Whipple Disease
Clinical Manifestations
Intestines and Lymphatic System
Central Nervous System
Cardiovascular System
Musculoskeletal System
Other Manifestations
Whipples disease is a systemic disorder, and almost any organ or organ system can be affected.Manifestations in the intestinal tract are most commonly reported; they are largely responsible for the classic clinical features of Whipples disease. In many cases, arthralgias precede intestinal symptoms by several years (1 to 10 years; up to 30 years reported), and in some cases, low-grade intermittent fever also occurs for years before the diagnosis is made. More recent reports provide a wider spectrum of manifestations, especially those that are extraintestinal. This probably reflects advances in diagnostic procedures. As a result, patients tend to be diagnosed with less advanced disease.
Intestines and Lymphatic System
Bacterial and macrophage-predominant inflammatory cell infiltration of the small intestinal mucosa and obstruction of mesenteric lymph nodes lead to a malabsorption syndrome with weight loss, diarrhea, and abdominal pain as the dominant signs and symptoms.Weight loss occurs gradually, usually over a period of at least 1 year and in amounts of 5 to 15 kg, sometimes leading to severe cachexia in the terminal stage of untreated disease.Diarrhea may consist of voluminous steatorrheic stools or may be watery. Occult gastrointestinal bleeding is common, and in some cases gross gastrointestinal bleeding occurs.
Abdominal (mesenteric and retroperitoneal) and peripheral lymphadenopathy are common, and in some instances enlarged abdominal lymph nodes raised the suspicion of malignancy. In rare instances, malignant lymphomas have occurred in patients with Whipples disease.
Radiographic examination of the intestinal tract with barium contrast may reveal nonspecific abnormalities that are also found in other malabsorption syndromes,such as prominent and edematous duodenal and jejunal folds and dilatation . Computed tomography or magnetic resonance imaging may detect retroperitoneal or paraaortic lymphadenopathy.Enlarged abdominal lymph nodes have a hypodense appearance on CTs and are hyperechoic on ultrasonograms.
Abdominal (mesenteric and retroperitoneal) and peripheral lymphadenopathy are common, and in some instances enlarged abdominal lymph nodes raised the suspicion of malignancy. In rare instances, malignant lymphomas have occurred in patients with Whipples disease.
Radiographic examination of the intestinal tract with barium contrast may reveal nonspecific abnormalities that are also found in other malabsorption syndromes,such as prominent and edematous duodenal and jejunal folds and dilatation . Computed tomography or magnetic resonance imaging may detect retroperitoneal or paraaortic lymphadenopathy.Enlarged abdominal lymph nodes have a hypodense appearance on CTs and are hyperechoic on ultrasonograms.
Central Nervous System
Symptomatic CNS manifestations have been reported in 10% to 43% of patients with intestinal Whipples disease. Neurologic disease can occur concurrently with intestinal manifestations at the time of diagnosis, but it is more frequent at the time of clinical relapse during or after treatment. Relapses affecting the CNS are ominous, because they can be refractory to renewed antibiotic treatment.Although rare, several cases of neurologic Whipples disease have been reported in patients without intestinal manifestations.
According to a meta-analysis of 84 published cases, common neurologic findings are progessive dementia and cognitive changes (71%), supranuclear opthalmoplegia (51%), and altered level of consciousness (50%). Other less frequent signs are psychiatric symptoms, hypothalamic manifestations (e.g., polydipsia, hyperphagia, insomnia, cranial nerve abnomalities, nystagmus, seizures, and ataxia. Two signs are considered to be characteristic of CNS Whipples disease: oculomasticatory myorhythmia and oculofacial skeletal myorhythmia. These have not yet been documented in other CNS diseases.Both consist of slow rhythmic and synchronized contractions (1/sec) of ocular, facial, or other muscles. However, both occur in less than 20% of patients with CNS Whipples disease.
Results of neuroimaging (computed tomography or magnetic resonance imaging) may be normal or may reveal mild to moderate brain atrophy or focal lesions without a predilection for specific sites. These abnormalities are not specific for Whipples disease, but focal lesions may be used to guide stereotactic biopsies, which in most cases reveal characteristic histology.[65] Results of standard CSF examinations are most often normal, although sometimes there is mild pleocytosis.CSF cytology reveals PAS-positive sickleform particle-containing cells, and PCR often yields positive results for T. whippelii DNA, even in a considerable proportion of neurologically asymptomatic patients.
