Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

oral ingestion. It has a similar mechanism of action with prolonged duration of activity compared to 6- mercaptopurine. Azathioprine was first introduced into ophthalmic use in 1966.

Azathioprine is a prodrug that is quickly metabolized in the liver to 6-MP, which in turn interferes with purine metabolism of DNA, RNA and protein

25 III synthesis. 6-Mercaptopurine, through its conversion to thioinosine-5-phosphate, a purine analogue, impairs adenine and guanine nucleotide formation in actively dividing cells in a cell cycle-specific (S phase) fashion. Both B and T cells are suppressed.

Azathioprine is available in 50 mg tablets for oral administration, and approximately 50 % of the medication is absorbed in the gastrointestinal system within 2 h. A single or divided dose of azathioprine is administered at a concentration of 2 – 3 mg/kg/day. The dose is reduced by 25 % if allopurinol is concomitantly administered. One of the more common side effects of azathioprine is nausea and anorexia, common reasons for discontinuation of therapy. Ultimately, the frequency and severity of adverse effects of azathioprine therapy depend on the dose, duration of therapy and underlying hepatic and renal disease. Other less common potential side effects include hepatotoxicity, myelosuppression, pneumonitis, pancreatitis and alopecia. Ingestion of a large dose of azathioprine may lead to bone marrow hypoplasia, bleeding and even death. Azathioprine has been implicated in potentiating the risk of future neoplasia in transplant patients. Several clinical studies have demonstrated no statistical difference in the overall frequency of malignancy in patients treated with azathioprine when compared to the frequency of malignancy in the general population. Although azathioprine is well tolerated, routine hematologic monitoring is crucial and should include liver function testing and complete blood counts with differential.

Many reports document the use of azathioprine for treating ocular inflammatory disease both as a single or combination therapy. Newell demonstrated efficacy of azathioprine in patients with pars planitis [24]. Azathioprine has been effective in the treatment of JIA associated uveitis. Foster demonstrated efficacy of azathioprine in the treatment of patients of Adamantiades-Beh¸cet disease, preventing the development of new lesions, reducing the frequency and intensity of ocular inflammation [10]. Currently, we are using azathioprine in our clinic as a steroidsparing agent for disease entities such as multifocal choroiditis, sympathetic ophthalmia, Vogt-Koyana- gi-Harada syndrome, sarcoidosis, par planitis, JIA associated uveitis, and Reiter’s syndrome associated uveitis. The use of azathioprine for the treatment of uveitis and retinal vasculitis is considered off-label.

Mycophenolate Mofetil (Cellcept)

Mycophenolate mofetil is an immunosuppressive agent developed for use in the prevention of solid organ transplant rejection in 1995. Since then, its use in ocular inflammatory disease is increasing, and it is often used in place of various other drugs such as azathioprine, cyclosporine and methotrexate. Mycophenolate mofetil is a pro-drug of mycophenolic acid. The mechanism of action involves the selective, noncompetitive, reversible inhibition of proliferating T and B cells through inhibiting inosine monophosphate dehydrogenase, an enzyme critical in de novo purine synthesis. Unlike most cells that use the salvage pathway for growth and proliferation, rapidly dividing activated B and T cells cannot, and thus they are highly sensitive to mycophenolate mofetil.

The common side effects of mycophenolate mofetil therapy include diarrhea, nausea, vomiting, headache and fatigue. More severe and less common potential side effects include leukopenia, hepatic toxicity, risk of malignancy and sepsis. Drug dosing starts at 500 mg/day to a maximum dose of 3,000 mg/ day. Routine liver function testing and complete blood cell count are critical for monitoring therapy. Drugs such as acyclovir and ganciclovir may compete for renal excretion. Concomitant use of antacids may reduce the absorption of mycophenolate.

Mycophenolate mofetil is often better tolerated than the aforementioned immunosuppressive drugs with less risk for renal and hepatic toxicity. The use of mycophenolate mofetil in the treatment of uveitis patients is considered off-label. Various small studies have demonstrated efficacy of mycophenolate mofetil as a monotherapy and also in a combination therapy for uveitides such as JIA associated uveitis, sarcoidosis, multifocal choroiditis, inflammatory bowel disease associated uveitis, orbital pseudotumor, and Admantiades-Beh¸cet’s disease.

25.7.3.3.3 Alkylating Agents

Cyclophosphamide (Cytoxan)

Cyclophosphamide is an alkylating agent derived from nitrogen mustard gas. The effect of leukopenia and aplasia with this class of agent was discovered during World War I after the use of sulfur mustard gas. The first medical application of cyclophosphamide was in the treatment of systemic lymphoma patients. Since then, it has been widely used for the treatment of various forms of systemic vasculitis.

