Características Agropecuarias de la Provincia

Th e role of orbital biopsy in the diagnosis of IOIS is con- troversial and has been debated extensively in the litera- ture. Briefl y, some experts posit that an orbital biopsy should be attempted in all patients prior to the initiation of steroid treatment of IOIS, provided the tissue in ques- tion is easily accessible, arguing that “infl ammation” is not a diagnosis but may be a sign of a potentially danger- ous underlying tissue process [49] (Fig. 3.9). Others counter that orbital exploration may expose the typical IOIS patient to unnecessary surgical risk (Fig. 3.11). In one study of IOIS in pediatric patients, those who under- went orbital biopsy were more likely to experience “seri- ous residua from their disease,” such as decreased visual

acuity, persistent proptosis, and EOM pareses and restric- tion [36]. Th ese clinicians concluded that orbital biopsy should be reserved for patients with an atypical presenta- tion, those who do not experience an immediate and sus- tained response to corticosteroids, and those whose symptoms recur.

Close inspection of the arguments from both camps, however, reveals that in clinical practice the chasm between them may be quite narrow and possibly nonexis- tent. For example, both agree that in the case of orbital myositis or an infl ammatory lesion located at the orbital apex, the benefi ts of histopathologic confi rmation should be carefully weighed against the possibility of iatrogenic damage [46]. In a similar vein, while the advocates for biopsy may argue that there is an unacceptably high inci- dence of malignancy in cases of lacrimal gland masses [47, 53], in many cases IOIS and lacrimal gland tumors can be distinguished by the history (tempo of onset, asso- ciated symptoms, etc.), clinical exam, and results of radio- logic studies. In cases that may be uncertain, few would argue with the legitimacy of biopsy. In addition, any atyp- ical variable (e.g., a subacute or smoldering onset, lack of associated pain, bony destruction on imaging), recurrent episodes of infl ammation, or a history of local or distant malignancy should prompt a biopsy in most cases.

3.3 Treatment

Th e infl ammation in IOIS results from the escalation of a series of cascading enzymatic processes that occurs in target tissues as a result of some unknown inciting factor. Localized cellular damage can lead to the activation of phospholipases, which mediate the release of arachidonic acid and perpetuate the cascade of infl ammatory media- tors in an explosive fashion. While an in-depth discus- sion of infl ammation is beyond the scope of this text,

Summary for the Clinician

IOIS is classically exquisitely sensitive to corti- ■

costeroids. Patients who do not quickly respond to adequate steroid therapy are considered “atypical.”

Corticosteroid therapy should be considered a fail- ■

ure only if adequately dosed and tapered. Relapse is common if steroid therapy is tapered too quickly.

Atypical cases of suspected IOIS either at presen- ■

tation or aft er failed corticosteroid therapy should undergo further workup, including tissue biopsy.

Fig. 3.11 Levator injury aft er orbital biopsy. Note the signifi - cant right eyelid ptosis with poor levator function in this patient who underwent orbitotomy for biopsy of the levator–superior rectus complex. Biopsy was consistent with IOIS. Eyelid func- tion did not improve, and fi nal correction required two addi- tional surgeries

Summary for the Clinician

Some experts believe that an orbital biopsy ■

should be attempted in all patients prior to the initiation of steroid treatment of IOIS.

Others recommend an orbital biopsy only in ■

select patients who (1) present in a manner atypi- cal for IOIS; (2) fail to respond to corticosteroid therapy; or (3) experience recurrent disease. Proposed algorithms for the management of typ- ■

ical and atypical IOIS cases are listed in Figs. 3.12 and 3.13, respectively.

some knowledge of this infl ammatory cascade is neces- sary to understand the treatment options available for patients with IOIS.

