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

ies to Toxocara is instrumental in the diagnosis. However, ocular toxocariasis patients may routinely have low to absent serum titers. Therefore, positive serum results may help support the diagnosis, yet a negative serum antibody does not rule out the diagnosis. For VLM, the ELISA cutoff dilution of 1:32 is used to indicate a positive result. Since serum antibody levels may be much lower or even absent in ocular toxocariasis, any antibody titer, including undiluted, should be considered significant when there is also a suspicious clinical examination. Aqueous or vitreous fluid has been found to yield much higher sensitivity making diagnostic vitrectomy or anterior chamber tap an option in difficult cases.

Loss of vision is often due to chronic inflammation as the body reacts to the larvae. Therefore the mainstay of treatment in these patients focuses on steroid therapyduringtheacuteinflammatoryphases.Topical, periocular, or systemic steroids are commonly used.

Otherstudieshavefoundmixedsuccesswiththeuseof cyclosporine A in conjunction with systemic steroids

[42]. In cases where there is retinal traction or severe vitreous opacity, vitrectomy may become necessary. In most cases, laser photocoagulation or cryoretinopexy of the larvae is not suggested since destruction of the nematode may cause a severe inflammatory process. The use of antihelmintic medications such as albendazole or thiabendazole are common in treating systemic disease, but remain controversial with ocular disease [3]. As with laser photocoagulation, it is believed that the destroyed larvae are responsible for a severe inflammatory reaction. In the case of peripheral lesions that are asymptomatic, simple observation may be recommended while host immunity controls and eliminates the infection over time.

28.3.2Traumatic Iritis, Blunt Injury, and Hyphema

Blunt trauma is a common emergent presentation in pediatrics. Traumatic iritis is generally self-limited, but far less symptomatic and persistent when effectively and proactively treated with topical steroids and dilation. A wide variety of findings and sequelae result from blunt trauma, as indicated in Table 28.4. Acute iritis following blunt trauma should be aggres-

sively treated with topical steroids and cycloplegics until all cellular response in the anterior chamber has disappeared, then topical steroids weaning judiciously in order to prevent rebound inflammation.

Patients and their family should be informed that the injured eye is forever thereafter subject to a litany of potential complications, most important of which are cataract, glaucoma, and retinal detachment. These patients should have regular eye examinations for the remainder of their lives to ensure early detection of these sequelae. In cases of anisocoria, proper wristband, medical record, and driver’s license documentation of pupillary asymmetry should be ascertained.

Hyphema is also a common result of blunt ocular trauma in the pediatric population. As many as 90% of hyphemas occur in boys, in concordance with other data regarding blunt and penetrating injury. The mechanism of injury can vary widely and should be ascertained. Non-accidental trauma in these patients should also be ruled out. A hyphema is usually caused

Table 28.4  Sequelae of blunt ocular trauma

Traumatic iritis Traumatic iridocyclitis Traumatic hyphema

Secondary glaucoma due to meshwork inflammation

Secondary glaucoma due to crenated red blood cell obstruction of the meshwork

Hypotony due to ciliary body inflammation or dislocation

Angle recession and angle-recession glaucoma Iris sphincter rupture

Temporary and permanent ipsilateral pupillary dilation and anisocoria

Traumatic cataract

Traumatic zonular dehiscence, and subsequent lenticular dislocation or phacodinesis

Refractive or deprivation amblyopia Posterior vitreous detachment Symptomatic syneresis

Retinal detachment

Commotio retinae and optic nerve head hemorrhage Vitreous hemorrhage

Rhegmatogenous retinal detachment

Orbital blow-out fracture, and subsequent diplopia, fatty atrophy, and enophthalmos

Ruptured globe, usually at the muscle insertions or optic nerve insertion

by blunt force that when applied to the eye displaces the aqueous fluid out peripherally. This results in increased hydraulic pressure to the iris root and angle structures. If this pressure is great enough, bleeding will occur from broken vessels usually located within the peripheral iris and ciliary body. Such injury may also be great enough to cause scleral rupture; therefore ruptured globe should always be excluded in these patients. Spontaneous hyphema is less common, but should raise the concern for juvenile xanthogranuloma, retinoblastoma, and leukemia. Iris rubeosis, clotting disorders, Fuchs’ uveitis syndrome, and herpes are also possible causes of spontaneous hyphema.

The degree of bleeding can vary from microscopic red blood cells visible under the slit lamp to complete filling of the anterior chamber, the proverbial “eightball.” Less than 50% of hyphemas will fill greater than one third of the anterior chamber and less than

10% will fill the entire chamber [17]. The prognosis of these patients usually is rather good, but largely depends on whether the patient develops complications from the hyphema. The common complications are glaucoma, optic atrophy secondary to glaucoma, corneal blood staining, uveitis, and rebleeding. Evidence of rebleeding should be of high concern to the physician and is a poor prognostic factor of future visually acuity. Rebleeding occurs most frequently between days 2 and 5.