Cyclophosphamide is a prodrug and is converted by hepatic cytochrome P-450 oxidase into the active metabolites phosphoramide mustard and 4- hydroxycyclophosphamide. The drug targets the 7- nitrogen atom of guanine to cause guanine-thymi-

dine cross links in the DNA molecule, leading to miscoding, DNA strand breaks and formation of phosphodiester bond after repair of DNA breaks. Cyclophosphamide has profound effects on lymphoid cells. B-cell functions are affected more than T cells. It is the only immunosuppressive agent that can induce immunologic tolerance to the exposure of a particular antigen. But due to the potency and potential toxicity associated with all alkylating agents, cyclophosphamide is reserved for sight threatening refractory severe uveitis.

Cyclophosphamide is supplied in 25 and 50 mg tablets, and as a powder in 100, 200, 500 mg, 1 g and 3 g vials for injection. Effective dosing ranges from 1 to 3 mg/kg/day. Seventy-five percent of an oral dose is absorbed from the gastrointestinal tract reaching peak levels in 1 h. The half-life of the metabolized drug is 4 – 6 h. The oxidized inactive metabolite acrolein is the agent most responsible for the bladder toxicity associated with cyclophosphamide use. The most common side effect of cyclophosphamide is bone marrow suppression. The dose of cyclophosphamide is usually titrated to a white blood cell count between 3,000 to 4,000. Severe leukopenia significantly increases the risk of infection and severe sepsis. A portion of all patients receiving cyclophosphamide develop hemorrhagic cystitis. All patients on the drug should drink 3 – 4 L of fluids to reduce the bladder toxicity and risk for bladder cancer. Other associated potential side effects include gonadal toxicity, nausea, vomiting, and alopecia. Long-term therapy of greater than 1 year or a cumulative dose of greater than 76 g of cyclophosphamide is associated with hematopoietic malignancies. Routine monitoring of patient’s CBC and urine analysis is critical.

Cyclophosphamide is the drug of choice for all patients with ocular manifestation of Wegener’s granulomatosis or polyarteritis nodosa. Other applications of the drug include peripheral ulcerative keratitis (PUK) associated with rheumatoid arthritis, bilateral Mooren’s ulcer, progressive ocular cicatricial pemphigoid, and Adamantiades-Beh¸cet disease with retinal vascular involvement. While chlorambucil is a more commonly and safer agent used for retinal vascular ABD, intravenous cyclophosphamide is highly effective for providing rapid control of inflammation. Alkylating agents are most likely to induce long-term drug free remission in patients with chronic severe uveitis. Akpek reported a series of serpiginous choroiditis patients with persistent active disease on nonalkylating immunosuppressive medications. After switching to a regimen of cyclophosphamide or chlorambucil, no patient developed recurrence and seven patients had drug free remission [1].

Using the stepladder approach of treatment for various recalcitrant uveitides such as par planitis,

sympathetic ophthalmia, Vogt-Koyanagi-Harada disease, in addition to the group of systemic vasculitis with associated retinal vasculitis, cyclophosphamide is used for these patients unresponsive to other immunosuppressive therapies. The use of cyclophosphamide is considered off-label for the treatment of

uveitis and retinal vasculitis.

III 25

Chlorambucil (Leukeran)

Chlorambucil is another alkylating agent that crosslinks DNA in a mechanism similar to cyclophosphamide. The drug was first synthesized in the 1950s for the treatment of systemic lymphoma. Its use in ophthalmology was first reported for patients with Admantiades-Beh¸cet’s disease, and it is now commonly used for the treatment of this disease. Similar to cyclophosphamide, chlorambucil is a nitrogen mustard derivative with a common mechanism of action interfering with DNA replication and RNA transcription. The cytotoxic effects of the drug are cell cycle nonspecific. The normal efficacious dose for the drug is in the range of 4 – 18 mg/day with target white blood cell count in the range of 3,000 – 4,000. Long-term use of chlorambucil can be associated with unpredictable and sudden pancytopenia. Routine monitoring of white blood cell count is critical due to the risk of severe leukopenia, and the duration between laboratory testing is shortened as the therapy continues. Additional potential side effects include secondary malignancy, infertility, infection and gastrointestinal discomfort. The risk of secondary malignancy increases with treatment duration greater than a year. The advantage of chlorambucil therapy over cyclophosphamide is the reduced risk of hemorrhagic cystitis and bladder cancer.

