were discovered. Whipple’s disease is quite rare, and its incidence is estimated at less than one case per million persons/year [26]. A postmortem study revealed a prevalence of 0.1%. A previous study reported 18–30 systemic cases per year/100,000 people. Most of those affected are Caucasian middle-aged men.

The classic, previously described symptoms present in approximately 85% of patients, with 15% of patients having atypical manifestations. Without treatment, Whipple’s disease is ultimately fatal. Even with antibiotic treatment, 2–33% [27] of cases relapse, usually with neurologic involvement and a poor prognosis.

Whipple’s disease is caused by infection by the gram-positive bacillus Tropheryma whipplei [28]. However, there appears to be a certain genetic susceptibility for the actual disease given the very specific type of population that is affected (middle-aged Caucasian men) and the finding of healthy subjects with T. whipplei in their saliva and stools. Data regarding the prevalence of T. whipplei in healthy subjects is controversial as the results are very variable, although the latest data seems to indicate a prevalence of T. whipplei in 0.6% of saliva samples and 1.5% in stool samples. HLA-B27 has been related to this susceptibility, but no causative relationship has been established.

Pathologic studies of Whipple’s disease patients usually show tissue with a massive infiltration by macrophages. In healthy subjects, the bacillus multiplies in macrophages but not monocytes, whereas in affected individuals, it appears to replicate in both types of cells. Additionally, it is believed that patients with Whipple’s disease may have antigen-presenting cells that do not process T. whipplei properly and therefore cannot contain it. Various interleukins and cytokines have been implicated in this abnormal reaction. An increase in interleukins 10 and 16 and a decrease in g (gamma) interferon and interleukin-12 have been associated with an abnormal performance of antigen-presenting cells [29]. Additionally, T. whipplei has been found to replicate within macrophages and monocytes that have been deactivated with interleukin-16.

Diagnosis

Up until a few years ago, the diagnosis was made with pathologic studies of biopsy samples, mainly staining with periodic acid-Schiff (PAS). The diagnosis is made by demonstrating intracellular PAS-positive rod-shaped bacillary bodies within macrophages. At least five different samples are needed from different parts of the duodenum. PAS staining can also be performed in any of the suspected tissues (synovial fluid or tissue, cerebrospinal fluid, hepatic biopsy, aqueous humor). Polymerase chain reaction (PCR) is beginning to be used more frequently for the diagnosis and especially for the follow-up and response to treatment. However, PCR alone does not make a definitive diagnosis due to the large number of false positives. Both PCR and PAS staining need to be positive to confirm the diagnosis.

Extraintestinal Manifestations

Central Nervous System

Neurologic manifestations are found in 6–63% of patients [30]. They are very diverse, although most (71%) present with some kind of cognitive change. Patients can also present with depression and personality changes. Neuro-ophthalmologic findings such as supranuclear ophthalmoplegia are frequently seen, as well as ptosis, nystagmus, and other alteration of the extraocular muscles. Patients also present with generalized motility alterations, such as myoclonus. Hypothalamic dysfunction has also been described. The prognosis is poor with a mortality rate of 25% in 4 years.

Others

Joint involvement is seen in 65–90% of cases. It usually manifests as intermittent polyarthralgia and/or polyarthritis.

Cardiac involvement, most frequently pericarditis, is seen in over 50% of patients. Importantly, T. whipplei has been associated with blood culture–negative endocarditis, a difficult diagnosis to make.

Pulmonary involvement occurs in an estimated 30–40% of patients, manifested as pleural effusion,

Fig. 16.3 Patient with Whipple’s disease. Photograph shows multiple faint, white choroidal lesions (Courtesy of Lawrence A. Yanuzzi, M.D.)

Fig. 16.5 Patient with Whipple’s disease. Cotton-wool spot in superior macula (Reprinted with permission from Chan RY, Yannuzzi LA, Foster CS. Ocular Whipple’s disease: earlier definitive diagnosis. Ophthalmology. 2001;108:2225–2231)

Fig. 16.4 Patient with Whipple’s disease. Photograph shows multiple faint, white choroidal lesions (Reprinted with permission from Chan RY, Yannuzzi LA, Foster CS. Ocular Whipple’s disease: earlier definitive diagnosis. Ophthalmology. 2001;108:2225–2231)

pulmonary infiltration, or granulomatous mediastinal adenopathies [26]. Occasionally, it presents with cutaneous and renal manifestations, among others.

Ocular Manifestations of Whipple’s

Disease

The first case of ocular compromise in Whipple’s disease was published in 1949 by Jones and

Paulley. Ocular involvement usually occurs late in the disease in patients with both gastrointestinal and neurologic symptoms. It presents in approximately 10% of patients with classic Whipple’s disease [31, 32]. Patients complain of blurred vision or visual loss. The ophthalmologic exam may reveal any of the following: keratitis, uveitis, vitritis, retinal hemorrhages, retinitis (Fig. 16.3), choroiditis (Fig. 16.4), and even optic atrophy.

Anterior or posterior uveitis is the most frequent finding and is usually bilateral and chronic in nature [31, 32]. Retinal involvement can also include retinitis, exudates, retinal capillary occlusion (Fig. 16.5), and choroidal folds [33].

Vitreous or aqueous humor samples may make the definitive diagnosis in patients with few systemic manifestations [34].

Treatment

Death was certain from Whipple’s disease before the use of antibiotics. Tetracycline was the mainstay of therapy initially, but a high recurrence rate has been documented (28%), especially since it does not penetrate the blood-brain barrier.

Historically, the most frequently used treatment was oral administration of 160 mg of trimethoprim and 800 mg of sulfamethoxazole