The first step in treating a hyphema begins with a thorough history. The mechanism of injury is important and the clinician should rule out penetrating injury when applicable. The date of injury is helpful in assessing the likelihood of rebleeding and to aid in determining a proper follow-up schedule. The child should be screened for any preexisting eye diseases such as glaucoma, corneal diseases, or amblyopia. It should also be known whether the child has any clotting disorder, or is on systemic anticoagulation.

All African American patients should be tested for sickle cell disease. Sickle cell patients are at risk for sickling of red blood cells in the anterior chamber. The abnormal red blood cells can inhibit outflow through the trabecular meshwork and lead to increased intraocular pressure (IOP). Sickle cell patients are also at a greater risk for optic neuropathy which has been theorized to be due to decreased blood flow to the optic nerve head making it more susceptible to IOP increases.

During serial examinations, the size of the hyphema should be documented and followed for improvement. The cornea should be evaluated for evidence of blood staining. The cornea should also be assessed for evidence of any preexisting conditions that may increase the patient’s risk for blood staining. The iris and lens should also be examined for evidence of cyclodialysis or subluxation. If possible, the fundus should also be assessed for vitreous hemorrhage or retinal detachment. Often, the fundus view is obscured necessitating B-scan ultrasound to rule out retinal detachment or a mass in the fundus. Gonioscopy should be delayed for up to 6 weeks to avoid the chance of causing a rebleed. Gonioscopy is eventually necessary to examine for angle recession, a condition that necessitates closer follow-up for the increased risk of open-angle glaucoma. IOP measurement is very important as glaucoma is a common and serious complication with hyphema patients and may dictate the course of treatment.

Treatment of hyphema begins with having the child refrain from physical activity and sleeping with the head elevated 35 degrees to avoid obscuration of the entire trabecular meshwork circumference. The use of a hard eye shield is also helpful to prevent further trauma, but employed only for appropriate cases. Hospitalization was often used with pediatric cases in the past, but has largely fallen out of favor.

However, hospitalization is still considered reasonable during the first 5 days of treatment to closely monitor for development of a rebleed [23]. Patients who are at a high risk for developing complications such as children with glaucoma, sickle cell, or who have already developed a rebleed during follow-up are also good candidates for hospitalization. Bilateral pressure patching to immobilize the eyes during the first five critical days post-injury has also largely fallen out of favor.

Medical therapy includes long-term dilation with either homatropine, Cyclogyl, or atropine which helps with patient pain and may reduce the risk of rebleed and the formation of synechiae. Prednisolone acetate is also used four times per day (q.i.d.) or more depending on the degree of inflammation. Oral prednisone has also been used at 0.75–1.00 mg/kg in a divided dose and has been shown in some studies to prevent rebleed. Antifibrinolytics such as oral aminocaproic acid (Amicar) are well studied and shown to prevent rebleed in high-risk patients. While systemic

Amicar has well-known systemic side effects including vomiting, topical aminocaproic acid gel (Caprogel; Ista Pharmaceuticals, Irvine) has been shown to significantly reduce the risk of rebleed while avoiding systemic side effects [10–12, 35].

Because elevated IOP can lead to corneal blood staining and optic atrophy, patients with increasing IOP should be placed on a topical beta-blocker or other appropriate topical agent. Carbonic anhydrase inhibitors and adrenergics need to be avoided in sickle cell patients as these medications can induce sickling in the anterior chamber.

Generally, corneal blood staining can occur with IOPs that are greater than 25 for a period greater than 6 days. Blood staining can be seen histologically as blood products in the corneal stroma which may take from months to years to fully resolve. The clinician should always be mindful of earlier development of staining, as this would be an indication of surgical evacuation of the hyphema. Blood staining may also occur earlier or under a lower IOP in patients with complete hyphemas or who have preexisting corneal pathology. Blood staining in younger children presents the challenge of dealing with amblyopia. Severe staining may necessitate corneal transplantation.

While a hyphema is generally managed medically, surgical intervention is necessary at times. IOPs greater than 35 for more than 2–3 days despite medical therapy may lead to corneal blood staining and therefore indicate an anterior chamber washout. Sickle cell patients who have pressures greater than 25 for more than 24 h also require a washout. Surgical washout is usually performed using a simple irrigation/aspiration technique. Vitreous cutting instrumentation with aspiration may also be used if a large clot does not aspirate well.

28.3.3 Fuchs’ Uveitis Syndrome

Fuchs’ uveitis syndrome (FUS), previously known as Fuchs’ heterochromic iridocyclitis, is a condition that was first described by the legendary Austrian ophthalmologist Ernst Fuchs in 1906. For many years, standard terminology termed this condition Fuchs’ heterochromic uveitis due to the characteristic heterochromia seen in most cases by simple external examination. FUS is largely (over 90%) a unilateral,

chronic iridocyclitis that is usually seen with heterochromia, which may be subtle in early cases. Likely because of the paucity of symptoms, FUS is an uncommon presentation in the pediatric ophthalmologist’s practice. However, in some studies 2–11% of childhood uveitis patients had FUS [56]. FUS has no racial or sex predilection and can present anywhere from late adolescence to adulthood. While some studies show the average age of presentation at 40 years old, pediatric FUS is well reported and should be included in any uveitis differential diagnosis. FUS diagnosis in the pediatric population is important because proper diagnosis may allow the clinician to avoid the use of chronic immunosuppressive medication and the resultant side effects.