Miserocchi reported 56 eyes of 28 patients with various uveitides unresponsive to corticosteroids and other immunosuppressive agents. Upon switching to chlorambucil, vision improved or stabilized in 82 % of the patients, and 50 % were in remission off medications [21]. Goldstein used chlorambucil in short-term high dose therapy to minimize cumulative drug toxicity. The treatment duration averaged 16 weeks with maximum daily dose of 30 mg. Seven- ty-seven percent of patients were in remission during follow-up [14]. The use of chlorambucil is considered off-label for the treatment of uveitis and retinal vasculitis.

25.7.3.3.4 Biologics

Recent research in the field of molecular biology has elucidated many of the pathways of the inflammatory cascade. Some of the key molecules involved in this pathway are the cytokines produced by lympho-

cytes and macrophages, including tumor necrosis factor- (TNF-), interferon-gamma (IFN-), inter- leukin-1 (IL-1), interleukin-2 (IL-2), and interleu- kin-10 (IL-10). A new class of drugs directed against the specific cytokines and its receptor are called “biologics,” based on the fact that this class of drugs is produced by cultured cells rather than manufac-

25 III tured through a man-made chemical process. Biologics are usually very well tolerated compared to traditional immunosuppressive therapy, but are also far more expensive compared to traditional immunosuppressants.

Interferon

During the past 10 years, several studies have described the use of interferon for the treatment of retinal vasculitis, especially that associated with Adamantiades-Beh¸cet’s disease. Interferon- has been used to treat ABD resistant to conventional immunosuppressive therapy. Wechsler reported efficacy of IFN- treatment in eight patients with ABD with improvement of vision and reduction of oral prednisone [41]. Kotter, in a large study of 50 patients, reported a positive response in 92 % of them, with significantly improved visual acuity and reduction in disease activity [19]. Dose dependent side effects of interferon therapy including reddening at the site of injection, flu-like symptoms, depression, and leukopenia were common. Sixteen percent of patients developed autoimmune phenomena, including antithyroid and antinuclear antibodies. The use of IFN-for the treatment of uveitis and retinal vasculitis is considered off-label.

Daclizamab (Zenapax)

Daclizumab is an immunoglobulin G (IgG) monoclonal antibody directed against the CD25 subunit of human IL-2 receptor on activated T cells. The drug was first developed for the treatment and prevention of solid organ transplant rejection. Daclizumab is a humanized monoclonal antibody with its mechanism of action on the IL-2 receptor causing the blockade of the IL-2 mediated activation of the T cells. Daclizumab is supplied in 25 mg/5 ml concentrate for intravenous administration. The drug has an in vivo half-life of 20 days. Treatment using daclizumab is relatively safe, with main side effects being constipation, diarrhea, nausea, vomiting, and increased risk of infection during various multicenter studies for the treatment of acute renal allograft rejection. Daclizumab was highly effective for the treatment of renal transplant rejection in a combination therapy with prednisone, CSA and azathioprine, later with prednisone, CSA and mycophenolate

mofetil. The use of daclizumab for the treatment of uveitis is considered off-label use.

Nussenblatt reported the use of daclizumab in ten patients with bilateral uveitis. Patients treated included those with diagnoses of sarcoidosis, idiopathic intermediate uveitis, Vogt-Koyanagi-Harada disease, multifocal choroiditis and idiopathic panuveitis. Eight of the ten patients responded with stable or improvement in visual acuity. No therapy was stopped due to side effects or intolerance to therapy [27]. We reported favorable results in a nonrandomized trial of daclizumab in the treatment of 14 patients with scleritis, uveitis, or mucous membrane pemphigoid unresponsive to other immunosuppressive therapies. And we have recently treated seven patients with birdshot retinochoroidopathy recalcitrant or intolerant to conventional immunomodulatory therapy, and who were switched to intravenous daclizumab therapy. All seven patients responded clinically to daclizumab with stable or improved visual acuity and ERG abnormalities. As with all biologics used for the treatment of uveitis, no ideal dosing and frequency have yet been determined.

Infliximab (Remicade)

Infliximab, a chimeric human-mouse anti-TNF- monoclonal antibody, is currently approved for use in patients with rheumatoid arthritis, Crohn’s disease, psoriasis and ankylosing spondylitis. In animal and human studies, there is evidence for the efficacy of TNF- antagonists in the treatment of uveitis. Hematologic studies have shown elevated levels of serum TNF- in patients with chronic uveitis when compared to patients with a single flare up. PerezGuijo found that serum levels of TNF- are higher in patients with HLA-B27 associated uveitis compared to uveitis patients who were HLA-B27 negative [31]. Recent clinical trials of TNF- antagonists have demonstrated significant efficacy in the treatment of patients with rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease. TNF- antagonists are usually well tolerated, with relatively few side effects such as fatigue, activation of latent tuberculosis, leukopenia, and serious infections. Other side effects include optic neuritis, worsening of multiple sclerosis, lupus-like reaction and anaphylaxis. Before initiation of therapy, prior tuberculosis exposure should be excluded by purified protein derivative intradermal skin testing and chest radiograph. Infliximab is typically given intravenously 5 – 10 mg/kg every 2 – 4 weeks.

