C. Stephen Foster, MD: CNS intraocular large cell lymphoma should be suspected in any age group, not just the elderly, whenever "vitritis" exists, with no other diagnostically suggestive features of intraocular inflammation occurring as a consequence of some other reason. Particularly suggestive is the finding of large cells grouped in strings, clumps, or sheets.

The presence of subtle subretinal lesions is additionally highly suggestive of lymphoma, and, finally, in any patient with posterior uveitis that is unresponsive or unexpectedly only partially responsive to systemic steroid therapy, malignant masquerade should be suspected.

Our studies indicate to us that extraocular diagnostic studies in the patient with intraocular lymphoma are always negative unless CNS involvement exists to the extent that it is producing at least some subtle neurologic sign or symptom. Therefore, any suspected intraocular large cell lymphoma must be pursued with diagnostic vitrectomy.

The details of the vitrectomy are very important, as is the handling of the material and the studies to be performed. The studies we find extremely helpful include cytology by a true expert in lymphoma cytology (i.e., not simply a general pathologist), flow cytometry, PCR analysis for IgH gene rearrangements, and a determination of the relative proportions of the cytokines IL-6 and IL-10, with an IL-10/IL-6 ratio of greater than one being highly suggestive of lymphoma, and an IL-10/IL-6 ratio of less than one being highly suggestive of inflammation rather than lymphoma.

Emmett T. Cunningham Jr., MD, PhD, MPH: Although more common in older patients, intraocular lymphoma is still a rare disease, even in patients 60 years of age or older. Most patients have nongranulomatous intermediate or diffuse uveitis. Suggestive ophthalmologic findings include the presence of atypical sheets of vitreous cells, yellow-white subretinal infiltrates, and/or serous retinal detachment. Patients with CNS involvement may have altered mental status or sensorimotor deficits.

Unfortunately , there is no perfect test for detecting intraocular lymphoma ;early diagnosis requires a high degree of suspicion and a willingness to retest over time. I usually ask older patients with otherwise nonspecific intermediate or diffuse uveitis to see a neurologist to

have a complete neurologic examination. The neurologists with whom I work routinely obtain a contrast-enhanced MRI study and perform a spinal tap for cytology to rule out gross CNS involvement. If these tests are negative, I reserve diagnostic vitrectomy for those patients who have incomplete or transient response to corticosteroid therapy , or who have otherwise suggestive eye findings , such as " atypical " vitreous cells or subretinal infiltrates.

Scott M. Whitcup, MD: Intraocular lymphoma can masquerade as an idiopathic uveitis in the elderly. The mean age of patients with intraocular lymphoma is about 60 years. Most patients complain of floaters or blurred vision early in the course of disease. Interestingly, neurologic symptoms are present in only approximately 15% of patients at the time of initial presentation. The disease can start in one eye, but bilateral involvement is common later in the disease. Although an anterior uveitis can be seen, a prominent vitritis is seen in almost all patients. Small white-yellow subretinal lesions are also a key finding.

Intraocular lymphoma should be considered in any elderly patients with a chronic idiopathic uveitis, especially when they have some of the characteristic findings described above. I obtain MRI imaging on all patients as part of the workup, since the disease affects the entire CNS, including the brain and meninges. A neurology consultation is also useful in patients with symptoms of CNS disease.

Diagnosis of intraocular lymphoma is usually based on identification of malignant cells in the vitreous or CSF in a patient with ocular signs consistent with the disease. Since corticosteroids can be cytotoxic to lymphoma cells, I try to stop corticosteroid therapy prior to vitrectomy or CSF evaluation for lymphoma.

Proper handling of these specimens is critical to obtaining the correct diagnosis. The laboratory should process vitreous and CSF specimens within 15 to 30 minutes; otherwise the malignant lymphocytes can degenerate. When performing a vitrectomy, I will take undiluted vitreous and add cell culture media prior to transporting the specimen to the lab. Importantly, a diagnosis of intraocular lymphoma is often based on the identification of a handful of malignant cells. Therefore, review of the specimens by an experienced cytopathologist is an absolute must.

Additional immunologic tests can help improve the sensitivity and specificity of the diagnostic evaluation of the vitreous and CSF specimens. Immunostaining for kappa or lambda light chains is often helpful. In a collaboration between the NEI and National Cancer Institute (NCI), Dr. Chi-Chao Chan and I reported elevated levels of IL-10 in the vitreous of patients with intraocular lymphoma, and I routinely obtain IL-10 levels on vitreous specimens when the diagnosis is suspected !

Finally, intraocular lymphoma can elude diagnosis. Negative vitrectomy or MRI study results do not rule out the disease. If intraocular lymphoma is suspected based on clinical findings, repeat the diagnostic workup over time to ensure that the diagnosis is not missed.

R. Christopher Walton, MD, MHA: Intraocular lymphoma typically refers to ocular involvement by primary CNS lymphoma. This disease should be suspected in elderly patients with several forms of uveitis: multifocal creamy yellow subretinal lesions with or without vitritis, isolated vitritis, and chronic panuveitis that recurs with taper of corticosteroids. Additionally, for elderly patients with uveitis associated with focal neurologic defects, gait abnormalities, headaches, or new-onset seizures, one should be suspicious of intraocular lymphoma.