Fuchs’uveitis syndrome is a low-grade inflammatory process that leads to iris atrophy and potential secondary glaucoma and cataract. Vitreous opacification can rarely occur, but posterior synechiae formation is unusual. While the cause of FUS is not known, several theories exist including infectious and autoimmune. Multiple autoimmune mechanisms have been implicated. Of those theories the most studied is with retinitis pigmentosa. In 2000, Chowers et al. studied 338 patients with retinitis pigmentosa finding a statistically significant connection between FUS and retinitis pigmentosa. However, no significant positive human leukocyte antigen (HLA) associations have been found.

The infectious mechanisms that have been theorized to cause FUS include rubella, toxoplasmosis, toxocariasis, and herpes simplex. Some studies have shown toxoplasmosis to have a significant link to FUS [4, 48, 56]. In a 25-patient study by Schwab,

16 FUS patients had fundus lesions that were suspicious for ocular toxoplasmosis while 13 of these had positive serology for toxoplasmosis [56]. Recently, rubella has been heavily studied and then implicated in its association with FUS. A study by de Groot-

Mijnes confirmed earlier work by Quentin which showed intraocular antibodies against rubella virus in FUS patients [15, 48]. In 2007, Birnbaum showed a statistically significant decrease in the number of

American-born FUS patients, when compared to other forms of uveitis, after the advent of rubella vaccination in the USA [4].

Fuchs’ uveitis syndrome is often an asymptomatic disease, particularly in younger patients. A paper by La Hey found that none of the studied FUS

patients presented with photophobia or eye redness

[36]. When symptomatic, patients may complain of decreased vision secondary to cataracts or vitreous haze. The diagnosis is one of exclusion and based principally on physical examination. The diagnostic triad consists of stellate KP, cataract, and iris atrophy leading to heterochromia. The conjunctiva and sclera are usually white and quiet; however, vessels may be prominent on the sclera or conjunctiva.

The La Hey study showed stellate KP in 86% of patients [36]. Although stellate KP is highly suggestive of FUS, these KP are also evident in toxoplasmosis, herpes simplex, herpes zoster, and CMV infectious uveitis cases. The anterior chamber may or may not show a low-grade cell and flare even in the presence of stellate KP. Stellate KP are characterized by a diffuse distribution throughout the endothelium, without an obvious predilection for Arlt’s triangle inferiorly. Furthermore, stellate KP show definitive dendritic or stellate projections from a central core when viewed at high magnification, unlike the characteristically discoid morphology of the more common non-granulomatous KP or the globular appearance of granulomatous KP.

Heterochromia can be seen in 82% of patients, but in the same Le Hey study, iris stromal atrophy was seen in 100% of patients [36]. 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. Koeppe and Busacca nodules may also be seen. Posterior synechiae are uncommon in FUS patients. The presence of posterior synechiae should in fact lead the clinician away from a diagnosis of FUS. Neovascularization of the iris and chamber angle can lead to bleeding and hyphema during procedures such as paracentesis or cataract surgery. A wispy filiform angle hemorrhage after diagnostic aqueous paracentesis forms the basis of Arlt’s sign, thought in the early twentieth century to be diagnostic for FUS. The vitreous may have opacities that at times can lead to decreased vision and necessitate surgical intervention. Cystoid macular edema is usually not present differentiating it from other uveitis syndromes.

The low-grade inflammation seen in FUS usually does not require aggressive treatment. How-

ever, periodic flare-ups may require corticosteroids, but chronic therapy is not indicated. Many patients fare well on a single dose of topical steroid such as Pred Forte (prednisolone acetate; Allergan, Irvine) or

Lotemax (loteprednol etabonate; Bausch & Lomb,

Rochester). The elimination of all aqueous cell and flare should not necessarily be the goal of therapy in these patients and may only predispose the patient to the complications of chronic steroid use.

The two main complications of FUS stem from cataract and glaucoma. A rapidly progressing posterior subcapsular cataract has been found in 80–90% of patients. Secondary glaucoma is also another serious complication seen in 22–59% of patients studied. Posterior subcapsular cataract, a common complication of FUS, will eventually require surgical intervention in every patient, especially in pediatric patients in the amblyogenic age group. Studies have found these patients do well with small incision, clear cornea phacoemulsification with an intraocular lens placed in the capsular bag. Pretreatment with prednisolone q.i.d. 4 days prior to surgery and continued postoperatively aid in reducing postoperative inflammation. The surgeon should also be mindful that FUS patients often have abnormal iris and anterior angle vessels which may cause excessive bleeding during procedures leading to an iatrogenic hyphema.

