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Development of a Differential Diagnosis
Key Concepts
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Diagnosis of uveitis is often challenging, and developing an erudite differential diagnosis is the key to success.
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Classification of uveitis is the first step and is guided by a series of questions that can be answered from both the medical history and clinical examination.
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Classification of uveitis and development of a list of potential diagnoses will help determine appropriate diagnostic testing, guide therapy, and help determine prognosis.
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Diagnostic tests should not be used to develop a differential diagnosis but instead to investigate diseases on the list.
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Associated symptoms and signs are important sources of information and require a systemic review of symptoms and a detailed physical examination. Examination of the skin can be extremely rewarding in diagnosing uveitis. Referral to an internist, primary care physician, rheumatologist, or other specialist is often required in the workup of uveitis.
Accurate diagnosis of uveitis is often challenging, not only for the general ophthalmologist but also for the uveitis specialist. Patients present with a plethora of ocular findings and associated systemic symptoms and signs. Ocular inflammation may be the initial presentation of an underlying systemic disease that, if undiagnosed and untreated, may lead to significant morbidity and even death. For example, we have seen a number of patients with intraocular lymphoma, which had been misdiagnosed and inappropriately treated as idiopathic uveitis. Even in patients with uveitis without an underlying systemic disease, misdiagnosis can lead to inappropriate therapy. A patient with fungal endophthalmitis who is thought to have sarcoidosis may be treated with corticosteroids, leading to exacerbation of the infection, when appropriate antifungal therapy could have been curative. In this chapter, we review our diagnostic approach to patients with uveitis and present two cases to illustrate our approach.
Diagnosis is based largely on recognition of patterns that include findings from the medical history, clinical examination, and ordered tests, including laboratory tests and medical imaging. Medical experts are much better at recognizing the patterns consistent with medical diagnoses than are novices. Studies on memory suggest that this pattern recognition can be learned and takes practice. It should therefore not be surprising that doctors with many years of clinical practice are often better diagnosticians compared with less experienced care providers.
Much of what we know about memory and pattern recognition comes from the study of chess. In the 1960s, de Groot , performed an intriguing study comparing the ability to recall chess patterns among players of varying abilities. A chessboard position, taken from a master game unknown to the subjects, was presented to participants for a short period varying from 2 to 15 seconds. Participants then had to reconstruct the board on the basis of their memory. The findings were dramatic. Grandmasters remembered board positions accurately, recalling an average of 93% of the pieces correctly after seeing the chess layout for only 2 to 5 seconds. The least experienced players only recalled about 50% of the pieces correctly. de Groot hypothesized that chess masters encode the positions of the pieces not as individuals but as groups. The data also suggest that the ability to recognize these patterns improves with experience and can be learned with appropriate teaching and a great deal of practice.
The goal of this chapter is to provide the framework for clinicians to start collecting the information needed to form patterns of diseases that aid in diagnosis. Knowing what questions to ask, what findings to look for, and what tests to order are all critical in seeing clear patterns from background noise. Every patient seen should help fine-tune the pattern recognition skills and allow clinicians to better diagnose diseases. First, the clinician needs to collect the pieces of the puzzle to create the disease pattern. Second, the clinician needs to start putting the pieces together in ways that form several disease patterns. This is known as forming a differential diagnosis: identifying pieces of a puzzle that, when assembled, can form a handful of disease pictures. Finally, a specific diagnosis is made, often by ordering a key test that rules out all but one disease pattern. Recognizing potential disease patterns and forming a good differential diagnosis is the key to success in achieving the final diagnosis.
Forming A Differential Diagnosis
The first step in developing a differential diagnosis for patients with inflammatory eye disease is to classify uveitis in as detailed a fashion as possible. This can be achieved by systematically asking the eight questions listed in Box 4.1 . Then a list of possible diagnoses can be generated by combining the data obtained from the answers. Some of the information, such as the age and demographics of the patient and associated systemic symptoms, is obtained from the history. 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 careful physical and neurologic examinations of the patient by the ophthalmologist or by a consulting internist, internal medicine subspecialist, neurologist, or general medical practitioner.
BOX 4.1
Classification of Uveitis
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Is the disease acute or chronic?
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Is the inflammation granulomatous or nongranulomatous?
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Is the disease unilateral or bilateral?
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Where is the inflammation located in the eye?
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What are the demographics of the patient?
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What associated symptoms does the patient have?
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What associated signs are present on physical examination?
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What is the time course of the disease and response to previous therapy?
Once 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. One of the diagnoses that appear most frequently on these lists is then the most likely cause of the disorder. Of course, the lists provided here include many of the most common disorders, but the lists are not exhaustive. They do, however, illustrate the deductive diagnostic process. Once the initial lists of diagnoses are generated, ancillary examinations, including laboratory tests; specialized examinations (e.g., radiography electrophysiology); or a surgical procedure (e.g., 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
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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 human leukocyte antigen (HLA)-B27–associated iritis and idiopathic anterior uveitis, fall into this category. Other diseases that typically cause acute uveitis include Vogt-Koyanagi-Harada (VKH) syndrome; postoperative bacterial infection; toxoplasmosis; many of the “white-dot syndromes,” such as acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and multiple evanescent white-dot syndrome (MEWDS); and traumatic iritis. Although many diseases can cause acute uveitis, the above-mentioned conditions should be considered first in the differential diagnosis. Chronic forms of uveitis have an insidious onset and typically last longer than 6 weeks. Other authors have defined a limited duration of uveitis as 3 months or less and persistent disease as lasting longer than 3 months. Again, many diseases can cause uveitis that persists longer than 6 weeks; the uveitides that are characteristically chronic are listed in Box 4.2 . Knowing whether a particular case of 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
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Most cases of anterior uveitis: idiopathic, ankylosing spondylitis, Reiter syndrome, Fuchs heterochromic iridocyclitis
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Vogt-Koyanagi-Harada syndrome
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Toxoplasmosis
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White-dot syndromes: acute posterior multifocal placoid pigment epitheliopathy and multiple evanescent white-dot syndrome
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Acute retinal necrosis
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Postsurgical bacterial infection
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Trauma
Chronic Uveitis
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Juvenile rheumatoid arthritis
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Birdshot choroidopathy
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Serpiginous choroidopathy
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Tuberculous uveitis
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Postoperative uveitis ( Propionibacterium acnes, fungal)
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Intraocular lymphoma
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Sympathetic ophthalmia
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Multifocal choroiditis
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Sarcoidosis
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Intermediate uveitis/pars planitis
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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 having to take 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 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 later in the chapter). 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 of 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, which are listed in Box 4.3 .
BOX 4.3
Causes of Granulomatous Inflammation in the Eye
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Sarcoidosis
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Sympathetic ophthalmia
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Uveitis associated with multiple sclerosis
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Lens-induced uveitis
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Intraocular foreign body
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Vogt-Koyanagi-Harada syndrome
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Syphilis
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Tuberculosis
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Other infectious agents
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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 months. Therefore the history of the disease being 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 is seen involving a single eye in a number of patients, is sarcoidosis. Similarly, a number of patients, especially those of Asian descent, have Behçet disease involving a single eye.
BOX 4.4
Causes of Unilateral Uveitis
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Sarcoidosis
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Postsurgical uveitis
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Intraocular foreign body
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Parasitic disease
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Acute retinal necrosis
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Behçet disease
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