Herpes Zoster Ophthalmicus: a Teaching Case Report

Background he following case report on the diagnosis and management of herpes zoster oph- T thalmicus (HZO) is appropriate as a teaching guide for third- and fourth-year optometry students as well as optometry residents. The case report explores important clinical findings and considerations in the treatment of Herpes Zoster HZO in a patient with HZO, ocular manifestations of diabetes and atrophic Ophthalmicus: A age-related macular degeneration. This case emphasizes the need for a list of dif- Teaching Case Report ferentials when a patient presents with comorbid disease. Thus, it also teaches students to learn to manage multiple conditions in the same patient, all of which may contribute to a patient’s Kent Nguyen, OD decreased vision and may be important in the determination of treatment and Joseph Gallagher, OD, FAAO prognosis. Dorothy Hitchmoth, OD, FAAO, Diplom Learning Objectives At the conclusion of this case discussion, participants should be able to: 1. Describe the signs and symptoms Abstract of HZO Herpes zoster ophthalmicus (HZO) is a disease that occurs when the ophthal- 2. List the differential diagnoses of mic division of the trigeminal nerve is impaired as a result of reactivation of neurotrophic keratitis the varicella-zoster virus. HZO develops in 10-20% of patients who experience 3. Describe the stages of the Mackie reactivation of zoster in the fifth cranial nerve dermatome. The patient in this Classification teaching case report developed neurotrophic keratitis as a result of both HZO and 4. Understand treatment and man- diabetic neuropathy of V1. This teaching case illustrates many of the classic signs agement of HZO and neurotroph- and symptoms of HZO and discusses appropriate treatment, management and ic keratitis patient education. 5. Describe the pathophysiology and Key Words: herpes zoster ophthalmicus, neurotrophic keratitis, diabetes mel- demographics of herpes zoster litus, antiviral, Hutchinson’s sign, Zostavax (HZ) 6. Understand common morphologic changes that occur in corneas of patients with diabetes Key Concepts 1. Systemic, ocular and neurologic causes of neurotrophic keratitis 2. Pathophysiology of HZO 3. Ocular manifestations of HZ 4. Treatment considerations in comorbid presentations Dr. Nguyen is a 2012 graduate of the Southern California College of Optometry and a former Discussion Questions Optometry Resident at the Department of Veterans Affairs in White River Junction, Vt. 1. What is the pathophysiology of her- Dr. Gallagher is an Attending Optometrist at the Department of Veterans Affairs in White River pes zoster? Junction, Vt. Dr. Hitchmoth is Chief of Optometry at the Department of Veterans Affairs in White River 2. What are the demographics of her- Junction, Vt. pes zoster and HZO?

Optometric Education 65 Volume 39, Number 2 / Winter/Spring 2014 3. What are classic signs and symp- RT’s last visit to the eye clinic was retinal pigmented epithelium remain- toms of herpes zoster? March 29, 2006. His ocular history was ing, which was greater in size OD than 4. What are some of the acute and positive for retinal Hollenhorst plaque OS. The peripheral retina had extensive chronic signs of HZO? OD, involutional proliferative diabetic PRP OU that encroached on the poste- retinopathy with panretinal photoco- rior pole. No hemorrhages were present 5. Why might a HZO patient not agulation (PRP) OU, corneal epithe- OU. complain of symptoms? liopathy (likely diabetic neurotrophic The patient was diagnosed with HZ 6. What are the common signs and cornea) OU, dry eye syndrome OU, with V1 branch involvement. He was symptoms of neurotrophic kerati- pseudophakia OU and early dry macu- also diagnosed with chronic blepharitis? lar degeneration OS. tis-associated evaporative dry eye syn- 7. What are treatments for mild vs. His current medications included ba- drome. He was prescribed oral famciclo- severe forms of neurotrophic kera- clofen, camphor/menthol lotion, car- vir 500 mg Q8H and preservative-free titis? bamazepine, clobetasol proprionate artificial tears (carboxymethylcellulose ointment, colchicine, docusate, hy- 0.5%) Q1H OU, and was instructed 8. What neural factors are used in droxyzine, insulin (aspart and glargine), to discontinue ofloxacin ophthalmic treatment of neurotrophic kerati- lisinopril, loperamide, metformin, solution. Other diagnoses from the ex- tis? naproxen, permethrin cream, psyllium, amination were diabetic optic atrophy 9. How is the diabetic cornea differ- and triamcinolone cream. His fasting OU and atrophic age-related macular ent from the non-diabetic cornea? blood glucose measured at home the degeneration OU, each contributing to 10. What are some of the systemic, oc- morning of his appointment was 127 and consistent with the decreased visual ular and neurologic causes of neu- mg/dl. He was not a smoker. His aller- acuity. The patient was scheduled to re- rotrophic keratitis? gies included contrast media, terazosin turn in one week to monitor the HZ and Augmentin. and other conditions as needed 11. What are the stages of neurotrophic keratitis? Entering unaided visual acuities were Follow-up and management OD 20/60-2 and OS 20/200-1 with- (Table 1) 12. What are some differentials for red out improvement on pinhole. Notation eye? was made that the patient was possibly Visit #2 (8/15/12): The small erythematous, vesicular lesions on the left side Case Description viewing eccentrically with his left eye. Pupils were equally round and mini- of the patient’s face decreased in size. Patient RT, a 76-year-old Caucasian