Glaucoma in an FUS patient is initially treated with topical medications. When medication fails the surgical options include trabeculectomy and glaucoma drainage implant. Laser procedures such as argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT) are often not effective in these patients, but should be attempted prior to surgery. The customarily dense meshwork pigmentation seen in FUS may be more amenable to SLT therapy. The tendency of pediatric uveitis patients to form fibrous tissue quickly can lead to the failure of the surgical bleb. However, the success of trabeculectomy in the pediatric uveitis patient has been increased since the advent of antimetabolites. Glaucoma drainage implants are also a common choice for these patients where scar formation and bleb failure is a concern.

A small group of patients may experience vision loss secondary to vitreous floaters or debris. In these patients, pars plana vitrectomy has been shown in some studies to be an effective treatment and may in theory also protect against inflammatory damage to the posterior pole [57]. Planned elective pars plana

vitrectomy can be performed at the time of cataract extraction and intraocular lens implantation in selected patients.

28.3.4 Toxoplasmosis

Toxoplasma gondii is an obligate intracellular protozoan parasite that can infect any organ system in the human body. It is highly neurotrophic with a predilection for ocular and brain tissues. An estimated 13–50% of the world’s population is infected, with higher prevalence in areas of South America, Europe, and Africa, particularly where raw meat such as steak tartare is commonly ingested [18, 33]. However, most exposed individuals demonstrate no symptoms of disease. More virulent strains have been identified in

South America and Africa with ocular involvement in up to 20% of infected persons [29].The third National Health and Nutrition Examination Survey found a seroprevalence of Toxoplasma gondii in the USA of

23% in 17,658 persons and ocular toxoplasmosis is estimated to occur in 2% of seropositive patients. In 2001 the CDC/American Academy of Ophthalmology survey estimated 30,000 visits to ophthalmologists for ocular toxoplasmosis. These data presume as many as 1.26 million Americans could have ocular toxoplasmosis, active or inactive [33].

Infection occurs either by ingestion of fruits, vegetables, or undercooked meat containing the cystic bradyzoite form or through contamination by cat feces that may contain oocysts. Infected water sources have been recently proven a source of infection and cause for several epidemics in South America and

Canada. In the USAmost toxoplasmosis is thought to be acquired congenitally.

The life cycle of Toxoplasma gondii is complex starting with feline hosts where sexual reproduction of the protozoa produces oocysts in the intestinal tract of the host. These oocysts are quite resistant to environmental damage and can remain viable for long periods of time. Ingestion of oocysts causes activation and transformation into the active tachyzoite which replicates quickly, destroying host cells, and releasing more tachyzoites into the bloodstream. Immune regulation in immunocompetent hosts controls disease in a host–parasite stalemate in which the tachyzoite form transforms to the morphologically

identical bradyzoite form with much slower replication rates. Bradyzoites can persist in a host for a lifetime and evade immune detection in cystic form which can also be shed in feces and remain infective.

Bradyzoites can be released from cysts and transform into actively replicating tachyzoites at any time within a host. Reactivation of latent toxoplasmosis can occur at any time of decreased host immune control, such as immune-suppression for transplant patients, AIDS, severe illness, major trauma, childbirth, or general surgery [18, 29, 33].

Congenital toxoplasmosis occurs with primary maternal infection and dissemination to the placenta with protozoa crossing into the fetal circulation. The classic triad of congenital toxoplasmosis is chorioretinitis, intracranial calcifications, and hydrocephalus.

Other signs include anemia, jaundice, rash, hepatosplenomegaly, and low birth weight. Infection during the first or second trimester can severely affect the fetus causing significant morbidity and mortality. Infection during the third trimester can have little effect with normal-appearing newborns. However, if treatment is not given, children can develop chorioretinitis and growth delay. Treatment is recommended for all pregnant women who develop toxoplasmosis during their pregnancy and to all newborns for a duration of 1 year [2, 51].

In the USA an estimated 3,000 newborns are infected with Toxoplasma gondii per year. Approximately 10% of infected infants have noted chorioretinal lesions soon after birth although new lesions can appear at any time. Recent studies of 281 infected newborns in Europe showed 17% had developed retinal lesions at the 5-year follow-up mark with nearly two thirds having posterior pole lesions and almost 15% having bilateral posterior pole lesions. Eyes with posterior pole lesions had normal vision in that eye 52% of the time measured at 3 years of age, and 84% had normal vision in eyes with only peripheral lesions. Patients with ocular involvement had normal vision greater than 90% of the time in at least one eye and only 9% of patients had vision worse than 20/40 in both eyes [2, 51].

Ocular toxoplasmosis is thought to occur by parasite infection breaking down the blood–eye barrier with direct infection into the eye. This disrupts innate immune privilege within the eye and induces a hyperimmune response, involving CD4, CD8, along with interleukins and cytokines, against the protozoans

[29]. This immune response, however, also causes collateral damage to uninfected cells within the eye. Systemic corticosteroids are therefore necessarily used concurrently with antiprotozoan treatment by many clinicians to reduce the detrimental effects of the host immune response within the eye. Periocular injections of steroids, however, are contraindicated due to an overwhelming inhibition of host immunity and subsequent rampant replication of toxoplasmal organisms. Periocular steroid injections have led to the loss of infected eyes that may otherwise have been saved with systemic steroid and antiprotozoan agents [59].

