Ординатура / Офтальмология / Английские материалы / Pediatric Ophthalmology Current Thought and A Practical Guide_Wilson, Saunders, Trivedi_2008

28.3.6 Sarcoid Uveitis

Sarcoidosis is an inflammatory disease of unknown etiology that can affect virtually every organ in the body. Lung involvement is seen in 90% of patients’ disease course and can range from asymptomatic to severe lung disease. Uveitis is the most common extrapulmonary symptom seen in sarcoid patients with incidence ranging from 22% to 47% in various studies

[5, 39, 53]. Spagnolo et al. studied single nucleotide polymorphisms (SNPs) in patients with sarcoidosis, and found a 2.5-fold increase in sarcoid patients with uveitis with HSP-70 haplotype 2 compared to patients with sarcoid and no uveitis and non-sarcoid patients [62].

Additional ocular manifestations include conjunctival granulomas, episcleritis, scleritis, and interstitial keratitis. Inflammatory optic neuritis either anterior with disc edema or posterior without acute disc changes can also be seen in sarcoidosis. Extraocular muscle involvement can lead to painful ophthalmoplegia and diplopia. Lacrimal involvement in the form of adenitis or asymptomatic enlargement can occur. Chronic inflammation of the lacrimal gland can lead to fibrosis and decreased tear production causing severe keratoconjunctivitis sicca. Periocular cutaneous involvement creating a wide variety of nodules may be painful and disfiguring, as well as associated with ptosis and other lid deformities [5, 39, 53].

Sarcoidosis is characterized by non-caseating granulomatous inflammation seen on biopsy, and currently biopsy is required for definitive diagnosis. Histologically non-caseating granulomatous inflammation is manifest by epithelioid cells and multinucleated giant cells, Langhans type, with peripheral pallisading nuclei. The most common source of a diagnostic biopsy is the mediastinal lymph node plexus retrieved by mediastinoscopy. Other reliable sources include cutaneous nodules, swollen cervical and axillary lymph nodes, brain tissue, kidney and liver specimens, and conjunctiva.

With lung involvement being so frequent, chest radiograph is part of the standard workup. Diagnosis by transbronchial mediastinoscopic biopsy, a fairly invasive procedure, is required when more accessible lesions are not present. For this reason, a search for extrapulmonary involvement is performed looking for nodules, lymphadenopathy, or other lesions

throughout the body. Gallium 67 scanning may help identify other areas of sarcoid involvement where biopsy could prove easier and safer [5]. A small study in China evaluated the utility of blind conjunctival biopsy in sarcoidosis patients. Of the 26 patients enrolled 19 had “eye-related problems,” however no conjunctival nodules or follicles were noted. Blind biopsies, 1×3 cm, were obtained from bilateral lower fornices. Biopsy results were positive for sarcoidosis in ~37% of patients with sarcoidosis [9]. These results could prove very useful in diagnosing suspected sarcoidosis as conjunctival biopsy is much less invasive with relatively few complications, especially when compared to lung and mediastinal biopsy. More research needs to be performed, however blind bilateral conjunctival biopsy may be an excellent initial test for sarcoidosis diagnosis.

Serum angiotensin-converting enzyme (ACE) level is elevated in 56–86% of patients and is a useful test in suspected sarcoidosis. Elevated ACE levels and a positive gallium scan are quite sensitive (83–99%) for diagnosis of sarcoidosis, however biopsy is still currently required for diagnosis [5]. Disease course can range from asymptomatic lymphadenopathy to life threatening with CNS involvement.

Sarcoidosis can affect people of any age, gender, race, and ethnicity. More common presentations include women, people of African descent, and patients in their third and fourth decades. In the USA AfricanAmericans are at a 10-fold increased risk for developing sarcoidosis. Population studies have shown sarcoidosis incidence ranging from 1 to 150 per 100,000 in various groups [39]. Some regions of the country have disproportionately high prevalence levels of sarcoidosis, including North Carolina and Virginia, leading to the suspicions of an environmental factor such as atypical Mycobacteria or pine pollen.

Uveitis in sarcoidosis is classically chronic bilateral granulomatous iridocyclitis with mutton fat KP and iris nodules (Koeppe and Busacca), however acute anterior uveitis with fine KP can also be seen.

Intermediate and posterior uveitis can also occur.