mally reactive to light, without an af- His pain also slightly improved. Visual male, was referred to the White River ferent pupillary defect. During pupil acuity remained reduced at OD 20/70 Junction Veterans Affairs Medical Cen- testing, the patient reported that the and OS 20/400 uncorrected. Corneal ter eye clinic on Aug. 8, 2012 for a red trans-illuminator appeared dimmer in staining was graded as 2+ diffuse SPK left eye that started two days prior. The his left eye. Red cap desaturation test- OD and 3+ diffuse SPK OS, without patient was seen by an optometrist in ing revealed 40% desaturation OS. edema or dendrites OU. OCT imaging the private sector who diagnosed the of the optic nerves and maculae were Anterior segment evaluation revealed attempted to further evaluate the optic patient with bacterial conjunctivitis meibomian gland stasis OU, mild OS and prescribed ofloxacin QID OU. atrophy and atrophic macular degen- mucous discharge OS, and trace con- eration. However, image quality was The patient reported feeling pressure junctival hypermia OS. Fluorescein dye in his left eye, as well as pain radiat- poor secondary to corneal staining and evaluation of the corneas revealed 4+ keratitis. The plan was to continue with ing down the left side of his face. He diffuse punctate staining OS and trace also had small erythematous, vesicular oral famciclovir Q8H for three more punctate staining OD. There were no days and change the artificial tears from lesions on the left side of his face that ulcerations, edema or dendrites in the also started two days prior. carboxymethylcellulose 0.5% to 1.0% cornea OU. The anterior chamber was Q1H OU for additional viscosity. RT’s medical history was positive for di- deep and quiet OD but was difficult to abetes mellitus type 2 for 18 years with assess OS through the corneal epithelial Visit #3 (8/23/12): Visual acuity was associated complications of peripheral defects. Intraocular pressures were 11 OD 20/80+2 and OS 20/150-1 un- neuropathy, foot ulcers, dystrophic toe- mmHg OU by non-contact tonometry corrected. The skin lesions continued nails, polyneuropathy, chronic urinary (NCT). to reduce in size. Dermatomal facial tract infections and kidney failure. The pain symptoms were intermittent and Dilated fundus examination revealed not as severe as before. Corneal stain- patient also had erectile dysfunction, posterior chamber IOLs with periph- arthralgia, stenosis of the carotid artery, ing was noted to be 2+ diffuse OD and eral fibrosis OU. The vitreous was clear 3++ diffuse OS. There were also two spinal stenosis, colonic polyps, dyspha- and quiet OU. The optic nerves had gia, drop foot, hammer toe, hyperkera- new anterior stromal infiltrates near the distinct margins but there was moder- superior limbus OS. One infiltrate was tosis, hypertension, suspect gout, and ate pallor of the rims. The C/D ratios pulmonary embolism from unknown 1 mm in size and stained superficially; were 0.35 round OU. The maculae the other infiltrate was 1/3 mm in size cause. The patient had a remote surgi- had nearly complete geographic atro- cal history of lumbar discectomy. and did not stain. The patient was di- phy OU with a small central island of agnosed with stromal keratitis OS and

Optometric Education 66 Volume 39, Number 2 / Winter/Spring 2014 was prescribed prednisolone acetate 1% ophthalmic solution QID OS. Table 1 Polysporin ophthalmic ointment BID Summary of Follow-Up Visits OS and ciprofloxacin 0.3% ophthalmic solution QID OS were also prescribed Visit Visual Cornea Other Signs/ Treatment Acuity Symptoms for bacterial coverage. Carboxymethyl- 8/8/12 OD: 20/60-2 Diffuse inferior SPK OD>OS Pain/pressure left Famciclovir Q8H cellulose 1.0% was continued Q1H to OS: 20/200-1 face Refresh Q1H OU Q1.5H OU. Scattered lesions V1 8/15/12 OD: 20/70 OD: 2+ diffuse staining Dec pain/pressure Famciclovir Q8H Visit #4 (8/27/12): Visual acuity was OS: 20/400 OS: 3+ diffuse staining Dec lesion size Celluvisc Q1H OU OD 20/70-1 and OD 20/150-1 uncor- 8/23/12 OD: 20/80+2 OD: 2+ diffuse staining Dec pain/pressure Celluvisc Q1H OU rected. Facial pain was reported to be OS: 20/150-1 OS: 3++ diffuse staining Dec lesion size Pred F QID OS less frequent and less severe. Corneal 2 infiltrates 1 & 1/3 mm Polyspor BID OS staining reduced to trace OD but in- Cipro QID OS 8/27/12 OD: 20/70-1 OD: trace staining Dec pain/pressure Celluvisc Q1H OU creased to 4+ diffuse OS. The two stro- OS: 20/150-2 OS: 4+ diffuse staining Dec lesion size Pred F QID OS mal infiltrates OS reduced in size to 1/3 2 infiltrates 1/3 & 1/4 mm Polyspor BID OS mm and 1/4 mm, with only the larger 8/29/12 OD: 20/70 OD: trace staining Stable pain/pressure Celluvisc Q1H OU one staining. Only ciprofloxacin 0.3% OS: 20/150 OS: 4+ diffuse staining Dec lesion size Pred F QID OS ophthalmic solution was discontinued 2 fainter infiltrates 1/3 & 1/4 mm Polyspor BID OS 9/5/12 OD: 20/70+2 OD: trace staining Stable pain/pressure Celluvisc Q1H OU due to reduction of infiltrate sizes. The OS: 20/150-1 OS: 3+ diffuse staining; Dec lesion size Pred F TID 1 wk rest of the topical medications and arti- 2 fainter infiltrates 1/3 & 1/8 mm then BID 1 wk OS ficial tears were continued as prescribed. 