Part 2 • Diagnosis

Chapter 4 Development of a Differential Diagnosis

Box 4-1  Classification of uveitis

1.Is the disease acute or chronic?

2.Is the inflammation granulomatous or nongranulomatous?

3.Is the disease unilateral or bilateral?

4.Where is the inflammation located in the eye?

5.What are the demographics of the patient?

6.What associated symptoms does the patient have?

7.What associated signs are present on physical examination?

8.What is the time course of the disease and response to previous therapy?

symptoms. Other data, such as the type and anatomic location of the inflammation, are obtained from the ocular examination. Again, the need for information about systemic and neurologic signs necessitates a careful physical and neurologic examination of the patient by the ophthalmologist or by a consulting internist, internal medicine subspecialist, neurologist, or general medical practitioner.

Once the uveitis has been classified, a preliminary differential diagnosis should be generated. The answers to each of the questions in Box 4-1 will generate a list of possible diagnoses. The diagnoses that appear most frequently on these lists are then the most likely cause of the disorder. Ancillary examinations, including laboratory tests or specialized examinations such as radiography, electrophysiology, or a surgical procedure such as a diagnostic vitrectomy, can then be obtained to discern among the most likely diagnoses. In the next chapter on diagnostic testing, we show that the ‘shotgun approach’ of ordering every diagnostic test available will mislead the clinician into making the wrong diagnosis.

Classifying uveitis

1.  Is the disease acute or chronic?

Acute occurrences of uveitis usually have a sudden onset and last up to 6 weeks. The most common causes are listed in Box 4-2. Most occurrences of anterior uveitis, such as HLA- B27-associated iritis and idiopathic anterior uveitis, fall into this category. Other diseases that typically cause acute uveitis include Vogt–Koyanagi–Harada syndrome, postoperative bacterial infection, toxoplasmosis, many of the ‘white-dot syndromes,’ such as acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and multiple evanes­ cent white-dot syndrome (MEWDS), and traumatic iritis. Although many diseases can cause acute uveitis, these are the conditions to consider first in the differential diagnosis. Chronic forms of uveitis have an insidious onset and typically last longer than 6 weeks. Other groups have defined a limited duration of uveitis as lasting 3 months or less, and persistent disease as lasting longer than 3 months.3 Again, although many diseases can cause a uveitis that persists longer than 6 weeks, the uveitides that are characteristically chronic are listed in Box 4-2. Knowing whether the uveitis is acute or chronic is never sufficient to make a diagnosis, but it may aid in the diagnostic process.

Box 4-2  Causes of acute and chronic uveitis

ACUTE UVEITIS

Most cases of anterior uveitis: idiopathic, ankylosing spondylitis, Reiter’s syndrome, Fuchs’ heterochromic iridocyclitis

Vogt–Koyanagi–Harada syndrome Toxoplasmosis

White-dot syndromes: acute posterior multifocal placoid   pigment epitheliopathy and multiple evanescent white-dot syndrome

Acute retinal necrosis Postsurgical bacterial infection Trauma

CHRONIC UVEITIS

Juvenile rheumatoid arthritis Birdshot choroidopathy Serpiginous choroidopathy Tuberculous uveitis

Postoperative uveitis (Propionibacterium acnes, fungal) Intraocular lymphoma

Sympathetic ophthalmia Multifocal choroiditis Sarcoidosis

Intermediate uveitis/pars planitis

2.  Is the inflammation granulomatous or nongranulomatous?

The ocular examination offers a unique opportunity to determine the type of infiltrating inflammatory cells involved in the disease process without taking a biopsy sample for histologic analysis. In anterior uveitis, inflammatory cells attach to the corneal endothelium in conglomerates called keratic precipitates (KPs). The appearance of KPs has been used to classify the inflammatory process as granulomatous or nongranulomatous. The more common nongranulomatous type of KP is characterized by fine white collections of lymphocytes, plasma cells, and pigment. These precipitates can form in any disease and cause an anterior uveitis; the finding of nongranulomatous KPs does not help tremendously in the formulation of a differential diagnosis other than to alert the clinician that anterior inflammatory disease has occurred in the eye. Granulomatous KPs are large, greasy-appearing collections of lymphocytes, plasma cells, and giant cells (see Fig. 4-2). The finding of granulomatous KPs, also called ‘mutton-fat’ KPs, on slit-lamp examination can be a useful diagnostic clue. Patients with granulomatous KPs usually have a history of a chronic disease with an insidious onset, and frequently have posterior segment disease in addition to their anterior segment inflammation. Other ocular findings suggestive of granulomatous inflammation are iris nodules and choroidal granulomas. Importantly, the finding of granulomatous inflammation in the eye suggests a unique set of diagnostic possibilities that are listed in Box 4-3.