Retinal granulomas can be seen on dilated examination ranging from small one quarter disc diameter lesions to large granulomata up to four disc diameters. In adults and older adolescent children, severe retinal periphlebitis with exudate, resembling “candle-wax drippings” can be seen, the classic “taches de bou-

gie.” Interestingly, retinal periphlebitis has not been described in pediatric sarcoidosis uveitis [5]. Treatment of uveitis involves topical steroids and cycloplegia, however systemic steroids and non-steroidal immunosuppressants are usually required in advanced cases, as inflammation can be difficult to control.

This is particularly common in advanced cases and those presenting late in their course with significant permanent damage to the blood–aqueous barrier.

Sarcoidosis in the pediatric population is less common than adult-diagnosed sarcoidosis, representing at most 15% of all sarcoidosis with about a 60% female preponderance. Pediatric sarcoidosis exists in two distinct forms with differing characteristic features.

Infantile sarcoidosis, approximately 70% of pediatric sarcoidosis, typically is seen in ages 0–5 years and is characterized by uveitis, arthritis, and skin rash. Anterior uveitis is seen in ~77% of patients with infantile sarcoidosis. Blau syndrome is an autosomal dominant autoimmune disorder mapped to the CARD15 gene on chromosome 16 in most cases. It presents with signs associated with infantile sarcoidosis, noncaseating granulomatous arthritis, uveitis, and dermatitis, along with camptodactyly, which describes hand deformities similar to those seen in advanced rheumatoid arthritis. The rash is typically described as a tan-colored, scaly, ichthyosiform rash. Recent studies have shown that infantile sarcoidosis and Blau syndrome are a spectrum of the same disease associated with mutations in the CARD15 gene in 50–100% of patients studied. More research is being performed attempting to establish genetic testing for CARD15 gene mutations as a less invasive and more accurate method for diagnosis of Blau syndrome and infantile uveitis compared to biopsy [53].

Sarcoidosis diagnosed in school-aged and an adolescent patients, ~30% of pediatric sarcoidosis cases, more closely resembles adult sarcoidosis with primarily lung involvement and absence of rash and arthritis. Anterior uveitis in these patients is seen in ~30% of patients, about the same prevalence as in adult sarcoidosis [53].

In studies of patients with sarcoid uveitis at the onset, the most commonly involved extraocular organ was the lung in ~35%. Spread to other organ systems occurred in ~17% of patients, with a majority of these suffering neurosarcoidosis. Treatment of uveitis reported by uveitis referral centers in cohort studies showed that ~50% of patients required systemic ste-

roids with ~10% requiring additional immunosuppressants [5, 39, 47]. These statistics demonstrate the challenges in treating uveitis related to sarcoidosis.

28.3.7 Pars Planitis Syndrome

Pars planitis syndrome is an idiopathic inflammatory condition with uveitis characterized by inflammatory cellular infiltration over the pars plana and adjacent vitreous body. Associated with only mild anterior segment inflammation, pars planitis is considered an intermediate uveitis. The Standardization of Uveitis

Nomenclature working group has recommended that the term “pars planitis” or “pars planitis syndrome” be reserved for “that subset of intermediate uveitis associated with snowbank or snowball formation in the absence of an associated infection or systemic disease” [19]. Therefore, before a diagnosis of pars planitis is made, infectious causes must be ruled out, including Lyme disease, Epstein-Barr virus (EBV) infection, West Nile virus, tuberculosis, cat-scratch disease, toxocariasis, sarcoidosis, and Behçet’s disease. Pars planitis is a diagnosis of exclusion.

Pars planitis is a rare disorder with an incidence of approximately 1.5–2 per 100,000. It is mostly a disease of childhood and young adulthood with presentations above 40 years of age exceedingly rare. Pars planitis and intermediate uveitis represent 8–22% of all uveitis cases and 18–33% of uveitis in patients less than 16 years of age. The most frequent symptoms include decreased vision and floater, which are typically bilateral and asymmetric ~80% of the time. Rarely patients may report pain, photophobia, and redness. Patients may also be asymptomatic with snowballs and vitreous cells noted on routine examination [14, 19, 27, 52]. Visual acuity is typically well preserved with average best corrected visual acuity at presentation 20/25 [19]. Anterior uveitis can be seen in roughly 30% of cases, however vitreous cell is seen in ~90%. Snowbanks describe the typical inflammatory pars plana exudates seen in all but very mild cases. Snowballs are large aggregates of vitreous cells seen in approximately 75% of cases of pars planitis. Peripheral vascular sheathing may also be present leading up to snowbanks along with neovascularization in the periphery. These localized lesions may require focal laser or cryotherapy.