9/19/12 OD: 20/70+2 OD: 1+ diffuse staining Dec pain/pressure Celluvisc Q1H OU OS: 20/150-1 OS: 2+ diffuse staining Dec lesion size Bland lubricating Visit #5 (8/29/12) and #6 (9/5/12): Infiltrates resolved ointment BID OU Visual acuities at these two visits were 10/17/12 OD: 20/70-2 OU: 1-2+ diffuse SPK in Intermittent face Celluvisc 4-6x per stable at about OD 20/70 and OS OS: 0/150+2 scattered patches ache day OU 20/150 uncorrected. Facial pain was OS: 3 stromal scars all 1/4 mm Skin lesions resolved also stable without increase. The de- gree of corneal staining improved to trace OD and 3+ diffuse OS. The stro- was difficult to make. OCT of the optic lesions had resolved. Visual acuity re- mal infiltrates OS had greatly reduced nerve fiber layers revealed OD border- mained stable at OD 20/70-2 and OS in size and appeared more faint. Fol- line thinning of the superior quadrant, 20/150+2 uncorrected. Corneal stain- low-up was scheduled for two weeks. and OS thinning of the superior and ing decreased to 1-2+ diffuse OU, with Polysporin ophthalmic ointment was inferior quadrants and borderline thin- three superior stromal scars OS where discontinued and prednisolone acetate ning of the nasal quadrant. Again, the the previous infiltrates were. Corneal 1% ophthalmic solution was tapered to signal strength was much lower OS be- sensitivity testing with a cotton wisp TID OS for one week, then BID OS cause of signal interference from poor was noted to be equal and normal OU. for one week. Artificial tears were con- optics in the cornea. The patient was instructed to continue tinued as before. Prednisolone acetate 1% ophthalmic artificial tears 4-6 times per day or as Visit #7 (9/19/12): Visual acuity was solution was discontinued. Artificial needed, and to return in 4-6 months OD 20/70+2 and OS 20/150-1 uncor- tears were to be continued every 1.5 for a dilated exam. Unfortunately, RT rected. Pain symptoms remained stable hours. Additionally, a bland lubricat- passed away on Jan. 9, 2013. The cause but the skin lesions were almost fully ing ointment was prescribed QHS OU. of death was unknown. resolved. Corneal staining decreased to The patient did not have any com- Literature Review 2+ diffuse OS but increased to 1+ dif- plaints about his vision and wished to fuse OD. The stromal infiltrates OS lengthen the time until his next follow- Herpes zoster ophthalmicus had completely resolved. The patient up visit. A follow-up was scheduled for The varicella-zoster virus (VZV), which was dilated to obtain OCT images of one month to check the anterior seg- belongs to the same herpes subfamily as the maculae and optic nerves. Preser- ments, corneal sensitivities, and follow- herpes simplex, is responsible for caus- vative-free artificial tears were instilled up on blood sugar control. Careful ing both chickenpox (varicella) and every 5-10 minutes as the patient was patient education was provided at this shingles (herpes zoster).1 After an initial dilating to prevent additional keratitis time as well. The patient was told that infection of chickenpox, the VZV lays from the dilating drops. Fundoscopy the eye was not entirely healed and he dormant in the dorsal root ganglia of a revealed no changes OU. may not be able to feel disruption to his variety of nerves throughout the body, OCT of the macula revealed thinning cornea because of nerve damage. including the trigeminal nerve, which of the retinal tissue, mild disruption of Visit #8 (10/17/12): The patient re- is affected in herpes zoster ophthalmic- the retinal pigmented epithelium, and ported better blood sugar control. His us. The most commonly affected der- no edema OU. However, the signal fasting blood sugar that morning was matomes are in the thoracic region of the body, followed by the lumbar and strength and image quality were much 112 mg/dl. A left facial “ache” was still 2 lower OS and an accurate assessment present, but improving. The facial skin cervical regions. HZ can remain dormant for decades before reactivation

Optometric Education 67 Volume 39, Number 2 / Winter/Spring 2014 results from a decline in cell-mediated In the United States, the incidence of ure 2) The ophthalmic division further immunity.3 This decline in immunity HZ is 3.2 per 1,000 person-years. The divides into the frontal, lacrimal and can result from increasing age, immu- incidence increases with age, with the nasociliary branches. These branches nosuppressive conditions or medica- highest rate in individuals over 80 years innervate the forehead, upper eyelid, tions.4 Viral replication spreads along old. The incidence is also higher in pa- cornea, uvea, conjunctiva, sclera and the dermatome of the affected ganglia, tients with recent care for cancer, HIV the nose. The most common decade commonly presenting as a unilateral ve- infection, or transplantation compared of onset of HZO is between 50 and 59 sicular rash that does not cross the mid- to patients without these conditions.7 years of age.9 Current standard of care line of the body.5,6 The rash may affect HZ is uncommon in adults younger recommendations for patients with HZ one or two adjacent dermatomes (lo- than 40 years old who are not immuno- affecting the fifth cranial nerve include calized zoster) or be more widespread compromised. Younger patients tend to referral to an eyecare practitioner to and affect three or more dermatomes develop less severe forms of the disease rule out vision-threatening complica- (disseminated zoster).4 Associated pro- and have better response to treatment.8 tions. Most patients with HZ affecting dromal symptoms may include fever, V1 experience very little ocular involve- HZO occurs when reactivation of the 10 headache, malaise or unilateral pain. VZV involves the ophthalmic division ment. Only 10-20% of HZ cases in- Prodromal symptoms may occur days volving the fifth cranial nerve will have (V1) of the trigeminal nerve and may 2 to weeks before the rash. It is common be associated with ocular involvement. HZO. for individuals to have one episode of (Figure 1) The other two main divisions Ocular manifestations of HZO in HZ in their lifetime. However, periodic 4,6 of the trigeminal nerve are the maxil- the anterior segment may be acute or episodes of reactivation may occur. lary (V2) and mandibular (V3). (Fig- chronic, and the cornea is commonly