Infliximab appears to have good efficacy in the short term treatment of patients with AdamantiadesBeh¸cet disease including those with panuveitis and retinal vasculitis. Murphy showed that infliximab

was efficacious for the treatment of various ocular inflammatory diseases including scleritis, retinal vasculitis, intermediate uveitis and idiopathic panuveitis [23]. An important advantage of infliximab therapy is the rapid onset of action compared to other medications used for immunomodulation therapy. Sfikakis treated five ABD patients with severe panuveitis. In all five patients, the inflammation improved in 24 h and completely resolved in 7 days [35].

Due to differences in the penetration of blood-ret- ina barrier and in the mechanism of action for TNF- blockade, clinically, infliximab has been more effective than etanercept for treatment of ocular inflammatory disease. Currently, the evidence is lacking whether infliximab is equal or superior to conventional immunosuppressive therapy in the treatment of uveitis and retinal vasculitis. In addition, the lack of knowledge for the ideal dose and frequency also hampers the treatment of chronic uveitis and retinal vasculitis patients. The use of infliximab for the treatment of uveitis and retinal vasculitis is

considered off-label.

Etanercept (Enbrel)

Etanercept is a recombinant tumor necrosis factor receptor (p75)-Fc fusion protein that competitively inhibits tumor necrosis factor-alpha (TNF-). It binds extracellular TNF-, preventing the binding of native receptors and inhibiting downstream signaling. Etanercept has been successfully used in patients with rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, reducing pain and inflammation. The drug is administered subcutaneously in 25 mg two or three times per week. In the rat model, Koizumi found that etanercept reduced leukocyte rolling, adhesion, and vascular leakage, resulting in decreased breakdown of the blood-retina barrier and associated apoptotic cell death [18]. A double-blind placebo controlled study of etanercept showed efficacy in suppressing mucocutaneous manifestations of AdmantiadesBeh¸cets disease. Reiff evaluated etanercept therapy in children with chronic recalcitrant uveitis. Within 3 months, 10 of 16 patients showed decreased inflammation, and 4 of 10 showed improvement in visual acuity. There were no reports of serious adverse reactions except local injection site reaction [32]. Foster reported a study of 20 patients with uveitis well controlled on MTX and later tapered to a regimen of etanercept versus placebo. Relapse occurred in three of ten on etanercept and five of ten on placebo. The authors concluded that etanercept was no better than placebo in preventing the relapse of uveitis previously controlled with MTX [13].

Side effects associated with etanercept therapy included risk of infection and injection site reactions. Routine liver function test and complete blood count should be performed. The use of etanercept in the treatment of uveitis and retinal vasculitis is considered off-label.

Rituximab (Rituxin) III 25

The rituximab antibody is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 glycoprotein found on the surface of normal B-lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine lightand heavy-chain variable region sequences and human constant region sequences. The drug is currently approved for the treatment of B-cell lymphoma. Due to the selectivity of the chimeric antibody, it allows for the direct targeting of B cells and the inflammatory responses that are antibody mediated. Rituximab has been highly successful for the treatment of systemic anti-neutrophil cytoplasmic antibody-positive vasculitis associated with Wegener’s granulomatosis. In our clinic, it has been used successfully for a Wegener’s granulomatosis patient refractory to traditional immunosuppressive agents with associated retinal vasculitis and panuveitis. The drug is administered intravenously every week for 4 weeks or for 8 weeks at a dose of 375 mg/m2 surface area dosing.

Most side effects of rituximab therapy are encountered during the first infusion. Special attention should be paid to the rate of antibody infusion with a slow gradual increase in the hourly infusion rate. Fever, chills, respiratory symptoms, and occasionally hypertension are the most common effects. The side effects overall are much more mild compared to traditional immunosuppressive or chemotherapeutic agents. The use of rituximab for the treatment of uveitis and retinal vasculitis is considered off-label.

25.7.4Immunosuppressive Therapy in Children

The use of corticosteroid-sparing immunosuppressive therapy for the treatment of children requires a different approach than that for adult patients. Prompt control of inflammation is crucial for the prevention of vision loss from inflammation as well as from amblyopia. Chronic use of corticosteroids in children may result in growth suppression, cataracts, weight gain and acne. Corticosteroids associated glaucoma is far more common in children than in adults.