Complications of pars planitis are related to the chronic inflammation in these patients. Epiretinal membranes (ERMs) are seen in almost 50% of patients, although rarely severe enough to require surgery. Cataract formation, typically posterior subcapsular, occurs in a third of patients on average 10 years after their diagnosis of pars planitis. Cataract development results from the disease itself as well as steroid treatment. Cystoid macular edema (CME) is seen in roughly 40% of cases in various studies. Control and prevention of CME is essential in preserving good visual acuity in these patients. Many patients may be asymptomatic with 20/20 vision, yet demonstrate significant macular involvement by OCT or fluorescein angiography. These patients should be treated to prevent subsequent macular damage and visual loss

[14].Arelatively large retrospective review of pediatric pars planitis and intermediate uveitis in the Netherlands noted optic disc edema in 71% of patients, although other studies have shown much lower rates of 2–20%. Increased IOP occurs rarely and topical agents can be used to treat high pressures. Chronic inflammation and periphlebitis can lead to neovascularization in as many as 5–10% of patients. Vitreous hemorrhage, and even retinal detachment are seen in less than 5% of pars planitis cases. Chronic inflammation can also lead to posterior synechiae and band keratopathy [14].

Treatment of intermediate uveitis depends on the underlying etiology which should be treated according to the specific organism or disease process. If all testing is negative, then the diagnosis of pars planitis can be made. Treatment of pars planitis depends on clinical severity. Asymptomatic patients with normal vision may be observed and no treatment may be necessary. These patients still require close fol- low-up as the disease course can be quite variable. Topical, periocular, and systemic steroids can then be used as needed, titrated to disease severity [14]. Even young patients 5 years of age and over can be taught to cooperate for periocular steroid injections, avoiding systemic agents or trips to the operating room for sedation.

Oral steroids are usually started at 1.0–1.5 mg/kg dose with gradual taper to the lowest effective dose and a short-term goal of less than 15 mg per day. Cryotherapy or laser therapy to snowbanks can also be performed if not improving with steroid therapy or when peripheral neovascularization develops. Cryo-

therapy should be avoided in areas of retinal traction as this could worsen the traction in treated areas. Laser photocoagulation should be employed in these instances. Rarely, vitrectomy may be performed for inflammation not responding well to steroids. The pars plana vitrectomy approach allows separation of the posterior hyaloid membrane and endolaser treatment to snowbanks. Vitrectomy can also be used to treat non-clearing vitreous cell or debris obscuring vision, and repair of tractional retinal detachment and non-clearing vitreous hemorrhage [14, 19]. Steroidsparing immunosuppressants may rarely be required, including methotrexate and TNF inhibitors.

Visual outcome is relatively good in pars planitis with three fourths of patients retaining 20/40 vision or better in long-term follow-up. Most patients have vision in the 20/25–20/30 range, with acuity loss usually attributed to ERM, cataract, and CME [19].

Worse visual loss is seen in patients with optic nerve involvement. The clinical course tends to be less favorable with younger age of onset in some studies. Within the pediatric population, age was not noted to be a risk factor for disease severity. This same study showed an almost 50% “remission” rate in treated patients at the 5-year follow-up [14].

Correlation between cigarette smoking and pars planitis was noted recently in population studies of Olmstead County, MN. Although not noted in previous studies, recommending smoking cessation to patients is worthwhile. Multiple sclerosis (MS) and pars planitis correlation has been firmly established in many studies with prevalence of 12–16% of patients with pars planitis diagnosed with MS when compared to 0.1% of US population with MS [19]. A significant association between HLA-DR2 subtype and pars planitis has been determined, which is also seen in MS.

28.3.8Juvenile Idiopathic Arthritis and Juvenile Rheumatoid Arthritis

Juvenile rheumatoid arthritis (JRA) is now grouped into a broader category of juvenile idiopathic arthritis (JIA), an autoimmune disease that affects 1–2 per 1,000 children, with incidence ranging from 11 to 14

new cases per 100,000 children per year [55]. Early diagnosis is important to reduce morbidity from joint involvement and to prevent serious complications of uveitis commonly seen in the disease. Referral to an ophthalmologist is indicated in all patients suspected of JRA to rule out uveitis, especially as ocular inflammation is usually asymptomatic in JRA. Meticulously frequent follow-up care is mandatory to ensure uveitis does not develop. Arthritis-related uveitis in children can devastate an eye in short order despite the lack of symptoms other than the often-ignored unilateral blurring or floaters.