Figure 1 Figure 2 Unilateral Vesicular Rash Along V1 Dermatome in Three Main Divisions of the Trigeminal Nerve Herpes Zoster Ophthalmicus (Original image created by author) (Photo by Robert E. Sumpter, Image ID#12621, Centers for Disease Control and Prevention, Public Health Image Library.43)

Optometric Education 68 Volume 39, Number 2 / Winter/Spring 2014 involved. Acute ophthalmic complica- terior segment complications when al branches of trigeminal nerve V1.20,21 tions include acute epithelial keratitis, started within 72 hours of onset.11 The Loss or reduction of corneal innerva- conjunctivitis, episcleritis, scleritis, less frequent dosing of valacyclovir tion leads to compromised corneal in- nummular keratitis, stromal (intersti- and famciclovir compared to acyclo- tegrity, tear dysfunction and decreased tial) keratitis, disciform keratitis and vir increases the potential for patient corneal sensation.6 Dry eye syndrome anterior uveitis. Chronic complications compliance. Valacyclovir is a prodrug often results because the tear reflex can include neurotrophic keratitis, scleritis, of acyclovir, and has been found to be impaired.22 Neurotrophic keratitis mucous plaque keratitis, lipid degener- be equally effective in reducing ocular can lead to defective differentiation and ation, lipid-filled granuloma and eyelid complications, zoster-associated pain delayed wound healing of epithelial scarring.1,8 Immunocompromised pa- and skin lesions.12 A study of 86 immu- cells, which in turn can result in cor- tients are more likely to have bacterial nocompetent HZ patients revealed that neal ulceration and even perforation keratitis and poor visual outcome com- famciclovir may provide earlier reduc- without the patient feeling discom- pared to immunocompetent patients.8 tion in zoster-associated pain compared fort.9,22 Neurotrophic keratitis occurs at Posterior segment manifestations are to valacyclovir.13 a higher frequency with increasing age, uncommon, and may include retinal In a study surveying 100 eyecare practi- and develops in about 20% of cases of perivasculitis, ischemic optic neuritis tioners, the majority of them being cor- HZO. Older individuals are also at in- and necrotizing retinopathy.6 creased risk for secondary corneal infec- neal specialists, on treatment options 9 Acute epithelial keratitis, which devel- for stromal keratitis and anterior uveitis tions. ops in more than 50% of cases within associated with HZO, the most com- A number of ocular, systemic and neu- two days of rash onset, may be charac- mon treatment reported was a com- rologic conditions can cause corneal terized by dendritic lesions known as bination of oral antivirals and topical hypoesthesia that leads to neurotrophic “pseudodendrites.” Pseudodendrites are corticosteroids, with variability in the keratitis.23 (Table 2) These include elevated, opaque, white, fine branch- dosage and duration. The second most ocular surgery, trauma, topical medi- ing or stellate plaque-like lesions that common treatment was topical cor- cations, diabetes mellitus, contact lens have tapered ends without terminal ticosteroids alone. Oral antivirals are wear, trigeminal neuralgia and others. end bulbs. Pseudodendrites stain better typically administered for 7-14 days, Neurotrophic keratitis is divided into with rose bengal than with fluorescein. but there is no established guideline three stages known as the Mackie Clas- These lesions are more likely to form for the duration of antiviral treatment. sification.23 (Table 3) Stage 1 is charac- in younger HZO patients. Pseudoden- The most common corticosteroid used terized by decreased tear breakup time drites are treated with a topical antivi- to treat was prednisolone acetate 1% and punctate epithelial staining. Stage ral, while the other forms of keratitis QID.14 2 is characterized by stromal edema and are treated with topical steroids, such as loss of epithelium. Stage 3 is character- 1,9 Vaccination has been important in pre- prednisolone acetate 1%. venting the reactivation of VZV. The ized by stromal lysis and corneal perfo- Decreased visual acuity and corneal Shingles Prevention Study in 2005 ration. sensation are common symptoms, and found that the use of the Oka/Merck Standard treatments for milder cases patients may complain of foreign body VZV vaccine (“zoster vaccine”) reduced of neurotrophic keratitis include pre- sensation, irritation, burning and dry the incidence of HZ by 51% and the servative-free artificial tears, punctal eye symptoms.8 In some patients with incidence of post-herpetic neuralgia by occlusion and bandage contact lenses. decreased corneal sensitivity there may 66% in immunocompetent individuals Antibiotic ointments may be used pro- be no symptoms of discomfort at all5 60 years of age and older.15 The U.S. phylactically to prevent infectious cor- due to neurotrophic corneal nerves Food and Drug Administration (FDA) neal ulcers. Steroids may be needed if branching from CN V1. Loss of cor- approved Zostavax (Zoster vaccine live) the patient develops keratouveitis but neal sensitivity can lead to breakdown in 2006, for individuals 60 years of age should be used with caution due to of epithelium, which can in turn create and older.16 the known side effect