Walton demonstrated safety and efficacy of cyclosporine therapy in children for the treatment of

severe vision threatening intermediate uveitis and panuveitis with follow-up of 4 years. Over 80 % of the children responded to the CSA therapy [40]. Additional studies have further confirmed the safety of CSA as an immunosuppressive agent for the treatment of pediatric uveitis. Methotrexate is one of the most commonly used medications for the treatment

25 III of juvenile idiopathic arthritis associated uveitis because of its long track record of safety in children. The medication can be used as a monotherapy or a combination therapy along with CSA. Over 60 % of patients with JRA associated uveitis will have clinical response to MTX as a single agent therapy. Currently, mycophenolate mofetil is gaining popularity for the treatment of children with JIA associated uveitis, pars planitis, sarcoid associated uveitis, and psoriatic arthritis associated uveitis.

25.7.5 Combination Therapy

There is strong evidence in our clinic and others that combination therapy for the treatment of uveitis and retina vasculitis can help to rapidly taper corticosteroids and reduce side effects associated with immunosuppressive therapy. Synergistic activities of combination therapy can help to reduce the dose needed for each individual immunosuppressive medication and the associated side effects. Transcription factor inhibitors such as CSA, tacrolimus and rapamycin are often used in combination with antimetabolites such as MTX, azathioprine and mycophenolate. Additional medications that can be incorporated as a part of the drug regimen include NSAID, low dose prednisone (less than 6 mg/day), and biologics. Diseases responsive to combination therapy include panuveitis, HLA-B27 associated uveitis, Admantia- des-Beh¸cet disease, serpiginous choroiditis, sympathetic ophthalmia, VKH, and multifocal choroiditis with panuveitis.

25.7.6 Conclusion

Although retinal vasculitis is a rare ophthalmic condition, the evaluation and the treatment are often complicated and require a thorough understanding of the ocular disease and underlying systemic associations. The long-term prognosis visually and systemically must be weighed against the risks and benefits of the treatment regimen. Fluorescein angiography is critical for assessing the full extent of the disease and for monitoring the efficacy of treatment. In patients with infectious retinal vasculitis, treatment with the appropriate antimicrobial therapy is essential and may cure the patient of the associated retinal vasculitis.

For patients with noninfectious retinal vasculitis associated with ocular and systemic disease, cortico-

steroids are the mainstay of initial treatment. Traditional steroid-sparing immunosuppressive agents are used for patients who fail to respond to corticosteroids or who are intolerant to the side effects of chronic therapy. Due to the lack of clinical trials for the use of immunosuppressive therapy in the treatment of uveitis and retinal vasculitis, it is often difficult to make an evidence-based decision on which agent is best for which clinical situation. Studies of the efficacy for such drugs have been limited by the difficulty in enrolling large numbers of patients in clinical trials; hence the absence of a “gold standard” for comparison of all new immunosuppressive therapy. For all treating physicians and patients, a thorough understanding of the disease prognosis with the risks and benefits of treatment regimen is crucial. Collaboration with an internist and rheumatologist also can help to co-manage the disease and immunosuppressive regimen. It is especially important for those cases in which an ocular immunologist is not participating in treating the patient. In patients with mild to moderate uveitis and retinal vasculitis, single agent therapy of methotrexate and mycophenolate mofetil are commonly employed. In patients with severe retinal vasculitis, combination therapy or an alkylating agent is often required to control the inflammation. With the newly expanding class of biologics demonstrating efficacy against various recalcitrant uveitides, flexibility on the part of the treating physician is critical for formulating the proper treatment regimen.

References

1.Akpek EK, Jabs DA, Tessler HH, Joondeph BS, Foster CS (2002) Successful treatment of serpiginous choroiditis with alkylating agents. Ophthalmology 109:1508 – 1513

2.Antcliff RJ, Spalton DJ, Stanford MR, Graham EM, ffytche TJ, Marshall J (2001) Intravitreal triamcinolone for uveitic cystoid macular edema: an optical coherence tomography study. Ophthalmology 108:765 – 772

3.Becker MD, Rosenbaum JT (2000) Current and future trends in the use of immuno-suppressive agents in patients with uveitis. Curr Opin Ophthalmol 11:472 – 477

4.Berk PA, Goldberg JD, Silverman MN, Weinfeld A, Donovan PB, Ellis JT, Landaw SA, Laszlo J, Najean Y, Pisciotta AV, Wasserman LR (1981) Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 304:441 – 447

5.Carnahan MC, Goldstein DA (2000) Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol 11:478 – 483

6.Ciulla TA, Walker JD, Fong DS, Criswell MH (2004) Corticosteroids in posterior segment disease: an update on new delivery systems and new indications. Curr Opin Ophthalmol 15:211 – 220

7.Cunningham ET (2002) Diagnosis and management of acute anterior uveitis. In Focal Points, AAO