Classifications of childhood arthritis conditions are changing as we learn more about these related disease processes, while multiple classifications exist in different countries and among different specialties. In many European countries the term juvenile idiopathic arthritis (JIA) is used which encompasses JRA along with other autoimmune arthropathies, including psoriatic arthritis and ankylosing spondylitis. The American College of Rheumatology diagnostic criteria, first established in 1977, defines JRAas a chronic arthritis lasting longer than 6 weeks, with onset before the age of 16 years, excluding other forms of pediatric arthritis. JRA is the most common systemic disease associated with pediatric uveitis [7, 67].

Three main types of JRA are defined by the systemic symptoms seen within the first 6 months of onset. These types are:

1.Oligoarticular (pauciarticular) with <5 joints involved

2.Polyarticular with 5 or more joints involved

3.Systemic onset with arthritis associated with fevers

Pauciarticular JRA (<5 joints) accounts for ~60% of JRA cases. There is a strong female sex predilection with female:male ratio of 5:1. The age of onset is usually in early childhood with peak incidence in ages 1 through 3 years. Pauciarticular-type JRA is the type most frequently associated with uveitis, seen in 15–20% of cases. Serologic studies show rheumatoid factor (RF) to be rarely positive in these patients while a positive antinuclear antibody (ANA), on the other hand, is found in a vast majority of cases, reportedly ~75–85% of patients. Many times a negative or low titer ANA will rise sharply with subsequent testing or a proximal flare in systemic disease. The course of therapy as well as the natural history of the disease process itself can often be followed with ANA

serology, the ESR, or the CRP. Pauciarticular arthritis can persist into adulthood in 40–50% of cases. Many children experience a welcome diminution in the severity of their ocular and joint disease as they complete puberty [67, 69].

Polyarticular type (≥5 joints) represents ~30% of

JRA cases. Polyarticular type can present throughout childhood up to the age of 16 years with a peak at

1–3 years. Once again there is a significantly higher incidence in girls with a female:male ratio of 3:1.

Uveitis is seen in approximately 5% of polyarticular

JRA cases. Serologic tests show a positive RF in ~10% and a positive ANA in 40–50% of cases [7, 69].

Systemic JRA, characterized by multijoint arthritis and fever, is the diagnosis in ~10% of JRA cases. Systemic JRA, in contradistinction to the oligoarticular and the polyarticular forms of arthritis in children, is rarely associated with uveitis. Serologic studies show RF is rarely positive and a positive ANA is found in only 10% of these patients. Sex predilection is equal. This is the most severe type of JRA; it can cause profound joint destruction and has a mortality rate of 0.5–2.0% [7].

Ophthalmologists are rarely the first physician seeing JRA patients, particularly in light of the frighteningly negative symptoms produced by even advanced ocular disease. Most patients already carry the diagnosis since their joint involvement usually precedes uveitis, and is more readily apparent and symptomatic. Referrals most frequently arise from pediatric rheumatologists and primary care pediatricians. However, ophthalmology may occasionally be the first to see a patient in rare cases of uveitis presenting before arthritis or poor school vision screening. Any child with idiopathic uveitis warrants referral to rheumatology not only for appropriate rheumatologic workup of possible systemic disease, but also for assistance in guiding therapy in these notoriously difficult uveitis patients.

Early detection and treatment of uveitis is essential for preservation of normal vision and ocular anatomy. Studies have shown later presentation, and, specifically, formation of posterior synechia, is associated with worse visual outcomes and earlier cataract formation requiring surgery. Intense screening should be performed for JRA and other rheumatologic conditions (e.g., ankylosing spondylitis, psoriatic arthritis) to detect uveitis earlier and prevent the manifold complications associated with late presentation [61].

The American Academy of Pediatrics have devised ophthalmologic screening guidelines for patients with JRA based on several key factors shown to have increased risk and complications due to uveitis. Female sex, age <4 years, and a positive ANA titer are considered high-risk factors for developing uveitis (Table 28.5). Recent population studies from Canada show a small predisposition for JRA and uveitis associated with JRA among patients of European ancestry and a lower relative risk for children of African, Asian, and Indian ancestry. These population studies also concluded that female gender showed increased risk of asymptomatic uveitis compared to males with

JRA [6].