3.3.1 Corticosteroids

Corticosteroids inhibit the cascade of infl ammation and the immune response at virtually every level via the

suppression of proinfl ammatory cytokines. Th e eff ect is a nonspecifi c and global immune suppression. Herein lies the argument against the use of corticosteroids as part of the diagnostic algorithm for IOIS, as discussed. Nevertheless, in clinical practice, corticosteroids remain the mainstay of treatment for IOIS at present [18, 33, 34, 36, 46, 60].

Th e most common route of administration of corti- costeroids in the treatment of IOIS is oral, at a starting dosage of 1.0–1.5 mg/kg/day. Parenteral steroids may also

Blopsy if feasible

ATYPICAL IOI

(onset,symtoms,imaging)

Lower threshold for lacrimal gland, anterior orbital tissue, or discreet

orbital mass

Higher threshold for orbital apex,Eom or optic nerve

shealth Specific Inflammation (granulomatous, vasculitic) Neoplasia Nonspecific inflammation Systematic Corticosteroids

Tailored systemic work-up

Rheumatology conultation for immunosuppressants/modulars

Fig. 3.13 Proposed management algorithm for atypical IOIS (Modifi ed from ref. 18) Fig. 3.12 Proposed management algorithm for typical IOIS (Modifi ed from ref. 18)

TYPICAL IOI

(onset, symptoms, imaging)

Systematic Corticosteroids

Rapid and sustained

response Poorly tolerated side effects

Poor response or recurrence despite adequate dosage

and taper Biopsy Specific inflammation (granulomatous, vasculitic) Neoplasia Tailored systemic work-up

Rheumatology consultation for immunosuppressants Gradual taper over 6−8 weeks Cosider intraorbital steroids, NSAIDs, XRT (? Biopsy) Nonspecific inflammation

3

be employed, usually in cases of IOIS-related optic neu- ropathy. Th e initial dose is tapered over the course of weeks to months, as dictated by the patient’s symptoms. While too rapid a taper may predispose the patient to rebound infl ammation, a prolonged steroid taper will expose the patient to some of the more serious treatment- related side eff ects. Weight gain, gastritis, cushingoid facies, and mood swings are commonly cited eff ects. Corticosteroid treatment can also exacerbate or induce diabetes, hypertension, glaucoma, and cataract in suscep- tible patients. In light of the signifi cant side eff ects of sys- temic therapy, some authors advocate local intraorbital injection of triamcinolone acetonide in cases of infl am- matory masses or dacryoadenitis [15]. It should be noted that this is an off -label use of the medication, and it car- ries with it the inherent risk of retinal vasculature embo- lization of particulate matter.

A review of the literature reveals numerous examples of “steroid-resistant” IOIS as well as outright steroid fail- ures. Direct comparison of published studies is diffi cult, however, as inclusion criteria and treatment protocols are inconsistent at best. For example, Mombaerts et al reported a low cure rate (37%) and a high recurrence rate (52%) of IOIS treated with corticosteroids; however, patients with myositis and lacrimal gland involvement were excluded from analysis [34]. In a separate study looking only at patients with idiopathic infl ammatory myositis, the authors reported that all patients responded well to corticosteroid therapy, but symptoms recurred in 50% with prolonged follow-up [33]. In Yuen and Rubin’s study [60], 69% of patients were managed with corticos- teroids alone and a further 9% with the addition of a nonsteroidal anti-infl ammatory drug (NSAID) to man- age residual symptoms, for a total of 78%. An incom- plete resolution of symptoms was noted in approximately 30%, and these patients were designated steroid failures.

3.3.2 Radiation

Radiotherapy is eff ective treatment for IOIS, especially in patients who are steroid responsive but intolerant of ste- roid-related side eff ects. Th e studies demonstrating effi - cacy of radiation therapy are somewhat dated and, as is the problem with many studies concerning IOIS, are dif- fi cult to compare due to diff erent inclusion criteria and treatment measures. For example, Sergott et al [51] showed a response in 15 of 21 patients (72%) with a dose of 1,000– 2,000 cGy over 10–15 days. Orcutt et al [40], on the other hand, showed a 75% treatment eff ect at doses of 2,500 cGy over 15 days. Gunalp et al [17] reported successful results

of radiation treatment in 9 of 14 (64%) of patients who failed to respond to corticosteroid therapy.