8.Cunningham ET (2000) Uveitis in children. Ocul Immunol Inflamm 8:251 – 261

9.Eriksson P (2005) Nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis successfully treated with rituximab. J Intern Med 257:540 – 548

10.Foster CS, Baer JC, Raizman MB (1991) Therapeutic responses to systemic immunosuppressive chemotherapy agents in patients with Behcet’s syndrome affecting eyes. In: O’Duffy JD, Kokmen E (eds) Behcet’s disease: basic and clinical aspects. Dekker, New York, pp 581 – 588

11.Foster CS, Vitale AT (2002) Immunosuppressive chemotherapy. In: Foster CS, Vitale AT (eds) Diagnosis and treatment of uveitis. Saunders, Philadelphia, pp 141 – 214

12.Foster CS (2003) Diagnosis and treatment of juvenile idiopathic arthritis associated uveitis. Curr Opin Ophthalmol 14:395 – 398

13.Foster CS, Tufail F, Waheed NK, Chu D, Miserocchi E, Baltatzis S, Vredeveld CM (2003) Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate. Arch Ophthalmol 121:437 – 440

14.Goldstein DA, Fontanilla FA, Kaul S, Sahin O, Tessler HH (2002) Long-term follow-up of patients treated with shortterm, high dose chlorambucil for sight-threatening ocular inflammation. Ophthalmology109:370 – 377

15.Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS, Nussenblatt RB, Stiehm ER, Tessler H, Van Gelder RN, Whitcup SM, Yocum D (2000) Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol 130:492 – 513

16.Kilmartin DJ, Forrester JV, Dick AD (1998) Cyclosporin A therapy in refractory non-infectious childhood uveitis. Br J Ophthalmol 82:737 – 742.

17.Kiss S, Letko E, Qamruddin S, Baltatzis S, Foster CS (2003) Long-term progression, prognosis, and treatment of patients with recurrent ocular manifestations of Reiter’s syndrome. Ophthalmology 110:1764 – 1769

18.Koizumi K, Poulaki V, Doehmen S, Welsandt G, Radetzky S, Lappas A, Kociok N, Kirchhof B, Joussen AM (2003) Contribution of TNF-alpha to leukocytes adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo. Invest Ophthalmol Vis Sci 44:2184 – 2191

19.Kotter I, Zierhut M, Eckstein AK, Vonthein R, Ness T, Gunaydin I, Grimbacher B, Blaschke S, Meyer-Riemann W, Peter HH, Stubiger N (2003) Human recombinant interferon alfa2a for the treatment of Behcet’s disease with sight threatening posterior or panuveitis. Br J Ophthalmol 87:423 – 431

20.McGhee CN, Dean S, Danesh-Meyer H (2002) Locally administered ocular corticosteroids: benefits and risks. Drug Saf 25:33 – 55

21.Miserocchi E, Baltatzis S, Ekong A, Roque M, Foster CS (2002) Efficacy and safety of chlorambucil in intractable noninfectious uveitis. Ophthalmology 109:137 – 142

22.Mochizuki M, Masuda K, Tuyoshi S, Ito K, Kogure M, Sugino N, Usui M, Mizushima Y, Ohno S, Inaba G (1993) A clinical trial of FK 506 in refractory uveitis. Am J Ophthalmol 115:763 – 769

23.Murphy CC, Ayliffe WH, Booth A, Makanjuola D, Andrews PA, Jayne D (2004) Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology 111:352 – 356

24.Newell FW, Krill AE (1967) Treatment of uveitis with azathioprine. Trans Ophthalmol Soc 87:499 – 511

25.Nussenblatt RB, Palestine AG, Rook AH, Scher I, Wacker

28.Ozdal PC, Ortac S, Taskintuna I, Firat E (2002) Long-term therapy with low dose cyclosporine A in ocular Behcet’s disease. Doc Ophthalmol 105:301 – 312

29.Palestine AG, Nussenblatt RB, Chan CC (1985) Cyclosporine penetration into the anterior chamber and cerebrospinal fluid. Am J Ophthalmol 99:210 – 211

30.Papaliodis GN, Chu D, Foster CS (2003) Treatment of ocular inflammatory disorders with daclizumab. Ophthalmology 110:786 – 789

31.Perez-Guijo V, Santos-Lacomba M, Sanchez-Hernandez M, Castro-Villegas Mdel C, Gallardo-Galera JM, CollantesEstevez E (2004) Tumor necrosis factor-alpha levels in aqueous humor and serum from patients with uveitis: the involvement of HLA-B27. Curr Med Res Opin 20: 155 – 157