Aggressive treatment of uveitis is required in these patients and usually only mild cases can be treated successfully with topical steroids. Monotherapy with topical NSAIDs alone has not been effective in controlling uveitis in these patients, although a concurrent topical NSAID can provide sufficient anti-inflammatory benefits to reduce the overall necessary dosage of topical steroids. A combination of topical and systemic steroids is usually instituted in JRA patients with moderate to severe uveitis. Highfrequency topical prednisolone drops along with high induction dosages of oral prednisone (up to 2 mg/kg p.o. daily) or IV methylprednisone have been suggested. Tapering of steroids to avoid long-term complications of topical and systemic steroid use has been successful with adjunctive disease-modifying agents, or DMARDs. Methotrexate is the most commonly used of these medications as its safety pro-

file in the pediatric population and success is well documented. Oral naproxen is also useful in this age group, although less potent than the DMARDs. Cyclosporine, azathioprine, and newer TNF-inhibiting drugs like infliximab and etanercept have been used in small studies with moderate improvement. Longterm success and safety data are not as extensive as methotrexate in treating these patients, but results are extremely encouraging [67, 69].

Long-term studies on JRA patients have shown that a majority of the patients had a favorable outcome.Approximately 50% of patients have persistent disease activity and continued joint pain and edema with only 14% of patients with continued uveitis [67].

On the other hand, JRA-associated uveitis when undertreated or untreated due to delayed diagnosis can devastate an eye with permanent cicatricial or inflammatory damage.

28.3.9 Herpetic Uveitis

Human herpes virus (HHV) family is a group of eight viruses ubiquitous in human hosts due to their characteristic ability to establish a persistent latent ganglionic infection. After initial exposure these viruses lie dormant in a latency stage within various neural cells and are capable of reactivation at any time, usually during periods of host immune susceptibility. The most prevalent pathologic viruses being herpes simplex-1 (HSV-1, commonly called oral herpes),

herpes simplex-2 (HSV-2, commonly called genital herpes), varicella-zoster virus (VZV, virus implicated in chickenpox and shingles), cytomegalovirus

(CMV), and Epstein-Barr virus (EBV). Human herpes virus type 8 has been strongly associated with

Kaposi sarcoma [30].

The herpes viruses are the causative agent in many ocular diseases, including blepharitis/dermatitis, conjunctivitis, dendritic epithelial keratitis, corneal ulceration, stromal keratitis, endotheliitis, trabeculitis, episcleritis, scleritis, iridocyclitis, and acute retinal necrosis (ARN) syndrome. HSV ocular involvement is almost always unilateral with less than 3% of patients in the HEDS trial having bilateral disease [26].

The location of herpetic reactivation can be virtually anywhere in the eye, including multiple anatomic locations, none of which are either mutually exclusive or mandatory in combination (Table 28.6). Thus, a wide variety of presentations can occur, most commonly epithelial keratitis, stromal keratitis, herpetic uveitis, and cutaneous vesicular eruptions. Trabeculitis is common with keratitis or uveitis, creating an elevated IOP in contradistinction to most uveitis entities that lead to depressed IOP. Other uveitic conditions creating high

IOPs include toxoplasmosis, Fuchs’uveitis syndrome, and Posner-Schlossman syndrome [26, 30].

Herpetic corneal disease is an important cause of blindness, accounting for up to an estimated 500,000 cases annually in the USA. After active infection, herpes viruses lie dormant within the trigeminal ganglion or in corneal nerves and may reactivate to produce any of the many varieties of ocular herpetic disease [26]. The average age of onset for HSV uveitis

Table 28.6  Ocular localization of human herpes simplex virus may occur in any combination

Eyelids

Periocular skin

Corneal epithelium

Corneal stroma

Corneal endothelium

Trabecular meshwork

Iris stroma

Iris sphincter

Vitritis

Retinitis

Papillitis

is 46 years, accounting for approximately 9% of nontraumatic iritis cases in a referral clinic setting. The onset of HSV uveitis generally decreases with age, whereas VZV reactivation increases with age. About one in four individuals over the age of 80 years will suffer a bout of shingles, and one fourth of them will have trigeminal zoster. VZV is also triggered by periods of stress or impaired immunity [41].