The “classic” appearance of ocular toxoplasmosis is a focal necrotizing chorioretinitis accompanied by a vitreous inflammatory reaction. Commonly, this focal area arises from the border of an old chorioretinal scar. Immunocompetent patients almost always have only one area of active toxoplasmosis on examination whereas patients with decreased immunity can have several active lesions. The congenital form tends to be a bilateral disease with multiple satellite lesions located seemingly preferentially within the macula.

Ocular toxoplasmosis typically involves 8–16 weeks of active inflammation then periods of inactivity for several years. Recurrence rates vary and in a study of 154 patients with ocular toxoplasmosis 79% of patients had a recurrence within a 5-year follow-up period despite antiparasitic treatment [64].

Optic nerve involvement can have many different presentations typified by four presentations: (1) disc edema with distant retinal lesions, (2) juxtapapillary lesions (Jensen’s disease), (3) serous macular detachment, and (4) rarely with no other active lesions. Prognosis is still good with optic nerve involvement in 71% of patients showing improvement of vision with treatment [21]. IOP can be elevated in many cases of ocular toxoplasmosis due to trabeculitis, a phenomenon also observed in the other uveitic entities manifesting stellate KP. Westfall’s retrospective review of 61 patients showed IOP >21 in nearly 40% of patients and >30 in almost 30% [59]. Ocular toxoplasmosis can lead to severe vision loss with about one fourth of patients legally blind in at least one eye from the disease [64].

Diagnosis of ocular toxoplasmosis can usually be made on clinical grounds alone through documentation of the characteristic funduscopic lesions. If the diagnosis is questionable, laboratory tests can be used

to confirm the initial impression. Typically, serum antibody testing is obtained, but aqueous paracentesis specimens are also very useful. Recent comparative testing of PCR versus WDC (Goldmann-Witmer coefficient) was performed on 189 patients in India, 25 of these with clinical ocular toxoplasmosis and 164 controls. Toxoplasma PCR was determined a fast and effective test requiring only 50 μLof intraocular fluid, with a specificity of 100% and sensitivity of 59.1%.

PCR testing takes 5–12 h and is cheaper than other tests. WDC requires 100 μLof intraocular fluid, takes 12–48 h for results, and is 2–3 times more expensive than PCR. Specificity of WDC was also 100% with a sensitivity of 72.7%, slightly higher than PCR. Toxoplasma gondii immunoglobulin titers from peripheral blood may also be used when intraocular fluid testing is impractical [18].

Many treatment regimens for toxoplasmosis exist and usually multiple drugs are used to treat this fastidious protozoa. More studies are needed to compare efficacy, ocular disease response, and maintenance suppression therapy. Standard or classic treatment consists of systemic pyrimethamine and sulfadiazine with folinic acid supplementation. However, these drugs can have significant side effects including bone marrow suppression and Stevens-Johnson syndrome. Weekly initial blood counts followed by less frequent testing is needed when patients take pyrimethamine. Clindamycin can be added to pyrimethamine, sulfadiazine, and oral steroids as “quadruple therapy” [33]. A recent prospective randomized trial by Soheilian compared trimethoprim/sulfamethoxazole 960 mg

(generic Bactrim or Septra) alone for 6 weeks versus combination therapy with pyrimethamine and sulfadiazine, and found both treatments to be equally effective. Trimethoprim/sulfamethoxazole has improved the side effect profile of quadruple or classic treatment and provides the busy clinician with an effective alternative first-line therapy, obviating supplemental folinic acid [18].

Atovaquone is an antiprotozoa medication that affects mitochondrial electron transport and has been shown to be effective against central nervous system Toxoplasma gondii. Atovaquone is generally much better tolerated than classic therapy but it is much more expensive. Tetracycline antibiotics are also effective for treating toxoplasmosis with minimal and familiar side effects. Young children with immature dentition cannot use tetracyclines due to discolor-

ation of teeth and bone deposition. The macrolide antibiotics azithromycin and spiramycin have demonstrated effectiveness, and spiramycin is commonly used for pregnant women due to its low fetal toxicity [18, 33].

Small case series of patients non-responsive to oral medications and with vision-threatening disease have shown success with off-label usage of intravitreal clindamycin 1 mg with and without systemic steroid use. Systemic corticosteroids are usually added either concurrently or within the first few days after antimicrobial treatment is initiated to help control inflammation that can be detrimental within the eye. The use of steroids in immunosuppressed patients is controversial especially since inflammatory responses are usually mild [33]. Animal studies have shown that supplementation with zinc and melatonin could improve chorioretinitis seen in toxoplasmosis, although no corresponding human studies have been reported [2].

Prophylaxis is usually reserved for significantly immunocompromised patients and has been shown to reduce recurrences. Specific prophylactic regimens for these patients vary by clinician. With so many different accepted treatment options available and a lack of controlled trials, recommendations vary widely and no consensus has been determined regarding optimal treatment for ocular toxoplasmosis [33]. Hopefully future research can determine safe and effective treatment guidelines for toxoplasmosis, particularly in children.