32.Reiff A, Takei S, Sadeghi S, Stout A, Shaham B, Bernstein B, Gallagher K, Stout T (2001) Etanercept therapy in children with treatment-resistant uveitis. Arthritis Rheum 45:252 – 257

33.Rothova A (2002) Corticosteroids in uveitis. Ophthalmol Clin North Am 15:389 – 394

34.Samson CM, Waheed N, Baltatzis S, Foster CS (2001) Methotrexate therapy for chronic noninfectious uveitis: analysis of a case series of 160 patients. Ophthalmology 108:1134 – 1139

35.Sfikakis PP, Theodossiadia PG, Katsiari CG, Kaklamanis P, Markomichelakis NN (2001) Effect of infliximab on sightthreatening panuveitis in Behcet’s disease. Lancet 358:295 – 296

36.Shetty AK, Zganjar BE, Ellis GS, Ludwig IH, Gedalia A (1998) Low-dose methotrexate in the treatment of severe juvenile rheumatoid arthritis. J Pediatr 133:266 – 268

37.Solomon SD, Cunningham ET (2000) Use of corticosteroids and noncorticosteroid immunosuppressive agents in patients with uveitis. Compr Ophthalmol Update 1:273 – 286

38.Suttorp-Schulten MSA, Rothova A (1996) The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol 80:844 – 848

39.Thall EH (2003) Dosage of intravitreal triamcinolone. Am J Ophthalmol 136:1192

40.Walton RC, Nussenblatt RB, Whitcup SM (1998) Cyclosporine therapy for severe sight-threatening uveitis in children and adolescents. Ophthalmology 105:2028 – 2034

41.Wechsler B, Bodaghi B, Huong DL, Fardeau C, Amoura Z, Cassoux N, Piette JC, LeHoang P (2000) Efficacy of interferon alfa-2a in severe and refractory uveitis associated with Behcet’s disease. Ocul Immunol Inflamm 8:293 – 301

42.Yoshida A, Kawshima H, Motoyama Y, Shibui H, Kaburaki T, Shimizu K, Ando K, Hijikata K, Izawa Y, Hayashi K, Numaga J, Fujino Y, Masuda K, Araie M (2004) Comparison of patients with Behcet’s disease in the 1980’s and 1990’s. Ophthalmology 111:810 – 815

Core Messages

Hypertensive retinopathy is an acquired bilateral disease in patients with arterial hypertension

The clinical course is often only recognized after onset of visual symptoms

It is characterized by narrowing of the retinal arterioles, cotton-wool spots, hard exudates, retinal hemorrhages, and optic disk edema indicating severe parenchymal changes in the retina Treatment is the reduction of the elevated systemic blood pressure

The classification of fundus changes secondary to arterial hypertension has been used for monitoring the severity of vascular alterations. In the past, this was the only possibility to assess the status of the microcirculation. Therefore, very detailed classifications have been developed. These classifications are described below. The detailed classification of hypertensive vascular fundus changes may be still important for scientific reasons. However, for the clinical management of systemic hypertension today these detailed classifications are no longer necessary. Nevertheless, the separation between minor vascular changes in systemic hypertension (stage I and II) and hypertensive retinopathy (stage III and IV) is still very important for the management of arterial hypertension. Patients with hypertensive retinopathy have to be treated and monitored intensively by internal medicine since these patients are at high risk for cardiovascular and cerebrovascular complications.

The normal caliber of the arterioles in the fundus is two-thirds that of the venules. Generalized vascular constriction is recognizable by a narrowed column of blood.

Long-standing arterial hypertension over a period of months to years leads to organic vascular changes similar or identical to those in arteriosclerosis. Arterial hypertension is generally regarded as an important causative factor in arteriosclerosis. Findings in chronic hypertension include not only narrowed caliber of the arterioles but also wide, bright reflexes on the arteries.

26.1.1Pathophysiology of the Retinal Vessels in Arterial Hypertension

Constriction of the arterial vascular tract leads to hypertension due to increased vascular resistance. Increased cardiac output produces hypervolemic hypertension.

Vasospastic arteriolar stenosis on the fundus is a characteristic finding in hypertension due to increased vascular resistance. Examples of this include hypertension in toxemia of pregnancy, acute glomerulonephritis, or pheochromocytoma.

Fig. 26.1.1. Hypertensive retinopathy with cotton-wool spots, dilated capillaries, hard exudates, retinal hemorrhages, and optic disk swelling

Fig. 26.1.2. Hypertensive retinopathy with macular star of lipid deposition in the macula, retinal hemorrhages, and cottonwool spots

26.1.2Fundus Changes in Arterial Hypertension

The fundus is well perfused, glistening, and moist The vasculature tends to be tortuous

Arterioles will be narrow with bright reflexes; capillaries may be dilated on the optic disk and

in the vascular arcades III 26 The margins of the optic disk become blurred and

its parenchyma becomes somewhat hyperemic Other parenchymal changes include minor retinal bleeding, specifically spot hemorrhages or flame shaped hemorrhages in the nerve fiber layer

26.1.3Fundus Changes in Hypertensive Retinopathy

Severe parenchymal changes in the retina in arterial hypertension often manifest themselves in the vascular arcades as cotton-wool spots and as hard exudates.