Corneal epithelial involvement can be seen as a dendrite or pseudodentrite thought to contain active virus. Many patients with VZV or HSV uveitis do not have any evidence of active or inactive corneal disease, however, careful examination may often reveal a previously undetected subtle postinflammatory corneal scar or ectasia characteristic of herpetic disease. Therefore steroids should be avoided in patients with active or potentially active severe axial epithelial disease.

Herpes viruses can damage nerves during active inflammation, and decreased corneal sensation can be noted acutely or after resolution of corneal disease. Since the HEDS trial much more information regarding the treatment of HSV ocular disease is available. Treatment of HSV epithelial keratitis with topical trifluridine drops with or without debridement can shorten the duration of disease. Herpetic uveitis develops in ~10% of patients with epithelial keratitis. The HEDS trial noted no benefit of adding oral acyclovir for epithelial disease in preventing development of iritis. Corneal stromal involvement can be seen with or without epithelial defect and up to 20% of patients with epithelial HSV keratitis will develop stromal keratitis within 2 years. Stromal keratitis is thought to be a non-infectious immune reaction and should be treated with topical corticosteroids and either topical or systemic antiviral medications. The HEDS trial showed a 68% decrease in stromal keratitis progressing to keratouveitis with steroid use, and a significant decrease in recurrence of stromal keratitis with long-term acyclovir prophylaxis. Topical steroids and oral acyclovir is also the recommended treatment for herpetic endotheliitis [26].

Herpetic uveitis is most often an acute, anterior, non-granulomatous uveitis. A more severe granulomatous reaction, however can cause inflammation anywhere in the eye with herpetic reactivation. Herpes uveitis needs to be kept in the differential for any unilateral uveitis of unknown etiology. Prompt aggressive treatment of stromal herpetic keratitis often

avoids progression to anterior uveitis. Recurrence of HSV uveitis is common, occurring in around 70% of patients and is more frequent in non-whites. Anterior chamber cell can vary depending on severity, and hypopyon and hyphema have both been described in HSV uveitis.

Patients with anterior uveitis from any of the human herpes viruses characteristically develop stellate KP. These unique lesions are defined by a diffuse homogeneous distribution differing extensively from KP from other etiologies. Stellate KP also appear as wispy dendritic or starfish-shaped deposits throughout the endothelium. They are much smaller than either granulomatous or non-granulomatous KP which themselves are usually far more prominent in the inferior one third of the cornea known as Arlt’s triangle. Either coincidentally or by a pathophysiologic mechanism, the uveitic entities that create an elevated IOP are also those entities that produce stellate KP. Thus, stellate KP may result from a fluidic pathologic state that simultaneously creates trabecular meshwork congestion and subsequent aqueous humor outflow obstruction [26, 30].

Primary infection with VZV, better known as chickenpox, can occasionally cause a bilateral, selflimited, mild anterior uveitis. Reactivation VZV, or shingles, causes ipsilateral uveitis, usually concurrent with periocular skin involvement. Ocular involvement is said to occur in up to 70% of patients with involvement of the V1 or ophthalmic branch of the trigeminal nerve. Eye involvement is more likely with involvement on the tip of the nose (Hutchinson’s sign) indicating reactivation through the nasociliary nerve, an inferior branch of V1 traveling through the orbit [68].

Herpetic uveitis is associated with iris stromal necrosis leading to atrophy, best seen by slit-lamp retroillumination, and pupillary irregularity as a result. Typically VZV iris atrophy is described as sectorial while HSV-1 and HSV-2 causes more diffuse iris atrophy. Recent reports of aqueous humor samples in a small number of patients with VZV uveitis demonstrated that higher VZV DNA levels detected in aqueous samples correlated with more severe iris atrophy and pupil irregularity [41, 68].

Glaucoma is an important diagnostic sign in herpetic uveitis. Unlike most uveitis where IOP is decreased due to decreased aqueous production by the inflamed ciliary body, herpetic uveitis can result in

increased IOP resulting from trabeculitis. Chronic inflammation can cause scarring of the trabecular meshwork and chronic glaucoma. This elevation in IOP responds well to corticosteroid therapy. Posterior synechiae are another common outcome of HSV iridocyclitis, occurring in 58% of patients. Secondary glaucoma association with HSV was seen in up to 54% of patients and 38% of patients with VZV. This increase in pressure can be quite pronounced with

IOP as high as 50–60 [30].