3.  Is the disease unilateral or bilateral?

Although one eye may be affected first, uveitis resulting from most causes involves both eyes within the first several

Box 4-3  Causes of granulomatous inflammation in

the eye

Sarcoidosis

Sympathetic ophthalmia

Uveitis associated with multiple sclerosis

Lens-induced uveitis

Intraocular foreign body

Vogt–Koyanagi–Harada syndrome

Syphilis

Tuberculosis

Other infectious agents

Box 4-4  Causes of unilateral uveitis

Sarcoidosis

Postsurgical uveitis

Intraocular foreign body

Parasitic disease

Acute retinal necrosis

Behçet’s disease

months. Therefore, the history that the disease is both chronic and unilateral can help in diagnosing the condition. Diseases that frequently involve a single eye, even after months or years of the disorder, are listed in Box 4-4. Parasitic disease typically involves one eye, although some of the diseases, such as toxoplasmosis, occur bilaterally. Uveitis after ocular surgery or the presence of an intraocular foreign body is almost exclusively unilateral. The one disease that most ophthalmologists think of as a bilateral disease but which we see involving a single eye in a number of patients is sarcoidosis. Similarly, we have seen a number of patients with Behçet’s disease that involved a single eye, especially those of Asian descent.

4.  Where is the inflammation located in the eye?

It is important to determine the anatomic position of the inflammation within the eye. Table 4-1 delineates three similar methods for the anatomic classification of intraocular inflammatory disease. We based our anatomic classification on the scheme proposed by the International Uveitis Study Group.4 This was modified by the SUN Working Group by dividing the anatomic nomenclature into anterior, intermediate, posterior, and panuveitis and functions to both simplify and standardize the way the disease is described.4 In addition to classifying uveitis as anterior, intermediate, or posterior uveitis or panuveitis, we note whether there is a predominant involvement of the cornea (keratouveitis), sclera (sclerouveitis), or retinal vasculature (retinal vasculitis) because these findings point to specific causes.

Anterior uveitis describes a disease limited predominantly to the anterior segment of the eye. Other terms used in the literature for anterior uveitis are iritis, iridocyclitis, and anterior cyclitis. The inflammation is characterized by conjunctival hyperemia, anterior chamber cell and flare, KPs, and

Classifying uveitis

Box 4-5  Causes of anterior uveitis

Idiopathic

Ankylosing spondylitis

Reiter’s syndrome

Inflammatory bowel disease

Psoriatic arthritis

Behçet’s disease

HLA-B27-associated disease

Juvenile rheumatoid arthritis

Fuchs’ heterochromic iridocyclitis

Sarcoidosis

Syphilis

Glaucomatocyclitic crisis

Masquerade syndromes

Table 4-1  Anatomic classification of uveitis

*From Bloch-Michel E, Nussenblatt RB. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease. Am J Ophthalmol 1987; 103: 234–5.

†From Tessler HH. Classification and symptoms and signs of uveitis. In: Duane TD, Jaeger EA, eds. Clinical ophthalmology, vol 4. Philadelphia: JB Lippincott, 1987; 1–10.

iris abnormalities, including posterior synechiae and peripheral anterior synechiae. A mild cellular inflammatory response in the anterior vitreous is often seen. The common causes of anterior uveitis are listed in Box 4-5.

Intermediate uveitis is the anatomic diagnosis that causes the most confusion among ophthalmologists. However, the proper classification of a uveitis as intermediate is very important because an underlying cause for the disease can often be determined. Intermediate uveitis is characterized

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Box 4-6  Causes of intermediate uveitis

Sarcoidosis

Inflammatory bowel disease

Multiple sclerosis

Lyme disease

Pars planitis*

Box 4-8  Causes of panuveitis

Syphilis Sarcoidosis

Vogt–Koyanagi–Harada syndrome Infectious endophthalmitis Behçet’s disease

*Not an etiologic diagnosis, but patients with intermediate uveitis of the par planitis subtype tend to have a worse prognosis.

Box 4-7  Causes of posterior uveitis

FOCAL RETINITIS

Toxoplasmosis

Onchocerciasis

Cysticercosis

Masquerade syndromes

MULTIFOCAL RETINITIS

Syphilis

Herpes simplex virus

Cytomegalovirus

Sarcoidosis

Masquerade syndromes

Candidiasis

Meningococcus

FOCAL CHOROIDITIS

Toxocariasis

Tuberculosis

Nocardiosis

Masquerade syndromes

MULTIFOCAL CHOROIDITIS

Histoplasmosis

Sympathetic ophthalmia

Vogt–Koyanagi–Harada syndrome

Sarcoidosis

Serpiginous choroidopathy

Birdshot choroidopathy

Masquerade syndromes (metastatic tumor)

by inflammation that primarily affects the vitreous and peripheral retina. Aggregates of inflammatory cells are frequently seen in the inferior vitreous and have been termed vitreous snowballs. Similarly, the accumulation of inflammatory cells and debris along the pars plana and ora serrata have been called snowbanks. A mild anterior uveitis often coexists, and cystoid macular edema is a frequent finding. The conditions associated with intermediate uveitis are listed in Box 4-6.