Fortunately, the side eff ects of low-dose orbital radia- tion in the range of 1,000–2,500 cGy are rare. Th e eyelids tolerate approximately 5,000–6,000 cGy before exhibiting signifi cant signs of radiation dermatitis and eyelid scar- ring. Similar doses induce lacrimal gland atrophy, radia- tion retinopathy, and optic neuropathy. At the lower end, punctate keratopathy and conjunctivitis are noted with dosages of between 3,000 and 4,000 cGy. A radiation cata- ract may develop at 2,000 cGy [1]. However, these radia- tion dosage associations are averages; certain patients, such as those with vasculopathic risk factors (hyperten- sion, diabetes mellitus, etc.), may be more at risk for adverse events related to radiation therapy.

3.3.3 Other Agents

Following a lead from rheumatologists and dermatolo- gists, there has been a growing interest among orbital specialists in the use of immunomodulating agents in the treatment of IOIS. Although corticosteroids remain a fi rst-line treatment, immunosuppressive agents, includ- ing antimetabolites (e.g., methotrexate [MTX], azathio- prine); alkylating agents (e.g., cyclophosphamide, chlorambucil); T-cell inhibitors (e.g., cyclosporine, tac- rolimus); and biologics (e.g., infl iximab, etanercep) it are increasingly used as steroid-sparing alternatives.

Methotrexate is an antimetabolite that interferes with intracellular folic acid metabolism during DNA and RNA synthesis. It is a cytotoxic agent that is used in combina- tion with other chemotherapeutic agents in the treatment of many types of cancers. Lower doses of MTX have been shown to be very eff ective for the management of rheuma- toid arthritis, Crohn disease, and psoriasis [24]. Several small studies have addressed the usefulness of MTX in the treatment of orbital infl ammatory disease. Both Shah et al [52] and Smith and Rosenbaum [55] showed that MXT (7.5–25 mg/week) had some benefi t in patients with non- infectious orbital infl ammatory disease, including IOIS, who had failed to respond to systemic corticosteroids or orbital irradiation. Azithroprine is also an antimetabolite that works by inhibiting purine synthesis. Like MTX, it has been used in the treatment of various rheumatologic and dermatologic conditions (i.e., rheumatoid arthritis, infl ammatory bowel disease, pemphigus, systemic lupus erythematosis), but its effi cacy in terms of orbital disease is limited to a small number of case reports [9].

Alkylating agents slow or stop cell growth by forming cross-links between DNA strands, inducing apoptosis. Examples include cyclophosphamide (Cytoxan), a mainstay

in the treatment of systemic lupus erythematosus (SLE), and chlorambucil, used only in very refractive cases of rheuma- toid arthritis. Th ere are limited data on the use of these agents for IOIS, and the results are at times confl icting. Leone and Lloyd [29] successfully treated two patients with cytoxan (200 mg/day plus corticosteroids), while Mombaerts et al [34] found that two patients with steroid-resistant IOIS demonstrated no response to a similar regimen. Chorambucil has proven useful as an alternative to radiotherapy in the treatment of orbital and adnexal lymphoma [3], but there is little information in the peer-reviewed literature addressing its use in the treatment of IOIS.