Intermediate, posterior, and panuveitis uveitis are also seen in herpetic ocular disease. Somewhat unique to the herpes family of viruses is the development of retinitis, particularly in immunocompromised patients. Posterior involvement is more common with VZV than HSV. Herpes infection (HSV-1, HSV-2, CMV, VZV) can cause ARN or bilateral acute retinal necrosis (BARN), although VZV and HSV-1 are most commonly implicated. ARN is a syndrome characterized by peripheral necrotizing retinitis and vasculitis, accompanied by variable degrees of vitritis, papillitis, and anterior granulomatous uveitis. Predominately a disease of healthy people, ARN can be visually devastating [25, 26, 41, 68]. Causative organisms have been identified from vitreous sampling in several clinical reports. These studies have shown that ARN is most likely caused by VZV or HSV-1 in patients over 25 years of age. In patients less than 25 years old, HSV-1 and HSV-2 were the most likely organisms identified [41].

Severely immunocompromised patients can develop peripheral outer retinal necrosis (PORN). This rare syndrome reveals significant peripheral retinal necrosis, vasculitis, retinal artery occlusions, anterior segment ischemia, cranial nerve palsies, orbital involvement, and positive VZV titers in the majority of cases [25, 38, 68].

Herpetic retinal necrosis is rapidly progressive and visually devastating thus requiring aggressive systemic antivirals specifically directed against the presumed causative organism. These medications include acyclovir, foscarnet, and ganciclovir. Valacyclovir and valganciclovir are newer prodrugs that facilitate superior gastrointestinal absorption profiles and often allow early outpatient management of highly responsive cases. Augmentation with intravitreal injections of ganciclovir or foscarnet or intraocular implants of ganciclovir (Vitrasert; Bausch & Lomb, Rochester, NY) are also used to halt dis-

ease and preserve vision. Retinal detachment is frequently caused by the severe retinal necrosis seen in herpetic disease. Thus, prophylactic laser photocoagulation is sometimes used around areas of necrosis to prevent detachment, with variable degrees of success [25, 26, 68].

A Goldmann-Witmer coefficient antibody analysis (GWC) value >2 has proved to be a useful tool in determining the etiology of infectious uveitis. The sensitivity of these tests has an excellent correlation to vitreous PCR, with 91% true positives and 9% falsenegative GWC tests. The accuracy of GWC may suffer in comparison to PCR in immune-compromised patients due to impaired antibody production in AIDS and other immune deficiencies [16].

Animal and human studies have demonstrated a failure to develop delayed-type hypersensitivity skin reactions to herpes viruses in patients who have significant uveitis or acute retinal necrosis associated with either VZV or HSV [31]. This lack of delayed hypersensitivity may prove to be a helpful diagnostic tool. Also, this lack of responsiveness may reveal more insight regarding the pathophysiologic mechanism and immune dysfunction leading to ocular involvement from these ubiquitous viruses.

Comparison studies between VZVand HSV-as- sociated uveitis demonstrated that HSV presents with a more recurrent and remitting course whereas VZV was more typically a chronic uveitis. Secondary glaucoma association with HSV was seen in up to 54% of patients and 38% with VZV. Periocular and systemic steroids were required in 60% of patients with HSV uveitis and only 25% of patients with VZV. The same study showed approximately 20% of eyes were ultimately legally blind as a result of uveitis in both VZV and HSV [30].

Treatment of acute herpes zoster (shingles) with oral antivirals (acyclovir, valacyclovir, famciclovir) for 7–10 days has been proven to decrease episode time, severity, and complications if instituted within the first 72 h after vesicles first appear. There have been some reports of improvement after 72 h as well. The development of new skin lesions may also be an indication to start antiviral therapy even after 72 h. The use of concurrent systemic steroids in VZV has shown decreased pain and increased healing rates of cutaneous lesions, and may be considered particularly for severely afflicted patients. Live attenuated vaccine to VZV was approved by the FDA in 1995

and significantly decreased the incidence of VZV and subsequent complications. This vaccine, similar to the virus itself, can lie dormant in the trigeminal ganglion and reactivation can cause zoster in immunecompromised patients [43]. Rarely VZV can develop resistance to acyclovir usually from long-term lowdose therapy, especially in immune-compromised patients. Foscarnet is recommended for this scenario

[38].

