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Whipple's Disease                                                                        SX  |  DX  |  RX  

Whipple's disease is a rare disorder characterized by the infiltration of the lamina propria of the small intestine by glycoprotein-laden macrophages filled with bacilliform bodies. It was caused by a gram-positive actinomycete, the bacterium Tropheryma whippelii. Although many organs can be affected, the small intestine is the primary site involved. The mortality may approach 100% without treatment.  The HLA-B27 gene is more common in Whipple's disease patients.  Classically, the disease begins in a middle-aged male with a nondeforming arthritis that usually starts years before the onset of the intestinal symptoms.   

SX:
Most commonly diarrhea and malabsorption (steatorrhea); but other symptoms include fever, abdominal distention, weakness, fatigue, and weight loss. Various extraintestinal manifestations include arthritis and arthralgia, lymphadenopathy, pleuritis, bronchiectasis, fever, skin hyperpigmentation, and neurologic abnormalities (personality changes and dementia).

The arthritis of Whipple's disease mimics that of rheumatic fever in some respects. It is painful, and there is often warmth, redness, and swelling; it favors large joints, and subcutaneous nodules have been noted in a few patients. Recurrences are common, and the disease can be migratory.  Less often, small joints of the hands and feet are inflamed, and the arthritis becomes chronic and resembles rheumatoid arthritis. The synovial fluid white blood cell count is sometimes elevated to 50,000/mm3 , and rod-shaped bacilli (Tropheryma whippelii) have been identified, usually by electron microscopy, in synovial biopsy specimens.

The cardiac involvement of Whipple's disease includes the endocardium, myocardium, pericardium, and even the coronary arteries, it is not surprising that these patients occasionally have congestive heart failure and symptomatic pericarditis. Valvular lesions, especially of the mitral and aortic valves, may be sufficiently severe to cause hemodynamically significant stenosis or insufficiency. However, many patients with involvement of the heart have no cardiac symptoms.

A broad range of CNS symptoms of Whipple's disease has been reported because virtually all portions of the brain or spinal cord may be involved. Symptoms may include dementia with disorientation and loss of memory, headache, lethargy progressing to coma, convulsions, muscle weakness, sensory deficits, incoordination, polydipsia, Parkinsonism, and various cranial nerve symptoms such as deafness, tinnitus, dysarthria, facial numbness, diplopia, and diminished visual acuity. Dementia, ophthalmoplegia, and myoclonus compose a commonly described triad.

Occasionally, intestinal symptoms may be absent, even in some patients with CNS involvement.

DX:

• Steatorrhea and decreased D-xylose absorption occur in most patients. Vitamin B12 malabsorption is unusual.
• Small bowel roentgenogram - showing irregular thickening of the mucosal folds, particularly in the duodenum and jejunum.
• Identification of the organism is made by genetic analysis (polymerase chain reaction) of biopsy tissue; the organism is resistant to culture.
• Small intestinal biopsy, which reveals blunted swollen villi containing the classic periodic-acid-Schiff-positive (PAS-positive) macrophages in the lamina propria. Although this appearance was once thought to be pathognomonic of Whipple's disease, a very similar appearance is seen in some patients with AIDS enteropathy who have intestinal infection with Mycobacterium avium complex disease.  A stain for acid-fast bacilli should differentiate between them.
• Occasionally, a brain biopsy is required, which can be guided by magnetic resonance imaging. Cardiac and pulmonary involvement may also be found.  

RX:   (If undiagnosed or untreated, the disease can be fatal.)
Effective antibiotic therapy in patients with Whipple's disease is life saving and results in prompt and dramatic clinical improvement. The fever and joint symptoms often disappear within a few days, and the diarrhea and malabsorption disappear within 2 to 4 weeks if not sooner. 

A commonly used regimen is as follows:

• intramuscular procaine penicillin, 1.2 million units per day, and streptomycin, 1 g per day for 10-14 days. This should be followed either with
• trimethoprim-sulfamethoxazole, 1 double-strength tablet, two times a day for a year (preferable), or
  tetracycline, 1 g per day for a year.

If trimethoprim/sulfamethoxazole cannot be tolerated, the use of chloramphenicol is an option, although this potentially toxic agent is not required by the majority of patients. Another alternative in the patient intolerant to trimethoprim/sulfamethoxazole is to initiate treatment with a third-generation cephalosporin such as ceftriaxone. Until controlled prospective studies are available, it is impossible to recommend dogmatically an ideal antibiotic regimen and the optimal duration of treatment.

Supportive Care Treatment:
Fluid and electrolyte replacement should be administered when needed; anemic patients should receive iron or folate as indicated; vitamin D and calcium should be given at least until steatorrhea disappears; and parenteral calcium, magnesium, or both are indicated in patients who develop tetany. Because most patients in whom the diagnosis is established are malnourished, the diet should be high in calories and protein and should be supplemented with a therapeutic formula multivitamin preparation until absorptive function has returned to normal.

Although the intestinal and systemic symptoms respond readily to either treatment, the major fear is that of CNS manifestations. Usually, in those patients who don't have CNS involvement initially, CNS symptoms appear a year or more after treatment of the systemic and intestinal symptoms. A progressive dementia may be seen, but the pathognomonic signs of CNS disease, when present, are oculomasticatory myorhythmia and oculofacial-skeletal myorhythmia.   Antibiotics that cross the blood-brain barrier are therefore required. Interestingly, the short period of penicillin-streptomycin administration is enough to block CNS symptoms, whereas even long-term trimethoprim-sulfamethoxazole therapy can occasionally result in CNS manifestations of Whipple's disease.  Tetracycline alone does not eradicate CNS disease and should not be given by itself, even though it is effective in treating the intestinal and systemic symptoms. An important feature to keep in mind is that in 50% of patients, the CSF may contain Whipple's disease macrophages or PCR-positive material even in the absence of any CNS symptoms.  Once CNS involvement occurs, treatment is usually not helpful, although with treatment, some improvement may be noted and the disease may not progress.

Prognosis:
The prognosis for this disease so treated is excellent, and most patients are cured. Occasional patients may relapse when antibiotics are discontinued, necessitating their reinstitution. Rarely, patients may have neurologic symptoms and mental deterioration years after successful treatment because of disease recurrence in the brain.

REF:
ACP Library on Disk 2- (c) 1997 - American College of Physicians     
Scientific American Medicine - March 2000      
Goldman: Cecil Textbook of Medicine, 21st Ed., 2000 
Rakel: Conn's Current Therapy 1999, 51st ed.   
Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 6th ed.1998 
Whipple's Disease -- Past, Present, and Future - NEJM-- March 2, 2000 -- Vol. 342, No. 9

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