28.3.5Seronegative Spondyloarthropathies

Seronegative spondyloarthropathies (SS) are a heterogeneous group of disorders characterized by inflammatory joint disease predominantly affecting the lower limbs. They are all rheumatoid factor (RF) negative, and thus seronegative. The main disorders include ankylosing spondylitis (AS), Reiter’s syndrome (reactive arthritis), psoriatic arthritis, arthritis associated with inflammatory bowel disease

(Crohn’s disease, Whipple’s disease, idiopathic), and juvenile-onset spondyloarthropathies. These patients also show a common link with a large percentage

HLA-B27 positive. This major histocompatibility allele was the first ever reported in the literature as a risk factor or in association with human disease. The relative risk of a person with the HLA-B27 allele for developing AS is approximately 85:1, which means this person is about 85 times more likely to develop AS then a B27-negative individual. This relative risk remains among the highest in all of human genetics

[58].

The high association with HLA-B27 and enteric infections has lead to the hypothesis that these disorders are related to a genetic predisposition for immune system dysfunction to form autoantibodies after exposure to certain bacteria (Shigella, Campylobacter, Yersinia, Salmonella). Small retrospective studies on spondyloarthropathies and HLA-B27- positive patients showed that the HLA-B*2705 allele, a subtype of HLA-B27, was found in 100% of patients with uveitis. The actual gene involved may be in close linkage equilibrium with the B27 locus, or it may act through molecular mimicry with certain foreign genes to initiate an autoimmune response [1].

The gram-negative lipopolysaccharide (surface LPS) may have highly similar surface antigenicity when compares to the B27 gene, thus creating a hit-and- run scenario wherein the instigating infectious agent induces autoimmunity, is eliminated by routine host defenses, but initiates a perpetual cascade of inflammatory events even in the absence of the initial offending organism [1, 58].

Ocular involvement is common in these disorders and uveitis is one of the most common ocular manifestations associated with SS. Other important ocular manifestations include band keratopathy, scle­ ritis and episcleritis, blepharitis, secondary glaucoma, cataract formation, conjunctivitis, posterior synechiae formation, macular edema, and amblyopia in the pediatric population. Uveitis, seen in 15–25% of B27-positive AS patients, presents classically as acute or hyperacute recurrent alternating or bilateral anterior uveitis with rare posterior involvement. SS, along with Behçet’s syndrome, are in the short differential diagnosis of non-infectious causes of noninfectious, atraumatic hypopyon [1, 40]. With such a high association with ocular disease, all patients with SS should be screened and followed by an eye-care professional conversant with the widespread ramifications of uveitic disease, as complications can be avoided with proper early treatment.

Uveitis associated with SS typically shows excellent response with topical steroids. Severe cases require additional steroids through adjunctive ocular injections or systemic therapy. In approximately 10% of patients chronic uveitis persists or the side effects of steroids are sufficiently prohibitive to their continued use. Chronic uveitis is frequently due to delayed diagnosis, insufficient medication recommendations, poor compliance, and resultant permanent damage to the blood–aqueous and blood–retina barriers. In other successfully treated cases, steroid side effects including intractable glaucoma may be sufficiently prohibitive to chronic steroid use. In all of these cases, a now vast array of adjunctive non-steroidal immunosuppressants and disease-modifying antirheumatologic drugs (DMARDs) such as methotrexate, cyclosporine, mycophenolate and the TNF-α inhibitors have shown good success in adult populations [49, 50]. Caution should be taken in the pediatric population where newer medications have not been as well studied, and these medications should be started only by physicians experienced in their use and side effects. This juncture in the therapeutic decision tree clearly involves close collaboration with a pediatric rheumatologist or hematologist.

An important point regarding TNF-α inhibitors is that they increase the risk of tuberculosis reactivation and other infections. One case report of tuberculosis uveitis in a patient on etanercept has been reported, further emphasizing the need for continued vigilance and perpetual suspicion of an infectious etiology in patients with atypical presentations. There are several case reports of patients with SS on etanercept treatment with either the new development of uveitis or exacerbations of preexisting uveitis following etanercept injections. Some have hypothesized that perhaps etanercept therapy could induce an autoimmune uveitis in rare instances, although no animal model or human studies have corroborated this theory [49].

Intraocular surgery in patients with SS and a history of uveitis can be challenging. As with any patient with recurrent uveitis, surgery should be delayed, if possible, until inflammation is completely resolved for a period of at least 3 months in adults and 6 months in children. Even with adequate control, these patients are at higher risk of complications and recurrence of inflammation. The most common uveitis-related postoperative complications of cataract surgery include cystoid macular edema, hypot-

ony, and synechia formation. Patients with immobile pupils and synechiae are more likely to have postoperative pupillary complications, including anisocoria, irregular iris sphincter margins, iris atrophy, transillumination defects, and synechiae formation between the sphincter and the anterior capsule [1].