of reduction in inflammation (uveitis), secondary in- In 2011, the FDA approved Zostavax would healing. More severe cases may fection, corneal thinning, ulcers, corne- 17 require surgery, such as tarsorraphy or 5,8 for individuals 50-59 years of age. 20,22,24 al perforations and scarring. Edema However, the U.S. Centers for Disease conjunctival flap construction. of the eyelids, ptosis, lagophthalmos Control and Prevention (CDC) still Large corneal defects may require pen- or eyelid scarring may also lead to tear recommends the vaccine for 60 years etrating keratoplasty; however, any evaporation and corneal desiccation of age and older despite the FDA ap- surgical corneal intervention should be that ultimately results in damage to the proval.18 Furthermore, vaccination avoided due to further risks of corneal corneal nerves.5,6 ulcers, melting and perforations after rates are low for the 50- to 59-year-old 20 Oral antivirals are widely used to treat age group due to lack of awareness or surgery. Discontinuation of other non-essential topical drugs is necessary HZ. The most common oral antivirals understanding of the vaccine. The rate 20,24 used are acyclovir 800 mg five times increases for older age groups.19 to reduce toxicity. a day, valacyclovir 1 g TID, and fam- Neurotrophic keratitis Impairment of the trigeminal nerve ciclovir 500 mg TID for 7-10 days.1 causes an insufficient supply of neural These three antivirals have been shown Neurotrophic keratitis is a corneal dis- factors, which leads to corneal epithe- to reduce pain, virus shedding and an- ease caused by an impairment of corne- lial disorder. These neural factors in-

Optometric Education 69 Volume 39, Number 2 / Winter/Spring 2014 clude substance P (SP) and insulin-like growth factor-1 (IGF-1).22 Eye drops Table 2 containing SP and IGF-1 have been Causes of Neurotrophic Keratitis/Corneal Hypoesthesia shown to synergistically stimulate epithelial wound closure.25 Derivatives of Infection these neural factors (FGLM-amide Herpes zoster Herpes simplex and SSSR, respectively) have also been Leprosy shown to promote resurfacing of persis- Fifth Nerve Palsy tent epithelial defects in neurotrophic Surgery (such as for trigeminal neuralgia) 26 Neoplasia (such as acoustic neuroma) corneas. Autologous serum (AS) has Aneurysms Facial trauma also been shown to stimulate epithe- Congenital lial healing, improve corneal sensitivity, Familial dysautonomia (Riley-Day syndrome) Goldenhar-Gorlin syndrome improve visual acuity and increase lev- Mobius syndrome Familial corneal hypesthesia els of SP and IGF-1 in individuals with Congential insensitivity to pain with anhidrosis 27 neurotrophic keratitis. Topical Medications Diabetes mellitus and neurotrophic Anesthetics Timolol keratitis Betaxolol Sulfacetamide 30% Neurotrophic keratitis may occur in Diclofenac sodium patients with diabetes mellitus. Dia- Corneal Dystrophies Lattice betic patients have reduced basal tear Granular (rare) 28 production and corneal sensitivity. Systemic Disease Neurotrophic keratitis should be a dif- Diabetes mellitus ferential when a diabetic patient de- Vitamin A deficiency velops unexplained corneal epithelial Iatrogenic 21 Contact lens wear disease. Epithelial dysfunction puts Trauma to ciliary nerves by laser and surgery diabetic patients at greater risk for cor- Corneal incisions neal disorders such as recurrent corneal LASIK erosions, decreased sensitivity, delayed Toxic Chemical burns re-epithelialization, abnormal wound Carbon disulfide exposure repair and ulcerations.29 A study of cor- Hydrogen sulfide exposure neal structure and sensitivity in type 1 diabetics found that corneal sensitivity is positively correlated with the num- Table 3 ber of long nerve fiber bundles in the The Mackie Classification cornea, and inversely correlated to the duration of diabetes. A significant de- Stage 1 Rose bengal staining of the palpebral conjunctiva crease in long nerve fiber bundles was Decreased tear breakup time Increased viscosity of tear mucus observed in patients with even mild Punctate epithelial staining with fluorescein neuropathy. However, corneal sensitiv- Scattered small facets of dried epithelium (Gaule spots) ity may remain normal in patients with Stage 2 mild to moderate neuropathy. Epithe- Acute loss of epithelium, usually under the upper lid Surrounding rim of loose epithelium lial thickness and corneal sensitivity are Stromal edema Aqueous cells and flare significantly decreased in patients with Edges of the defect become smooth and rolled with time 30 severe corneal neuropathy. Stage 3 Discussion Stromal lysis, sometimes resulting in corneal perforation Adapted from: Groos EB. Neurotrophic keratitis. In: Krachmer JH, Mannis MJ, Holland EJ The patient in this teaching case re- (eds.) Cornea 2nd Ed: Fundamentals, Diagnosis and Management. Mosby: Philadelphia, 2005, port presented with a red painful eye p 1191. that was previously diagnosed as bacterial conjunctivitis and treated with a number of medical conditions and may A thorough case history was key in topical antibiotic. It is important for a be taking numerous medications that diagnosing this case. The patient had clinician to consider the referring diag- can broaden or change the differential classic signs and symptoms of HZ, nosis; however, it is imperative that he/ significantly. The astute clinician pays most notably a unilateral vesicular rash she differentiate the causes of red eye by attention to the systemic conditions with ipsilateral facial pain following careful clinical history and exam. Clini- that may have ocular manifestations the V1 dermatome. The patient had cal history should include a careful de- and the systemic medications that may acute manifestations of HZO in the tailed ocular and medical history. Older have ocular side effects and adjusts the form of epithelial keratitis and stromal patients and other immunocompro- differential and the physical exam ac- keratitis. The patient’s reduced acuity mised patients are more likely to have a cordingly. was not consistent with his presenting

