Uveitis Posterior

01Pathophysiology

Posterior uveitis refers to intraocular inflammation that primarily involves the choroid (choroiditis), and often extends to the overlying retina (chorioretinitis or retinochoroiditis) and the vitreous humor (vitritis). Understanding the anatomy is the key to understanding why this condition presents the way it does: the choroid is the most vascular layer of the eye, receiving a disproportionately high percentage of ocular blood flow. This rich perfusion makes it a natural target for hematogenous seeding of infectious organisms and for immune complex deposition in systemic autoimmune conditions.

In toxoplasmic retinochoroiditis, the most common infectious cause globally, the parasite Toxoplasma gondii establishes dormant tissue cysts within the retina during primary infection. Reactivation of these cysts triggers a focal necrotizing inflammatory response, producing the characteristic white-yellow retinal lesion sitting on top of or adjacent to an old, darkly pigmented scar from a prior episode. The overlying vitreous becomes hazy with inflammatory cells, creating the classic "headlight in the fog" appearance on fundoscopy. This is why patients describe painless floaters and blurred vision: the inflammation is deep, behind the lens, and does not irritate the anterior segment the way anterior uveitis does.

In CMV retinitis, the mechanism is direct viral cytopathic destruction of retinal cells. Because CMV reactivation occurs almost exclusively in patients with profound immunosuppression (CD4 count below 50 cells/microliter), the immune system cannot mount a vigorous inflammatory response. The result is a slowly progressive, full-thickness retinal necrosis with hemorrhage rather than a brisk inflammatory infiltrate. The retina becomes friable and prone to retinal detachment, a feared complication.

In non-infectious causes such as sarcoidosis, the choroid and retinal vasculature become infiltrated by non-caseating granulomas. Periphlebitis along retinal veins produces the "candle wax dripping" pattern (taches de bougie). In Vogt-Koyanagi-Harada (VKH) disease, an autoimmune attack against melanocyte antigens in the uveal tract causes bilateral, diffuse granulomatous inflammation. Because melanocytes are also found in the skin, meninges, and inner ear, VKH presents with a multisystem syndrome: uveitis, poliosis (whitening of eyelashes and hair), vitiligo, hearing loss, and meningeal signs.

The critical teaching point is that posterior uveitis is painless because the posterior segment lacks the sensory innervation density of the anterior chamber. Pain and redness point to anterior uveitis. The chief complaints of floaters (vitreous cells casting shadows on the retina) and blurred vision (macular or perimacular involvement) should immediately shift your differential toward a posterior process.

02Classification and Clinical Manifestation

By Anatomic Pattern

By Etiology

03Diagnostic Workup

The diagnostic approach to posterior uveitis follows a principle of pattern recognition on fundoscopy first, then etiology-directed laboratory testing.

Step 1 is always a dilated fundoscopic examination. The morphology of the lesion, its location, laterality, and the presence or absence of vitreous haze or retinal hemorrhage will narrow the differential dramatically. A focal white lesion with a pigmented scar strongly suggests toxoplasmosis. Hemorrhagic necrosis in an immunosuppressed patient points to CMV. Multiple serous retinal detachments bilaterally raise concern for VKH.

Step 2 involves baseline laboratory screening that should be ordered for nearly every patient with posterior uveitis of unclear etiology. This panel typically includes a chest X-ray (to evaluate for sarcoidosis and TB simultaneously), RPR/VDRL with confirmatory FTA-ABS (syphilis must be excluded in every case of bilateral or atypical uveitis), a complete blood count, IGRA or tuberculin skin test, and serum ACE level. The rationale for this broad screening is that syphilis, TB, and sarcoidosis can each mimic nearly any form of uveitis, and missing them has serious consequences.

Step 3 is directed testing based on the clinical picture. If the presentation is classic for toxoplasmosis (immunocompetent patient, focal lesion with adjacent scar, unilateral), the diagnosis is usually clinical, and serologic confirmation with Toxoplasma IgG is supportive but not required. A negative IgG, however, is valuable because it essentially excludes toxoplasmosis. For CMV retinitis, the combination of a characteristic fundoscopic appearance in a patient with a CD4 count below 50 is often sufficient, but PCR of aqueous or vitreous humor is the gold standard confirmatory test when there is doubt.

Fluorescein angiography is not a first-line screening tool but becomes important when retinal vasculitis is suspected (as in Behcet, sarcoidosis, or TB), when ischemic complications need to be evaluated, or when cystoid macular edema requires documentation. OCT has become increasingly central for detecting and monitoring macular edema, a common cause of vision loss in posterior uveitis regardless of etiology.