28.3.5.1Ankylosing Spondylitis

Ankylosing spondylitis is an idiopathic rheumatologic disorder of chronic inflammation primarily affecting the sacroiliac joints, spine, and entheses (muscle insertions to bone). The male:female ratio is at least 5:1 and as high as 9:1 in some epidemiologic studies. The peak incidence is in ages 15–35 years with a prevalence of 0.1–2% in different populations, and 90–95% of patients will be HLA-B27 positive, compared to 8% in the general population. The relative risk that a patient with the B27 allele will develop AS is approximately 88 times higher than a B27-negative patient. This important relative risk for the HLA-

B27 allele was the first ever reported for any genetic marker for any disease in the literature. Most patients will also have elevated CRP and ESR although these do not correlate well with disease activity as in other inflammatory conditions [39].

The hallmark of AS is sacroiliitis, with involvement of the lower third of the sacroiliac joints. Radiographic evidence in early disease is best seen with MRI of the sacroiliac joints showing early sacroiliitis. Early or moderate sacroiliitis can be missed in routine hip or pelvis x-rays because the pathology is best seen with an angled tunnel view parallel to each sacroiliac joint. Disease progression can lead to joint erosion, bony formation bridging vertebrae, and ultimately complete spinal fusion (bamboo spine) [39, 49, 50].

Because of a characteristically insidious onset, diagnosis may be delayed. Primary complaints are back pain with rest, especially on awakening, that improves with exercise. On examination, tenderness of joints and entheses is readily demonstrable, and decreased forward lumbar flexion and decreased lung expansion may be noted [39].

Rates of uveitis associated with AS range from 14% to 40%. Uveitis in AS has been associated with juvenile disease onset and the involvement of the lower limbs, especially the Achilles and plantar entheses. Conjunctivitis is the second most common oc-

ular manifestation in AS, which is typically bilateral, non-purulent, and self limited [1, 40, 49, 50, 54].

Besides ocular and joint involvement, patients with AS can develop aortic incompetence, cardiac conduction disturbances, and pulmonary fibrosis. Rarely, aortitis occurs with a significant mortality rate when undetected or undertreated [39].

Treatment of AS joint disease has historically employed physical therapy and non-steroidal anti-in- flammatory drugs (NSAIDs). Local steroid injections to affected joints are frequently recommended as well, despite the fact that newer analyses have shown good responses to the TNF inhibitors so commonly utilized against rheumatoid arthritis [1, 39].

28.3.5.2Reiter’s Syndrome

Reiter’s syndrome (RS) is a clinically diagnosed disorder historically defined by the presence of arthritis, non-gonococcal urethritis, and conjunctivitis. A relatively rare disorder, diagnosed RS is seen in ~1–3% of men following non-specific urethritis, and 4% or more of persons, male and female, after enteric infections with gram-negative bacteria. RS typically develops within 1 month of preceding infection. A high association with HLA-B27 antigen (75–90%) is seen with RS, however, the presence of this allele is not a part of the diagnostic criteria, so absence of HLA-

B27 does not exclude RS. RS is a spectrum of disease with pathology that can be categorized by four subgroups of related signs and symptoms: (1) arthritis, either acute or chronic, with migratory and asymmetric joint pain, usually involving the lower extremities;

(2) enthesopathy presenting with localized pain at muscle tendon insertion to bone most frequently seen as heel pain; (3) sacroiliitis and spondylitis causing lower back pain most highly associated with HLA-

B27 antigen; and (4) extra-articular with systemic symptoms including ocular symptoms, mucocutaneous lesions, and idiopathic inflammation of virtually any organ. Highly characteristic but non-diagnostic lesions include circinate balanitis of the penis, and keratoderma blennorrhagicum, seen primarily on the feet [32, 50].

Conjunctivitis is the most common ocular manifestation of RS occurring in up to 60% of patients in some publications. Conjunctivitis typically presents within a month of urethritis and arthritis with bilat-

eral asymmetric mucopurulent discharge, negative conjunctival cultures, and non-specific inflammation of the eyelids. Conjunctivitis is usually self-limited and resolves within 10 days. The second most common ocular pathology is uveitis, seen in ~12% of RS patients. Uveitis most commonly presents as nongranulomatous anterior disease. Uveitis is more common in patients positive for HLA-B27 [1, 32, 49, 50, 54]. Treatment of uveitis in RS includes topical and systemic steroids along with other steroid-sparing immunosuppressants when necessary. Oral NSAIDs have also been used for maintenance regimens. Additional reported ocular pathology includes scleritis, disc swelling, macular and retinal edema, vasculitis, and keratitis, although none of these are typical of the disease [32, 50].