If intraocular lymphoma is suspected, it is important to withhold any treatment with corticosteroids until a diagnostic biopsy is obtained. Corticosteroids quickly cause lysis of the malignant lymphocytes and therefore may lead to false-negative biopsy results. Since many patients have simultaneous CNS disease, coordination of the diagnostic evaluation with an experienced oncologist is essential.

Initial testing in most patients should include gadolinium-enhanced MRI of the head, lumbar puncture with cytopathologic examination of the CSF, and an undiluted vitreous biopsy.

Be sure elderly patients do not have any medical contraindications to immunosuppressive therapy when prescribing corticosteroids.

CSF and vitreous specimens should be sent immediately for processing since lymphoma cells are fragile and any delay in processing can lead to false-negative results. Additionally, the vitreous biopsy specimen should be examined by a cytopathologist with experience in primary CNS lymphoma.

Are there any special precautions that need to be taken with elderly patients vis--vis the use of systemic corticosteroids and noncorticoid immunosuppressive agents? Dr. Whitcup: It is especially important to make sure that patients do not have any medical contraindications to immunosuppressive therapy. Corticosteroids can severely complicate the management of diseases like diabetes mellitus and may be contraindicated in patients with systemic infections. Methotrexate is a medication commonly used in the elderly, but the drug is contraindicated in patients with abnormal liver function. Cyclosporine is contraindicated in any patient with diminished renal function and is often avoided in elderly patients.

Dr. Nguyen: The use of systemic corticosteroids can induce significant side effects and cause substantial morbidity in patients of any age, especially if they are used for more than 6 months at a dose greater than 10 mg of prednisone daily. In the elderly who are taking chronic corticosteroids, one must be concerned about acceleration or progression of osteoporosis, pre-existent diabetes mellitus, weight gain, mood instability, hypertension, and infections, among the numerous complications from steroid therapy.

Elderly patients who require noncorticosteroid immunosuppressive therapy must be carefully monitored. All elderly patients should be given a test dose of any immunomodulator prior to starting at full dosing. The ophthalmologist must be alert and vigilant for any symptoms that patients describe, because they may be early signs of evolving complications from the immunomodulators. Such symptoms should be thoroughly investigated and taken seriously.

In all patients who are treated with immunosuppressive therapy, and especially in the elderly, the ophthalmologist should have low threshold in sending the patients for full evaluations for potential complications, such as secondary infections. A patient who is taking cyclophosphamide for retinal vasculitis secondary to Adamantiades-Behcet's disease may suddenly complain of worsening vision during treatment. Such symptoms may be due to reactivation or progression of the vasculitis, or they may be due to the development of cytomegalovirus retinitis secondary to the patient's immunocompromised status from the cyclophosphamide.

Dr. Foster: Corticosteroids are particularly dangerous from the standpoint of peptic ulcer disease, osteoporosis, unmasking of latent tendency to diabetes mellitus, and aseptic necrosis of the hip joint. Contrary to popular belief, the elderly are not more delicate and likely to have problems with nonsteroidal immunomodulatory agents.

Dr. Walton: A detailed medical history including current medications is crucial when planning therapy with corticosteroids or immunosuppressive therapy. Elderly patients receiving corticosteroids are at higher risk for osteoporosis and pathologic fractures. Therefore, elderly patients should have bone mineral density measurement performed when initiating corticosteroids. If the anticipated duration of corticosteroids is greater than 3 months, alendronate sodium (Fosamax, Merck) and calcium are typically prescribed.

Immunosuppressive therapy in the elderly requires a team approach between the ophthalmologist and hematologist/oncologist or rheumatologist. The specific immunosuppressive agent is selected based upon the type of uveitis, medical history, concurrent medical problems, and systemic medications.

Dr. Cunningham: Corticosteroids are wonderful for gaining rapid control of inflammation, but prolonged use can cause a plethora of problems, including accelerated osteoporosis, avascular necrosis of the hip, systemic hypertension, diabetes mellitus, and mood swings, just to mention a few. In general, older patients tolerate noncorticosteroid immunosuppressive agents quite well. Therefore, when prolonged therapy is needed I try to get patients off corticosteroids and onto an appropriate noncorticosteroid immunosuppressive agent as quickly as possible.

While I've used all types of immunosuppressive agents in older patients, I tend to use less cyclosporine since one of the most common side effects is renal toxicity and older patients tend to start off with reduced renal function. Conversely, I tend to be more willing to use cytotoxic agents such as cyclophosphamide and chlorambucil in older patients with severe forms of uveitis because I am generally less concerned about infertility or the temporally distant occurrence of secondary malignancies.

Reference 1. Whitcup SM, Stark-Vancs V, Wittes RE, Solomon D, Podgor MJ, Nussenblatt RB, Chan CC. Association of interleukin-10 in the vitreous and cerebral spinal fluid and primary central nervous system lymphoma. Arch Ophthalmol 1997;115:1157-1160.