Cyclosporine and mycophenolate mofetil (CellCept) are T-cell inhibitors. Th ese agents prevent the transcrip- tion of interleukin 2 and inhibit lymphokine production, reducing the function of eff ector T cells. Cyclosporine is available in systemic formulations as well as topical prep- arations, well known to ophthalmologists by the brand name Restasis®_{. Similar to the previously mentioned}

agents, use of these T-cell inhibitors by the rheumatologic and dermatologic communities (e.g., for rheumatoid arthritis, infl ammatory bowel disease, polymyositis) has pioneered their use in orbital disease. Th ere are several case reports that suggested that cyclosporine may have a role in the treatment of steroid-resistant IOIS. Diaz-Llopis and Menezo [10] controlled the symptoms of one patient with low-dose cyclosporine (starting dose 5 mg/kg, main- tenance dose 2 mg/kg) for 10 months prior to a recur- rence. Sanchez-Roman et al [50] successfully treated one patient with recurrent myositis who became intolerant of steroid-related side eff ects with low-dose cyclosporine. With similar success, Bielory and Frohman [4] reviewed a small series of four patients with granulomatous optic neuropathy and orbitopathy and noted stabilization in two and improvement in the other two with low-dose cyclosporine therapy. Hatton et al [19] reported on the successful use of mycophenolate mofetil in four patients with refractory IOIS and in one patient with brittle diabe- tes for whom corticosteroids were contraindicated.

Finally, biologic agents are the newest addition to the armamentarium of drugs available to treat the various rheumatologic diseases. Th e development of these agents grew out of a more complete understanding of the immune response and its dysregulation. As opposed to the global immune suppression achieved by some of the previously discussed agents, biologics target specifi c cell surface and soluble molecules to intercept the immune cascade at a specifi c point with fewer side eff ects than tra- ditional immunomodulatory agents. Examples of such targets include tumor necrosis factor alpha (TNF-a), interleukin 2, and T-cell surface markers that supply costimulatory signals.

Anti-TNF-a agents such as etanercept and infl iximab have shown considerable effi cacy in treating a diverse group of autoimmune diseases such as rheumatoid arthri- tis, infl ammatory bowel disease, and psoriasis. Th ere are a number of factors that suggest that TNF-a may play an important role in the treatment of orbital infl ammation [25]: It is found in orbital connective tissue of patients with TED but not in normal controls. Furthermore, the levels of TNF-a messenger RNA (mRNA) seem to cor- relate with the size of EOMs in patients with TED. Paridaens et al [41] reported an improvement in soft tis- sue changes such as conjunctival chemosis and redness in ten consecutive patients with active TED treated prospec- tively with entercept studied the eff ects of etanercept. Th ese medications have also been used with some success in the treatment of ocular infl ammatory diseases such as uveitis and scleritis [37]. Promising results have also been observed in patients with IOIS. Garrity et al [13] reviewed data from three centers where infl iximab was used to treat patients with IOIS who failed conventional treat- ments such as steroids, radiation, and other anti-infl am- matory agents. Symptomatic improvement was reported in six of seven patients, and three experienced complete resolution. More recently, several small case series have confi rmed these earlier successes [32, 44].

Summary for the Clinician

Treatment of IOIS involves interrupting the ■

infl ammatory cascade.

Corticosteroids remain the mainstay of treat- ■

ment for IOIS. Th ey are oft en started at a dose of 1 mg/kg/day and tapered over the course of weeks to months, according to a patient’s symptoms. NSAIDs may be useful adjuncts during the tail end of the corticosteroid taper.

Patients who do not respond to corticosteroid ■

therapy are oft en considered “atypical,” and biopsy of the aff ected tissue should be attempted, if accessible.

Low-dose 1500-2000 cGy orbital radiation has ■

shown effi cacy in the treatment of steroid- resistant IOIS.

Immunomodulating agents have demonstrated ■

effi cacy in the treatment of rheumatologic, der- matologic, and uveitic infl ammation. Th e results of a small number of case series and case reports suggest that these agents may be useful in select patients with IOIS.

3

3.4 Special Circumstances

3.4.1 Pediatric IOIS

Pediatric IOIS comprises between 6% and 16% of all IOIS in published series [5, 7, 34, 60]. While the signs and symptoms of IOIS are generally consistent across all age groups, a number of large studies have ascribed several features of pediatric IOIS that are thought to be atypical in the adult population: (1) the presence of constitutional symptoms; (2) accompanying anterior chamber reaction; and (3) the presence of bilateral disease [34, 36].