28.3.5.3Psoriatic Arthritis

Psoriatic arthritis (PsA) is a chronic systemic inflammatory disorder associated with cutaneous psoriasis, which in turn afflicts up to 1% of the population. The clinical presentations can resemble oligoarticular juvenile rheumatoid arthritis. Distinct features of this disease are the association with cutaneous psoriasis, bony formation seen on radiographs of the distal interphalangeal joints, and dactylitis and psoriatic nail changes. Diagnosis can be difficult especially in the

~13% of patients with PsA who are rheumatoid factor positive. Spondylitis is seen in ~40% of patients, however PsA typically has a more widespread arthritis than the other spondyloarthropathies [37]. The presence of skin psoriasis, typically described as salmon pink patches with a silver scale on extensor surfaces and scalp, is the most distinguishing feature although it is not required for the diagnosis. These often disfiguring cutaneous lesions are especially tragic in a young child. HLA-B27 is positive in 20–60% of patients with PsA and spondylitis [39, 50].

Uveitis is seen in 10–20% of patients with PsA. A feature that distinguishes uveitis in PsA is more common posterior involvement than other SS [37]. Two distinct subgroups of PsA exist: early childhood presentation and late childhood presentation. In patients presenting in early childhood, uveitis is typically chronic with insidious onset, bilateral involvement, and asymptomatic in a white eye. Because uveitis is typically asymptomatic in this group, patients can

present later in the disease and have more complications than symptomatic patients. Uveitis in patients with arthritis developing in later childhood is most commonly symptomatic with recurrent acute anterior uveitisassociatedwithsignificantfibrinreactioninthe anterior chamber. Treatment of uveitis is essential and visual prognosis is relatively good in these patients. Severity of spine involvement is associated with a higher likelihood of uveitis. HLAsubtyping has shown a strong association with uveitis and HLA-DR13, however no association was noted for HLA-B27.

The German Uveitis in Childhood Study Group recommends ophthalmologic screening every 6 weeks in early childhood PsA and every 6 months for late childhood presentation where uveitis is usually symptomatic [69].

28.3.5.4Inflammatory Bowel Disease (Crohn’s Disease, Ulcerative Colitis, Whipple’s Disease)

Crohn’s disease and ulcerative colitis are autoimmune inflammatory bowel diseases (IBD) with primarily gastrointestinal morbidity including abdominal pain, malabsorption, and weight loss. HLA-B27 correlation is not as strongly associated as other disease processes, however increased incidence is found in the IBD. P-ANCA is positive in nearly 70% of ulcerative colitis patients and almost 20% of Crohn’s disease patients. There is increasing evidence of a role for

Mycobacterium paratuberculosis in Crohn’s disease and rifabutin and clarithromycin are being increasingly used in treatment [65]. Similar microscopic inflammatory lesions to those seen in Crohn’s disease have been noted in ~50% of AS on ileoscopy giving evidence to speculation that many of these disorders involve genetic predisposition and perhaps an inciting enteric infection [49].

Ten to twenty percent of IBD may initially present with extraintestinal manifestations prior to the onset of intestinal disease. Ocular manifestations are reported in 2–12% of patients with IBD and usually coexisting with arthritis and erythema nodosum. A small cohort study in Turkey found higher rates with ocular involvement seen in 60% of Crohn’s disease and 23% of ulcerative colitis [49, 65]. Ocular complications in IBD can result in significant morbidity

as they are underdiagnosed and may present late to ophthalmologists.

Episcleritis was the most common symptom seen in up to 29% of patients, however, it is often underdiagnosed due to a mild and self-limited disease course. Uveitis is the most commonly diagnosed ocular manifestation occurring in as many as 17% of patients with IBD. Uveitis is more commonly seen in women with IBD and strongly correlates to disease activity, improving with treatment for IBD. IBD-associated uveitis most commonly is a nongranulomatous, low-grade, recurrent, acute anterior uveitis which accounts for 60% of cases. Ten percent of patients have an isolated episode of non-recurrent acute anterior uveitis and the remaining 30% have panuveitis with associated vasculitis in a majority of these patients. Posterior involvement is seen in less than 1% of patients with IBD, however they can have significant visual morbidity from vasculitis and vitritis. Inflammation typically responds better to topical, periocular, and systemic steroids in IBD than other

HLA-B27 disorders [1, 49, 65].

Whipple’s disease is a rare bacterial infection caused by Tropheryma whippelii, affecting mostly the gastrointestinal tract although any organ can be involved. Ocular symptoms of Whipple’s disease are rare (about 5%) and include uveitis, vitritis, retinitis, optic neuritis, papilledema, and direct involvement of the lens epithelium. Ocular involvement in usually never seen without concurrent intestinal disease

[20].

Helicobacter pylori, a gram-negative rod associated with gastroesophageal reflux disease, gastritis, gastrointestinal ulcers, and gastric carcinoma has been implicated in the development of uveitis and spondyloarthropathies. Significantly higher levels of H. pylori antibodies have been documented in affected patients compared with controls. Treatment of H. pylori with multidrug regimens may be a therapeutic consideration although more research is needed to demonstrate improvement of ocular disease with standard gastric treatment protocols. Other gram-negative rods associated with gastrointestinal infections and diarrhea include Salmonella, Shigella, Klebsiella, and

Yersinia. These organisms have a strong association with reactive arthritis and uveitis. A recent survey of patients with confirmed Salmonella infection showed 34% of children with ocular complaints [1].