Optometric Education 70 Volume 39, Number 2 / Winter/Spring 2014 corneal condition, which required additional testing. A clinician should be Figure 3 aware that there may be multiple causes Vesicular Rash Due to the Varicella-Zoster Virus (Photo by Joe Miller, Image ID#5409, Centers for Disease Control and Prevention, of a patient’s reduced visual acuity. The Public Health Image Library.43) patient in this teaching case report had vision loss from a combination of neurotrophic keratitis secondary to HZO and diabetes, and atrophic macular degeneration. A good method for students to practice is to use the ‘axis ap- proach’, where the major structures go- ing from the front to the back of the eye along the visual axis are considered. This includes the cornea, the lens and the retina. A clinician should know how to address each cause and decide which ones can be treated and which ones should be monitored. Additionally, HZ skin lesions typically appear as a vesicular rash covering a large area that respects the dermatome vertical midline. However, skin lesions can be widely scattered and difficult to identify if they are beyond the hair- line. The patient in this case had several small, red lesions following the dermatome and respecting the midline but Unvaccinated individuals with a his- negative Hutchinson’s sign still has they were few in number and widely tory of HZO must exercise caution if about a 34% chance of ocular involve- scattered. A clinician should be aware they decide to get vaccinated. Hwang ment.37 However, not all studies agree of the different presentations of the et al. described the case of a 63-year-old on the predictive value of Hutchinson’s skin lesions that appear as erythema, male with a history of HZ keratouve- sign. Adam et al. 2010 instead found macules, papules or vesicles.6 (Figure itis and neurotrophic keratopathy who that blepharitis, eye redness and a rash 3) The presence of the rash in young- had been quiescent for 3.5 years, but in the supratrochlear nerve distribution er patients may be mistaken for other developed keratouveitis two weeks after (forehead above nasal bridge) were sta- diseases, such as herpes simplex derma- vaccination. Patients with a history of tistically significant associations with titis, insect bites or poison ivy, which HZO may have persistent viral anti- moderate to severe eye disease in HZ leads to incorrect management.9 gens. The live attenuated vaccine may patients.10 33 Interestingly, the patient in this case induce recurrence of keratouveitis. The epithelial disease and neurotrophic was at first in disbelief that he had HZ Also, Hutchinson’s sign was not evalu- keratitis that developed in the patient simply because he had been vaccinated ated in this patient. However, this sign in this case required regular use of ar- for it. The patient was educated that can help predict the clinical outcome tificial tears in addition to pharmaco- vaccinations do not work 100% of for the patient. Hutchinson’s sign is logical therapy. The artificial tears were the time. However, in a study examin- positive if the patient reports pain or a first-line defense in protecting the ing the incidence of recurrence of HZ discomfort on the very tip of the nose cornea and allowing it to heal. Another in immunocompetent individuals less on palpation. There may or may not be treatment consideration for this patient than 70 years of age, the incidence of a rash in the cutaneous region of the ter- was bandage contact lenses. Soft con- recurrence was 0.99 and 2.20 cases per minal branches of the nasociliary nerve, tact lenses are used in the management 1,000 person-years in vaccinated and which are at the tip, side and root of of many corneal conditions to provide unvaccinated individuals, respectively. the nose.10 Several studies have found pain relief and mechanical protection, Thus, regardless of vaccination status, that Hutchinson’s sign is a strong pre- facilitate epithelial healing and main- there is still a low risk of recurrence of dictor of ocular involvement and poor tain corneal hydration.38 Silicone hy- HZ.31 The efficacy of the vaccine- de visual outcome in HZ patients.34,35,36 drogel lenses work as effective bandage creases one year after administration Nithyanandam et al. found that other contact lenses due to high oxygen per- and continues to decline afterward. factors significantly associated with vi- meability, low water content, good wet- The efficacy of the vaccine is uncertain sual loss in HZO are anterior uveitis, ting properties and good patient com- after five years.32 Vaccinated individuals acute epithelial lesions, neurotrophic fort.39 However, use of contact lenses who developed HZ developed a milder keratitis and increasing age.34 A positive is not without risks, such as increased form of the disease compared to un- Hutchinson’s sign predicts about a 76% risk of infections. The management of vaccinated individuals in one study.3 chance of ocular involvement, while a this patient was more cautious in order