Th e diff erential diagnosis of IOIS in children includes orbital cellulitis and trauma as well as such potentially lethal entities as rhabdomyosarcoma and neuroblastoma, among others. While “classic” IOIS in a child may be approached in a manner similar to that used in adults, a high degree of suspicion should be maintained. As in the adult population, any patient with atypical presentation or recurrent disease should undergo orbital biopsy of the involved tissue.

Th e treatment algorithm for pediatric IOIS is also similar to that of the adult population. However, certain aspects deserve mention. Corticosteroids should be administered based on a weight-based formula, typically at a dosage of 1 mg/kg/day for oral prednisone. Steroid- related side eff ects, such as increased appetite, weight gain, gastritis, headache, and mood swings are common in children, and the classic cushingoid appearance may develop quickly. Corticosteroids also have an eff ect on linear growth, especially with prolonged therapy [8]. Fortunately, corticosteroids also inhibit closure of epi- physeal plates [22]. Once the steroids are tapered, chil- dren oft en experience rebound growth, allowing them to rejoin previous growth curves and attain normal adult height. Other known complications of steroid use, such as hypertension, diabetes, glaucoma, and cataract, are rare in the pediatric population [8, 22].

Th e data with regard to other treatment modalities are sparse for pediatric IOIS. Radiation therapy is generally avoided in children due to fears of inducing bony hyp- oplasia, soft tissue deformities, and secondary tumors, such as are seen in children receiving radiation for retino- blastoma and rhabdomyosarcoma. Although the dosages in the treatment are much lower (2,000 cGy vs. 5,000– 6,000 cGy), there are no studies in the literature docu- menting a “safe” dosage. Anecdotally, we have treated two patients, ages 11 and 15, with orbital radiation. Both have been followed for more than 4 years, and neither has experienced any treatment-related side eff ects.

Methotrexate, cyclosporine, and etanercept have been used with much success in the treatment of pediatric

uveitis [54] and rheumatologic diseases [38]. Th ese agents may also be employed in the treatment of children with refractory IOIS or in those who become intolerant of steroid-related side eff ects, although there is very little published to support this use. Consultation and coman- agement with a pediatric rheumatologist familiar with the use of these steroid-sparing and immunomodulating agents are recommended.

3.4.2 Sclerosing Pseudotumor

Idiopathic sclerosing orbital infl ammation (ISOI) is a rare cause of orbital infl ammation that some consider a distinct clinicopathological entity [48]. It is character- ized by a chronic, slowly progressive course and lacks the acute onset frequently associated with IOIS. Common signs and symptoms of ISOI include a dull pain, propto- sis, EOM restriction with diplopia, and mild-to-moder- ate infl ammation [21, 48]. Within the orbit, the superior and lateral portions, particularly the lacrimal gland, tend to be aff ected more oft en; however, up to 50% of patients may present with an apical mass [21, 48]. Th e disease is oft en unilateral but may be bilateral and asymmetric (Fig. 3.14).

On imaging, ISOS is characterized by a homoge- neously enhancing mass with irregular margins, which may obliterate adjacent structures such as EOMs, the lac- rimal gland, or bone. Th e masses are deeply hypointense on T2-weighted sequences. Histopathologically, normal anatomic structures are replaced by broad areas of fi bro- sis with a sparse infl ammatory infi ltrate of lymphocytes, plasma cells, histiocytes, eosinophils, and neutrophils [21, 48]. Th is characteristic picture is also seen in retro- peritoneal fi brosis, a condition with which ISOI may be associated [31]. Calcifi cation may also be present [61].

Summary for the Clinician

Th e signs and symptoms of IOIS in the pediatric ■

population are similar to those of adults. Th e presence of bilateral disease, constitutional symp- toms, and an accompanying anterior chamber reaction may be more common in children.