Treatment of herpetic anterior uveitis consists of cycloplegics and topical steroid drops with slow taper over weeks to months. Some patients may need chronic low-dose topical steroid therapy to remain quiescent, especially with VZV. Severe uveitis may benefit from systemic antivirals, as demonstrated in a small controlled trial. In this trial, patients with herpetic iridocyclitis using oral acyclovir 400 mg 5 times per day showed a trend toward improvement. IOP increase can be treated with glaucoma medications, although pressure usually returns to normal quickly with decreasing inflammation. Many patients who present with elevated IOP will return with normal pressures simply as a result of improved trabeculitis treated with topical steroids alone [30].

Oral acyclovir 400 mg twice daily for 1 year is recommended in patients who have two or more scarring epithelial infections per year or any stromal disease. Valacyclovir has recently been proven as effective as acyclovir and requires less frequent dosing. Unfortunately, there is no generic equivalent to valacyclovir in the USA, markedly increasing the cost [26]. A 7- to 10-day course of oral acyclovir, valacyclovir, or famciclovir is recommended within the first 72 h of a herpes zoster outbreak to reduce uveitis duration and severity [38]. Longer therapy may be beneficial as studies have shown active virus from cutaneous cultures up to 32 days after starting antiviral therapy. Adding oral steroids may help with resolution, and low-dose tricyclic antidepressants have been used to prevent post-herpetic neuralgia. Post-herpetic neuralgia can be extremely difficult to treat, testing the acumen of the managing physician and the psychologic fortitude of the patient [38]. A wide variety of treatments are available, including sophisticated pain management techniques, stellate ganglion and peripheral trigeminal nerve blocks, and multiple pharmaceutical agents. Post-herpetic neuralgia is less common and less severe in younger adults and children when compared to older adults and senior citizens.

Take Home Pearls

•A methodical and reproducible approach to each uveitis patient will improve clinic flow as well as cost effectiveness of treatment.

•In ocular toxocariasis laser photocoagulation or cryoretinopexy of the larvae is not suggested because destruction of the nematode may cause a severe inflammatory reaction.

•Topical aminocaproic acid gel (Caprogel; Ista Pharmaceuticals, Irvine) has been shown to significantly reduce the risk of rebleeding during the critical first 5 days following blunt trauma causing a hyphema, while also avoiding systemic side effects.

•In FUS, heterochromia can be seen in 82% of patients. Normally a lighter colored

iris becomes darker when stromal loss causes the underlying densely pigmented posterior iris pigmented epithelium to show through. Conversely, a darker colored iris becomes lighter as the deep brown iris stroma slowly melts away leaving more muscle fibers and less melanin visible.

•Ocular toxoplasmosis responds to a wide variety of therapies including systemic steroids and antibiotics. However, periocular and intravitreal steroids are absolutely contraindicated due to predictably poor outcomes resulting from a loss of immune control of the intraretinal protozoan parasites.

•Seronegative spondyloarthropathies constitute a spectrum of diseases frequently associated with the HLA B27 locus. This allele, along with HLA B29 associated birdshot chorioretinopathy, are the

two truly useful genetic determinants employed in the judicious laboratory evaluation of uveitis patients.

•Sarcoid uveitis can occur with or without signs of systemic sarcoidosis. Highfrequency topical, injection, or systemic steroid administration is often necessary in these patients to achieve the universal goal of a completely quiet eye. Failure to do so leads to permanent breakdown of the blood–aqueous barrier and thereby chronic flare, cystoid macular edema, and expectedly poor surgical outcomes.

•Pars planitis syndrome, an idiopathic intermediate uveitis, is a diagnosis of exclusion that is often associated with multiple sclerosis. However, a wide variety of uveitic syndromes may present with intermediate uveitis and must be ruled out first. These diseases include: Lyme disease,

Epstein-Barr virus (EBV) infection, West Nile virus, tuberculosis, cat-scratch disease, toxocariasis, sarcoidosis, and Behçet’s disease.

•Juvenile idiopathic arthritis associated uveitis is most commonly seen in pauciarticulartype females who are ANA positive.

This ocular disease is known also as “white iritis” due to the absence of classic

symptoms including redness. It is frequently asymptomatic, necessitating regular screening examinations by an ophthalmologist familiar with pediatric uveitis.

•Herpetic uveitis is not necessarily associated with corneal disease as the herpes virus may present in virtually any ocular tissue. Trabeculitis frequently accompanies herpes uveitis making this one of the few uveitic conditions associated with IOP elevation.

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