A key exam principle: never forget to test for syphilis. Syphilitic uveitis can present as anterior, intermediate, posterior, or panuveitis, and it is one of the few causes of uveitis that is fully curable with appropriate antibiotic therapy. Missing syphilis is considered a diagnostic failure.

04Management and Treatment

The single most important management principle in posterior uveitis is: identify and treat the underlying etiology before giving corticosteroids for infectious causes. Administering steroids to a patient with untreated infectious posterior uveitis (especially CMV or toxoplasmosis) can worsen the infection catastrophically. This is a frequent exam trap.

For toxoplasmosis, the classic "triple therapy" is pyrimethamine plus sulfadiazine plus folinic acid (leucovorin). It is critical to understand that folinic acid (not folic acid) is used to prevent pyrimethamine-induced bone marrow toxicity without interfering with the drug's antiparasitic mechanism. After 24 to 48 hours of effective antimicrobial coverage, an oral corticosteroid (prednisone 0.5-1 mg/kg/day) may be added to limit inflammatory tissue destruction. Self-limited episodes in immunocompetent patients with lesions away from the macula and optic disc may sometimes be observed without treatment, but vision-threatening lesions always warrant therapy.

For CMV retinitis, the immediate priorities are antiviral therapy and immune reconstitution. Valganciclovir is the preferred oral agent for both induction and maintenance. Ganciclovir's principal toxicity is myelosuppression (neutropenia, thrombocytopenia), which requires monitoring of the complete blood count. Foscarnet is the alternative for ganciclovir-resistant CMV or when myelosuppression is prohibitive, but foscarnet carries its own risk of nephrotoxicity and electrolyte disturbances (hypocalcemia, hypomagnesemia). Immune reconstitution with HAART is the definitive long-term strategy; maintenance antiviral therapy can be discontinued once the CD4 count has been sustained above 100 cells/microliter for 3 to 6 months.

For non-infectious posterior uveitis (sarcoidosis, VKH, Behcet, birdshot), the cornerstone of treatment is immunosuppression. Systemic corticosteroids are the initial agents, but most patients require steroid-sparing immunosuppressive therapy to avoid long-term corticosteroid complications (cataracts, glaucoma, osteoporosis, hyperglycemia). Methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine are all used as second-line agents. Biologic agents such as infliximab and adalimumab (anti-TNF) have become increasingly important, particularly in Behcet disease and refractory cases.

A crucial point for VKH: early and aggressive treatment with systemic corticosteroids is associated with better visual outcomes. Delayed or inadequate therapy leads to chronic recurrent inflammation, "sunset glow fundus" depigmentation, subretinal fibrosis, and permanent vision loss.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on posterior uveitis questions is by giving corticosteroids before ruling out or treating an infectious etiology. A vignette describing a patient with a focal retinal lesion, floaters, and blurred vision who is started on corticosteroids alone without antimicrobial coverage is testing whether you recognize that steroids will worsen untreated toxoplasmosis, CMV, TB, or syphilis. The correct sequence is always: confirm or strongly suspect the etiology, initiate targeted antimicrobial therapy, and only then consider adding corticosteroids as adjunctive anti-inflammatory treatment.

A second common trap involves CMV retinitis and the CD4 threshold. If the vignette describes a patient with HIV and a CD4 count of 200 who has retinal findings, students may reflexively select CMV. However, CMV retinitis overwhelmingly occurs at CD4 counts below 50 cells/microliter. At a CD4 of 200, toxoplasmosis, syphilis, or TB-associated posterior uveitis are far more likely.

A third pitfall is confusing folinic acid (leucovorin) with folic acid in the toxoplasmosis regimen. Pyrimethamine works by inhibiting dihydrofolate reductase in the parasite. Folinic acid bypasses this block in human cells to prevent bone marrow suppression without reducing the drug's efficacy against Toxoplasma. Folic acid, on the other hand, would be converted through the same blocked pathway and is therefore ineffective as rescue therapy. This distinction is a favorite test question.

Fourth, always remember that syphilis can mimic any form of uveitis. Any exam question presenting bilateral, atypical, or treatment-refractory uveitis where syphilis testing was not performed is likely testing whether you would order RPR/FTA-ABS. The principle is: test for syphilis in every unexplained uveitis case, because it is one of the few infectious causes that is completely curable.

Finally, the core competency being tested in posterior uveitis questions is threefold: (1) recognizing that painless floaters and blurred vision without redness or pain points to a posterior (not anterior) process, (2) matching the fundoscopic pattern and patient immune status to the correct etiology, and (3) sequencing the management correctly by treating infection before inflammation.