Hard exudates may appear like focal calcifications around the macula, forming a macular star. Severe hypertensive retinopathy may be characterized by edema in the central retina and optic disk edema, which may be as pronounced as papilledema. As hypertensive retinopathy is invariably bilateral, a differential diagnosis should consider a cerebral mass or primary elevated cerebrospinal fluid pressure (cerebral pseudotumor). Often patients are subjected to extensive examinations in an attempt to confirm the latter diagnosis before the physician considers measuring the blood pressure.

Fig. 26.1.3. Hypertensive retinopathy with macular edema, lipid deposition around the macula, retinal hemorrhages, and cot- ton-wool spots

Fig. 26.1.4. Hypertensive retinopathy with occluded retinal arteries, retinal hemorrhages, capillary dilatation, and cottonwool spots

26.1.4Clinical Diagnoses in Hypertensive Retinopathy

Glomerulonephritis Chronic renal insufficiency

Decompensated arterial hypertension Toxemia of pregnancy Pheochromocytoma

Treatment: management of the arterial hypertension

26.1.5Classification of Fundus Changes in Arterial Hypertension

Stage I

–Normal or widened arteriolar caliber

–Brighter reflexes on arterioles

–Vascular distension and tortuosity

–No parenchymal changes

–Arteriosclerosis of variable severity

–Hypervolemic hypertension

Core Messages

Pregnancy-induced hypertension (PIH) is a multisystem disorder affecting 6 – 8 % of all pregnancies

PIH is a major cause in both developed and developing countries of maternal and fetal morbidity and mortality

Ocular involvement is common in PIH, but permanent visual loss is rare

PIH affects both the retinal and choroidal vasculature, with clinical findings resembling hypertensive retinopathy

No specific treatment is indicated for PIH-relat- ed retinopathy, which generally resolves soon after delivery of the fetus. Care consists of appropriate management of the underlying systemic disorder by a qualified obstetrician

26.2.1 History

Preeclampsia/eclampsia, also long known as “toxemia of pregnancy,” has been recognized as a clinical entity for thousands of years. The danger of seizures during pregnancy was recorded in the literature as far back as ancient Egypt and China. Eclampsia is alluded to in the pre-Hippocratic Coan Prognosis, which reads “In pregnancy, drowsiness and headache accompanied by heaviness and convulsions, is generally bad.” Indeed the word “eclampsia” derives from the Greek word “eklampsis,” which means “shining forth.” Prior to the 18th century, the term eclampsia was used only to refer to the visual phenomena that were known to accompany seizures during pregnancy. It was not until the 19th century – when the resemblance of eclamptic patients to those with nephritis prompted a London physician to check the urine of 14 pregnant patients suffering from blurred vision, seizures, edema and headache – that the full clinical syndrome was recognized (reviewed by Purkerson and Vekerdy [38]).

Retinal changes related to hypertension have been recognized since the early 19th century. The first report in the literature of retinal changes in association with preeclampsia was written by the great German ophthalmologist Albrecht von Graefe, who described serous retinal detachments in a patient with toxemia of pregnancy [52]. The year 1921 saw the first large ophthalmologic case series of toxemia of pregnancy published by Schiotz, who reported on 680 hospitalized patients with toxemia of pregnancy.

Of these patients, 35 were found to have funduscopic changes, and 3 were found to have retinal detachments.

26.2.2 Hypertension in Pregnancy

Essentials

Hypertension is the most common medical disorder during pregnancy

Hypertension during pregnancy can be classified into one of four categories: chronic hypertension, gestational hypertension, preeclampsia/eclampsia, and superimposed preeclampsia

Hypertension is the most common medical disorder during pregnancy, affecting 6 – 8 % of all pregnancies [39]. Until recently, the diagnostic criteria delineating the various subtypes of hypertensive disease in pregnancy had not been well defined or standardized [24]. Since 2000, uniform diagnostic criteria have emerged through the cooperation of international working groups [7]. Currently, hypertension during pregnancy is classified into 4 categories: chronic hypertension, gestational hypertension, preeclampsia-eclampsia, and preeclampsia superimposed on chronic hypertension (Table 26.2.1).

Chronic hypertension is defined as hypertension which was preexisting prior to pregnancy, or which