Optometric Education 71 Volume 39, Number 2 / Winter/Spring 2014 to avoid introducing another potential initially understand why he needed to ease Control and Prevention. Shin- complication. Furthermore, the patient continue to come back for follow-up. gles (Herpes Zoster) Clinical Over- was already very compliant with all his Careful patient education was key in view. http://www.cdc.gov/shingles/ medications and his condition was im- managing the patient’s corneal disease. hcp/clinical-overview.html. Ac- proving. Pseudodendrites, keratitis, inflamma- cessed: March 6, 2013. It is important to note that the patient tion or loss of stromal clarity are often 5. Kaufman SC. Anterior segment in this case had persistent pain along present with few symptoms, so it is complications of herpes zoster important to understand the course of ophthalmicus. Ophthalmology. the affected dermatome that slowly 5 resolved over the course of follow-up neurotrophic keratitis. 2008 Feb;115(2 Suppl):S24-32. but not entirely. Two months after Conclusion 6. Liesegang TJ. Herpes zoster oph- initial presentation, the patient con- thalmicus natural history, risk tinued to report an “ache” on the left Any HZ patient with V1 branch in- factors, clinical presentation, and side of his face. This was diagnosed as volvement should be referred for an eye morbidity. Ophthalmology. 2008 post-herpetic neuralgia (PHN), a pain exam. HZO affects up to 20% of HZ Feb;115(2 Suppl):S3-12. that can persist throughout the acute cases involving the fifth cranial nerve 7. Insinga RP, Itzler RF, Pellissier JM, phase of HZO and for many months dermatome. It can lead to a host of acute Saddier P, Nikas AA. The incidence afterwards. The pain can be severe and or chronic ocular conditions, many of of herpes zoster in a United States has been associated with depression which involve the cornea. Thus, timely administrative database. J Gen In- and suicidal ideation if not controlled. and accurate management is important tern Med. 2005 Aug;20(8):748- PHN is the most common lingering in preventing further damage and vi- 53. symptom and most debilitating com- sion loss. Still, the most debilitating 8. Gupta N, Sachdev R, Sinha R, plication of HZ,6 occurring in about complication of HZ is PHN. Older Titiyal JS, Tandon R. Herpes zos- 75% of patients over 70 years old.1 A patients should be monitored more ter ophthalmicus: disease spectrum possible mechanism is inflammation carefully and treatment should be more in young adults. Middle East Afr J and destruction of nerve roots. PHN is aggressive, as the incidence and severity Ophthalmol. 2011 Apr;18(2):178- treated with opioids, topical analgesics, of the disease increase with age. Vacci- 82. antidepressants and anticonvulsants nation is helpful is reducing the inci- 9. Ghaznawi N, Virdi A, Dayan A, according to the patient’s individual dence of HZ and PHN, but recurrence et al. Herpes zoster ophthalmicus: needs.40 Oral famciclovir and valacyclo- is possible and the long-term efficacy of comparison of disease in patients vir are more effective than acyclovir in the vaccine is uncertain. Neurotrophic 60 years and older versus younger treating PHN. These oral antivirals can keratitis may complicate treatment, ex- than 60 years. Ophthalmology. reduce the severity of PHN, but they acerbating the corneal damage and pro- 2011 Nov;118(11):2242-50. do not prevent it.11 Studies have shown longing therapy. Patients may complain 10. Adam RS, Vale N, Bona MD, that the use of cimetidine, an H2 an- of various ocular symptoms or have no Hasanee K, Farrokhyar F. Triag- tihistamine receptor antagonist, short- symptoms at all. Good patient history, ing herpes zoster ophthalmicus ened the time to heal pain and skin careful observation and aggressive treat- patients in the emergency depart- lesions in HZ patients, although the ment are imperative in managing pa- ment: do all patients require re- mechanism for immunomodulation is tients with HZO. ferral? Acad Emerg Med. 2010 not completely understood.41,42 Disclosure: Dr. Dorothy Hitchmoth Nov;17(11):1183-8. is a consultant for Annidis Health Sys- 11. Pavan-Langston D. Herpes zoster In general, the patient in this case was antivirals and pain management. followed very closely at first. As his tems Corporation and is on the speak- ers bureau for Zeavision. Ophthalmology. 2008 Feb;115(2 condition became more controlled, the Suppl):S13-20. interval between follow-ups became References 12. Colin J, Prisant O, Cochener B, et longer. The patient did become frus- al. Comparison of the efficacy and trated with the number of follow-up 1. Kanski JJ, Bowling B. Clinical safety of valaciclovir and acyclovir visits required because of the lack of Ophthalmology: A Systemic Ap- for the treatment of herpes zoster acute pain and improved acuity over proach 7th Edition. Elsevier: New ophthalmicus. Ophthalmology. time. After several visits, the patient did York, 2011, pp 187-191. 2000 Aug;107(8):1507-11. not have any complaints about his vi- 2. Ragozzino MW, Melton LJ 3rd, 13. Ono F, Yasumoto S, Furumura sion and wanted to be seen much later Kurland LT, Chu CP, Perry HO. M, et al. Comparison between for his next follow-up, despite the fact Population-based study of herpes famciclovir and valacyclovir for that there were persistent signs of in- zoster and its sequelae. Medicine acute pain in adult Japanese im- flammation and neurotrophia. Patients (Baltimore). 1982 Sep;61(5):310- munocompetent patients with are often aware of their reduced vision; 6. herpes zoster. J Dermatol. 2012 however, the corneal esthesia associated 3. Gelb LD. Preventing Herpes Zos- Nov;39(11):902-8. with an HZO infection may elude the ter Through Vaccination. Oph- 14. Sy A, McLeod SD, Cohen EJ, et patient and lead to a false understand- thalmology. 2008 Feb;115(2 al. Practice patterns and opinions ing of the resolution of the disease pro- Suppl):S35-8. in the management of recurrent or cess. The patient in this case did not 4. The nitedU States Centers for Dis- chronic herpes zoster ophthalmic-

