterior pole and midperiphery, extending to the periphery
  • Retinal vasculitis, focal or multifocal retinochoroiditis
  • Papillitis, neuroretinitis, and optic neuritis

Clinical diagnosis

Diagnosis of VZV-associated uveitis is often clinical and based upon the presence or history of HZO on the affected side. In the absence of skin lesions, it may be diagnosed by the presence of unilateral hypertensive uveitis, especially with corneal involvement and patchy or sectoral iris atrophy. This characteristic iris atrophy is secondary to occlusive vasculitis from chronic uveitis and is visualized as transillumination defects upon retro-illumination at the slit lamp. Similarly, ocular hypertension associated with VZV-uveitis may be a helpful diagnostic hallmark. In contrast to most other inflammatory syndromes, which are associated with decreased intraocular pressure (IOP) as a result of ciliary body hyposecretion, HZ uveitis presents with ocular hypertension secondary to trabeculitis or trabecular obstruction by inflammatory cells.

Posterior segment involvement, albeit rare, may manifest as PORN in immunodeficient patients or ARN in immunocompetent patients with subsequent rhegmatogenous and/or tractional retinal detachment in more than 50% of the cases. Retinitis, retinochoroiditis, or optic neuritis can also be found. In some patients, a complete neurologic evaluation is warranted to rule out meningitis or encephalitis, specifically in cases of posterior uveitis and immunosuppression.

Diagnostic procedures / Laboratory testing

While the clinical history and ocular findings generally confirm the diagnosis, analysis of aqueous, and sometimes vitreous, samples for viral genome (through Polymerase Chain Reaction) or antiviral antibodies may be helpful, especially in case of uncertain diagnosis or no response to treatment. Given the high population-based prevalence of anti-VZV antibodies, serologic testing is typically of limited value.

To avoid progression and bilateral spread of the disease, the initiation of empirical treatment should never be delayed by testing, especially in VZV-associated posterior uveitis.

Brain MRI and lumbar puncture should be performed without delay when meningitis is suspected, especially in cases of PORN.

Differential diagnosis

Differential diagnosis of HZ anterior uveitis:

  • Acute angle closure glaucoma
  • Bacterial, fungal, viral, toxic, or allergic uveitis
  • Uveitis associated with systemic inflammatory conditions: HLA-B27, inflammatory bowel disease, psoriatic arthritis, sarcoidosis, tubulointerstitial nephritis and uveitis, post-infectious
  • Lymphoma, retinoblastoma


Differential diagnosis of HZ posterior uveitis:

  • Toxoplasma retinochoroiditis
  • Syphilitic retinitis
  • Bacterial or fungal endogenous endophthalmitis
  • Primary intraocular lymphoma
  • Retinitis associated with Behçet disease
  • CMV retinitis
  • Acute multifocal hemorrhagic retinal vasculitis
  • Sarcoidosis
  • Sympathetic ophthalmia
  • Vogt-Koyanagi-Harada syndrome
  • Commotio retinae
  • Central or branch retinal artery occlusion
  • Ocular ischemic syndrome
  • Collagen-vascular disease

Management

Medical therapy

The mainstay of HZ uveitis treatment is oral antiviral agents and topical steroids for 10 to 14 days. Patients with recurrent disease can benefit from an extended duration of anti-viral therapy. Available systemic antiviral agents include acyclovir 800 mg five times daily, valacyclovir 1 g three times daily, or famciclovir 500 mg three times daily. Prednisolone acetate 1% is the first-line topical steroid, to be used four times daily on a gradually-tapering regimen to control active anterior chamber inflammation. Adding topical cycloplegic/mydriatic agents may improve comfort and decrease the risk of posterior synechiae. The use of systemic steroids is controversial and contraindicated if the patient is immunosuppressed.

Posterior uveitis is treated with intravenous anti-virals; systemic corticosteroids are deferred for a minimum of 24h after initiation of antiviral therapy, then added with gradual taper. Management of ARN or PORN may require intraocular antivirals. In these cases, ganciclovir and foscarnet have been demonstrated to be superior to acyclovir due to their higher ocular bioavailability[6], and systemic steroids should be avoided. Neurologic consultation is recommended to rule out central nervous system involvement.

Increased IOP should be treated aggressively with topical aqueous suppressants. Prostaglandin analogues are avoided due to the risk of VZV reactivation.

Surgery

Pars plana vitrectomy with silicone oil tamponade is required for HZ-related retinal detachment or vitreous hemorrhage. Some authors suggested that early vitrectomy with intravitreal injection of antiviral and laser retinopexy may lower the rate of subsequent retinal detachment[7][8]; however, this remains controversial[9].

Cornea transplantation may be required for severe corneal thinning and scarring.

Glaucoma filtration surgery may be used as a last resort in cases of resistant intraocular hypertension.

Lens opacification may develop secondary to intraocular inflammation and/or steroid treatment and require cataract surgery.

Prognosis

In case of HZ anterior uveitis, visual prognosis is usually favorable with timely diagnosis and appropriate treatment. However, posterior segment involvement has a poorer prognosis, especially in case of retinal detachment, retinal necrosis, or ischemic optic neuropathy. Visual loss can also result from neurotrophic keratopathy with recurrent or persistent epithelial defects.

HZ uveitis-related complications depend on the severity of the eye disease as well as the patient’s characteristics. Potential complications include dry eye, corneal neovascularization and scarring, corneal ulcer, bacterial or fungal infection, secondary glaucoma, cataract formation, postherpetic neuralgia, retinal detachment, optic nerve atrophy, and total retinal necrosis.

Additional Resources

CDC Information on Varicella Vaccination

References

  1. Chan NSW, Chee SP. Demystifying viral anterior uveitis: A review. Clin Exp Ophthalmol. 2019;47(3):320-333.
  2. Schmader K, George LK, Burchett BM, Hamilton JD, Pieper CF. Race and stress in the incidence of herpes zoster in older adults. J Am Geriatr Soc. 1998;46(8):973-977.
  3. Thomas SL, Hall AJ. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis. 2004;4(1):26-33.
  4. Thean JH, Hall AJ, Stawell RJ. Uveitis in Herpes zoster ophthalmicus. Clinical & Experimental Ophthalmology.2001;29(6):406-10.
  5. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22):2271-2284.
  6. Aizman A, Johnson MW, Elner SG. Treatment of acute retinal necrosis syndrome with oral antiviral medications. Ophthalmology. 2007;114(2):307-312.
  7. Hillenkamp J, Nölle B, Bruns C, Rautenberg P, Fickenscher H, Roider J. Acute retinal necrosis: clinical features, early vitrectomy, and outcomes. Ophthalmology. 2009;116(10):1971-1975.
  8. Ishida T, Sugamoto Y, Sugita S, Mochizuki M. Prophylactic vitrectomy for acute retinal necrosis. Jpn J Ophthalmol. 2009;53(5):486-489.
  9. Iwahashi-Shima C, Azumi A, Ohguro N, et al. Acute retinal necrosis: factors associated with anatomic and visual outcomes. Jpn J Ophthalmol. 2013;57(1):98-103.
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