Disease limited to the posterior segment of the eye, particularly to the retina and choroid, is termed posterior uveitis. A large number of diseases cause posterior uveitis, so to further subdivide the disorders we classify posterior uveitis as predominantly a retinitis or choroiditis and as a focal or multifocal disease. The disorders that cause focal and multifocal retinitis and choroiditis are listed in Box 4-7. The term panuveitis is reserved for diseases that involve all segments of the eye, typically with a severe sight-reducing inflammatory response. The common causes of panuveitis are listed in Box 4-8.

Severe scleritis in association with uveitis is most frequently seen in patients with underlying connective tissue diseases such as rheumatoid arthritis and ankylosing spondylitis. Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, also cause sclerouveitis. Finally, severe retinal vasculitis is associated with a subset of diseases that cause uveitis. Like scleritis, retinal vasculitis is often associated with underlying connective tissue disease. A full list of the disorders that cause retinal vasculitis can be found in Chapter 27.

5.  What are the demographics of the patient?

Demographic information can lead the ophthalmologist to suspect certain types of uveitis, although there are always patients whose presentation varies from the usual age, gender, race, ethnic heritage, or social parameters characteristic of any particular disease. The age of the patient can be particularly useful in developing a differential diagnosis because certain causes of uveitis are more common among patients of specific age groups. A list of the diseases that occur more frequently in certain age groups is found in Table 4-2. One must be careful, however, not to rigidly apply these guidelines to patients. For example, although intraocular lymphoma is typically found in patients older than 65 years, we have seen patients with this disease in their 30s. Nevertheless, these guidelines are clearly useful, especially in diagnosing uveitis in children. Other demographic considerations in patients with uveitis are listed in Table 4-3.

6.  What associated symptoms does the patient have?

As stated in Chapter 3, a thorough medical history is often the key to accurate diagnosis. Specific symptoms, both those relating to the eye and those suggesting systemic disease, should lead the clinician to suspect certain types of uveitis. We find that carefully defining a patient’s symptoms is the most important step in determining the correct diagnosis. Many of the symptoms that suggest specific diagnoses are listed in Table 4-4. However, the enthusiasm to classify the patient within a diagnostic category may tempt the clinician to stretch the symptoms to fit a particular disease. For example, a patient who noted mild knee pain after playing basketball for the first time in 2 years should not be classified as having a chronic arthritis consistent with rheumatoid arthritis. Similarly, ringing in the ears after a 4-hour rock concert does not qualify as tinnitus suggestive of Vogt– Koyanagi–Harada syndrome. Importantly, the clinician must be careful not to suggest symptoms to the patient. Avoid asking questions such as ‘You must have had some joint pain with this, haven’t you?’ Although it is important

Table 4-2  Age considerations in patients with uveitis*

*Parentheses indicate noninflammatory diseases.

to interview patients about their medical history, the use of a standardized questionnaire helps ensure that symptoms are not missed or inappropriately suggested.

7.  What associated signs are present on physical examination?

If it is rare to find ophthalmologists taking a detailed medical history in the office, it is almost unheard of for a detailed physical examination to be performed in the office. Unless you are prepared to do a thorough physical examination, it is probably more practical to refer patients to their primary care physician for this part of the evaluation. Nevertheless, it is fruitful for the ophthalmologist to examine a few things before making the referral. We have found that examination

*Not in Americans of Japanese extraction.

of the skin can be extremely rewarding in diagnosing uveitis. We have discovered sarcoid granulomas, rashes consistent with Lyme disease and syphilis, and Kaposi’s sarcoma. A brief examination of the joints for signs of inflammation is also useful, and a screening neurologic examination is warranted, especially in patients who may have intraocular lymphoma, sarcoidosis, or Behçet’s disease. Table 4-4 lists the systemic signs associated with specific uveitic conditions.

8.  What is the time course of the disease and response to previous therapy?

The time course of the disease and the response to therapy can provide useful information in determining the cause. Is the disease responsive to antiinflammatory therapy? Does it require continued corticosteroid therapy? If so, how much corticosteroid is needed? Is the disease resistant to corticosteroid therapy? These questions can help the clinician determine the correct diagnosis. In general, infectious diseases may initially improve with antiinflammatory therapy but later worsen. Postoperative endophthalmitis caused by Propionibacterium acnes typically improves temporarily with topical or systemic corticosteroid therapy but then recurs. A temporary and partial response to therapy also suggests that the ocular inflammation may be associated with a chronic systemic disease such as sarcoidosis or a malignancy-like lymphoma. A long history of intermittent response to therapy tends to be more suggestive of a chronic noninfectious and nonmalignant disease, because both infection or malignancy often become evident after several years.

The old adage, ‘When you hear hoofbeats, think of horses and not zebras,’ also applies to the evaluation of the patient with uveitis. Common diseases are frequently the cause of uveitis even in cases that are difficult to diagnose. Table 4-5 lists the most common causes of anterior and posterior uveitis from two published surveys of patients with uveitis.

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