Optometric Education 72 Volume 39, Number 2 / Winter/Spring 2014 us. Cornea. 2012 Jul;31(7):786- growth factor-1 on corneal epi- involvement in HIV-positive pa- 90. thelial wound closure of rab- tients with herpes zoster ophthal- 15. Oxman MN, Levin MJ, Johnson bit in vivo. Curr Eye Res. 1997 micus. S Afr Med J. 2010 Mar GR, et al. A vaccine to prevent her- Mar;16(3):275-8. 8;100(3):172-4. pes zoster and postherpetic neural- 26. Yamada N, Matsuda R, Morishige 36. Zaal MJ, Völker-Dieben HJ, gia in older adults. N Engl J Med N, et al. Open clinical study of eye- D’Amaro J. Prognostic value of 2005;352:2271-84. drops containing tetrapeptides de- Hutchinson’s sign in acute her- 16. Baylor NW, US Food and Drug rived from substance P and insulin- pes zoster ophthalmicus. Graefes Administration. Approval letter like growth factor-1 for treatment Arch Clin Exp Ophthalmol. 2003 – Zostavax [letter online]. May of persistent corneal epithelial de- Mar;241(3):187-91. 25, 2006. Available at: http:// fects associated with neurotrophic 37. Harding SP, Lipton JR, Wells JC. www.fda.gov/BiologicsBloodVac- keratopathy. Br J Ophthalmol. Natural history of herpes zos- cines/Vaccines/Approve Products/ 2008 Jul;92(7):896-900. ter ophthalmicus: predictors of ucm132873.htm. Accessed: Janu- 27. Matsumoto Y, Dogru M, Goto postherpetic neuralgia and ocular ary 22, 2013. E, et al. Autologous serum appli- involvement. Br J Ophthalmol. 17. Sun W, US Food and Drug Ad- cation in the treatment of neuro- 1987 May;71(5):353-8. ministration. Approval letter – trophic keratopathy. Ophthalmol- 38. Arora R, Jain S, Monga S, Naray- Zostavax [letter online]. March ogy. 2004 Jun;111(6):1115-20. anan R, Raina UK, Mehta DK. Ef- 24, 2011. Available at: http:// 28. Cousen P, Cackett P, Bennett H, ficacy of continuous wear PureVi- www.fda.gov/BiologicsBloodVac- Swa K, Dhillon B. Tear production sion contact lenses for therapeutic cines/Vaccines/ApprovedProducts/ and corneal sensitivity in diabetes. use. Cont Lens Anterior Eye. 2004 ucm248608.htm. Accessed: Janu- J Diabetes Complications. 2007 Mar;27(1):39-43. ary 21, 2013. Nov-Dec;21(6):371-3. 39. Ambroziak AM, Szaflik JP, Szaflik 18. The nitedU States Centers for 29. Bikbova G, Oshitari T, Tawada A, J. Therapeutic use of a silicone hy- Disease Control and Prevention. Yamamoto S. Corneal changes in drogel contact lens in selected clin- Shingles (Herpes Zoster) Vaccina- diabetes mellitus. Curr Diabetes ical cases. Eye Contact Lens. 2004 tion. http://www.cdc.gov/shingles/ Rev. 2012 Jul 1;8(4):294-302. Jan;30(1):63-7. vaccination.html. Accessed: March 30. Rosenberg ME, Tervo TM, Im- 40. Sanjay S, Huang P, Lavanya R. 9, 2013. monen IJ, et al. Corneal structure Herpes zoster ophthalmicus. 19. Javed S, Javed F, Mays RM, Tyring and sensitivity in type 1 diabetes Curr Treat Options Neurol. 2011 SK. Herpes zoster vaccine aware- mellitus. Invest Ophthalmol Vis Feb;13(1):79-91. ness among people ≥ 50 years of Sci. 2000 Sep;41(10):2915-21. 41. Komlos L, Notmann J, Arieli J, age and its implications on immu- 31. Tseng HF, Chi M, Smith N, et al. et al. IN vitro cell-mediated im- nization. Dermatol Online J. 2012 Herpes zoster vaccine and the in- mune reactions in herpes zoster Aug 15;18(8):2. cidence of recurrent herpes zoster patients treated with cimetidine. 20. Bonini S, Rama P, Olzi D, Lambi- in an immunocompetent elderly Asian Pac J Allergy Immunol. 1994 ase A. Neurotrophic keratitis. Eye population. J Infect Dis. 2012 Jul Jun;12(1):51-8. (Lond). 2003 Nov;17(8):989-95. 15;206(2):190-6. 42. Miller A, Harel D, Laor A, Lahat 21. Lockwood A, Hope-Ross M, Chell 32. Schmader KE, Oxman MN, N. Cimetidine as an immuno- P. Neurotrophic keratopathy and Levin MJ, et al. Shingles Preven- modulator in the treatment of her- diabetes mellitus. Eye (Lond). tion Study Group. Persistence of pes zoster. J Neuroimmunol. 1989 2006 Jul;20(7):837-9. the efficacy of zoster vaccine in Mar;22(1):69-76. 22. Nishida T, Yanai R. Advances in the shingles prevention study and 43. The nitedU States Centers for Dis- treatment for neurotrophic kera- the short-term persistence sub- ease Control and Prevention. Pub- topathy. Curr Opin Ophthalmol. study. Clin Infect Dis. 2012 Nov lic Health Image Library (PHIL). 2009 Jul;20(4):276-81. 15;55(10):1320-8. http://phil.cdc.gov/phil/home.asp. 23. Groos EB. Neurotrophic kerati- 33. Hwang CW Jr, Steigleman WA, Accessed: July 9, 2013. tis. In: Krachmer JH, Mannis MJ, Saucedo-Sanchez E, Tuli SS. Re- Holland EJ (eds.) Cornea 2nd activation of Herpes Zoster Kera- Ed: Fundamentals, Diagnosis and titis in an Adult After Varicella Management. Mosby: Philadel- Zoster Vaccination. Cornea. 2013 phia, 2005, pp 1190-91. Apr;32(4):508-9. 24. Reynolds SA, Kabat AG. Thera- 34. Nithyanandam S, Stephen J, Jo- peutic options for the management seph M, Dabir S. Factors affecting of early neurotrophic keratopathy: visual outcome in herpes zoster a case report and review. Optom- ophthalmicus: a prospective study. etry. 2006 Oct;77(10):503-7. Clin Experiment Ophthalmol. 25. Nakamura M, Ofuji K, Chikama 2010 Dec;38(9):845-50. T, Nishida T. Combined effects 35. Van Dyk M, Meyer D. Hutchin- of substance P and insulin-like son’s sign as a marker of ocular

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