According to a meta-analysis of 84 published cases, common neurologic findings are progessive dementia and cognitive changes (71%), supranuclear opthalmoplegia (51%), and altered level of consciousness (50%). Other less frequent signs are psychiatric symptoms, hypothalamic manifestations (e.g., polydipsia, hyperphagia, insomnia, cranial nerve abnomalities, nystagmus, seizures, and ataxia. Two signs are considered to be characteristic of CNS Whipples disease: oculomasticatory myorhythmia and oculofacial skeletal myorhythmia. These have not yet been documented in other CNS diseases.Both consist of slow rhythmic and synchronized contractions (1/sec) of ocular, facial, or other muscles. However, both occur in less than 20% of patients with CNS Whipples disease.
Results of neuroimaging (computed tomography or magnetic resonance imaging) may be normal or may reveal mild to moderate brain atrophy or focal lesions without a predilection for specific sites. These abnormalities are not specific for Whipples disease, but focal lesions may be used to guide stereotactic biopsies, which in most cases reveal characteristic histology.[65] Results of standard CSF examinations are most often normal, although sometimes there is mild pleocytosis.CSF cytology reveals PAS-positive sickleform particle-containing cells, and PCR often yields positive results for T. whippelii DNA, even in a considerable proportion of neurologically asymptomatic patients.
Cardiovascular System
Cardiac manifestations of Whipples disease comprise endocarditis, myocarditis, and pericarditis.In one autopsy series from the preantibiotic era,valvular endocarditis with vegetations was noted in 58% of cases. In contrast, in a more recent series,clinically apparent endocarditis was less frequent (3 of 52 patients). All valves may be affected, with the mitral valve most frequently altered pathologically and the aortic valve leading to the most significant symptoms.Some patients require valve replacement. PAS-positive macrophages and bacteria have been documented on valve tissue by histology and electron microscopy, respectively,including on a porcine prosthetic valve and in the myocardium.Recent reports of patients with T. whippelii endocarditis have described a syndrome of blood culture-negative endocarditis with only minor or no apparent intestinal Whipples disease.
Musculoskeletal System
Oligo- or polyarthralgias, usually involving the ankles, knees, elbows, or fingers, are a common complaint of patients with Whipples disease.Rheumatoid factor is usually absent. Destructive joint changes or synovial fluid accumulation are rare, but, if present, PAS-positive macrophages (by histology), bacteria (by electron microscopy), or DNA of T. whippelii (by PCR) can be found in synovial tissue or joint fluid.Sacroiliitis and spondylitis may occur, but ankylosing forms are rare and there does not seem to be a strong association of these manifestations with HLA-B27. [8] Rare manifestations are infectious spondylodiscitis and prosthetic joint infection.
Other Manifestations
One common feature of Whipples disease is skin hyperpigmentation, which has been found in 17% to 66% of patients in different series. This finding tends to occur in light-exposed areas of the skin and is unrelated to adrenal dysfunction or hyperbilirubinemia. Histopathologic changes in the skin are, however, extremely rare.
Diverse ocular manifestations of Whipples disease have been described but are rare. These include uveitis, vitritis, retinitis, retrobulbar neuritis, and papilledema. They are usually associated with CNS disease, and almost all reported patients had clinical or histologic evidence of intestinal involvement. PAS-positive macrophages or DNA of T. whippelii may be detected in vitrectomy specimens. A case of uveitis has been reported in which the vitreous fluid and one intestinal biopsy specimen yielded positive PCR results, although intestinal histology was normal.
Chronic cough was a symptom in Whipples original patient and was reported relatively frequently in earlier seriesbut has been reported less frequently since then.Some patients have pleuritis with effusion or granulomatous pulmonary disease resembling sarcoidosis.
Diverse ocular manifestations of Whipples disease have been described but are rare. These include uveitis, vitritis, retinitis, retrobulbar neuritis, and papilledema. They are usually associated with CNS disease, and almost all reported patients had clinical or histologic evidence of intestinal involvement. PAS-positive macrophages or DNA of T. whippelii may be detected in vitrectomy specimens. A case of uveitis has been reported in which the vitreous fluid and one intestinal biopsy specimen yielded positive PCR results, although intestinal histology was normal.
Chronic cough was a symptom in Whipples original patient and was reported relatively frequently in earlier seriesbut has been reported less frequently since then.Some patients have pleuritis with effusion or granulomatous pulmonary disease resembling sarcoidosis.
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