eMedicine Specialties > Neurology > Neurological Infections

Whipple Disease

Author: George C Bobustuc, MD, Neuro-Oncology, MD Anderson Cancer Center Orlando
Contributor Information and Disclosures

Updated: Apr 11, 2006

Introduction

Background

Whipple disease (WD) constitutes a rare, relapsing, slowly progressive, infectious, systemic illness characterized by fever of unknown origin, polyarthralgias, and chronic diarrhea.

Other manifestations include skin and ocular involvement (ie, uveitis, retinitis, optic neuritis); generalized lymphadenopathy; afebrile, blood culture-negative endocarditis which, reportedly, can be complicated with cardioembolic strokes; and a sarcoidosis-like syndrome with mediastinal lymph nodes and central nervous system (CNS) involvement (ie, dementia, sensory and motor deficits, ophthalmoplegia, myoclonus, stroke and hypothalamic damage with dysautonomia, emotional impairment, endocrinopathy).

Less than 1000 cases have been reported, and less than one half (6-43%) of these patients presented with neurological manifestations. This likely represents an underestimate due to both a low index of suspicion in some cases and difficulties in reaching a diagnosis in others.

This article, besides being a general presentation of WD, focuses on both the neurological manifestations and specifics of diagnosis and treatment of WD with symptomatic CNS involvement (CNS-WD).

Despite the slowly progressive course of most cases of WD, CNS-WD may have a fulminant course, and manifest isolated CNS-WD cases have been reported in the literature. Prompt diagnosis is imperative, as very effective therapies are easy to employ with typically rapid limitation of CNS progression and even partial reversal of CNS symptoms. If left untreated, progression to death may come as quickly as 1 month after CNS involvement begins.

Pathophysiology

Historical perspective

1907: Whipple proposed the name of "intestinal lipodystrophy" for a new, distinctive clinical syndrome. Whipple's case report presented a 36-year-old medical missionary with a 5-year history of episodes of relapsing-progressive polyarthritis subsequently complicated by weight loss, cough, fever, diarrhea, hypotension, abdominal swelling, increased skin pigmentation, and severe anemia. The hallmark of the pathologic report was the marked infiltration by foamy macrophages of joints and aortic valves, and prominent deposits of fat within intestinal mucosa and mesenteric lymph nodes, which made Whipple consider this case an obscure disease of fat metabolism and propose the name intestinal lipodystrophy. Whipple pointed out the existence of great numbers of peculiar rod-shaped bacteria found in extracts of lymph node tissue and lamina propria of the intestine.

1923: A second case of Whipple disease was reported in the literature.

1947: Peroral small bowel biopsy was used for the first time to make the first reported premortem diagnosis.

1949: Black-Schaffer advanced the diagnosis, proved the systemic nature of this disease, and raised the suspicion of an infectious cause for WD.

• He identified periodic acid-Schiff (PAS)–staining granules, most likely representing degenerating bacterial forms, within macrophages isolated from the small bowel as well as other tissue and fluid specimens (eg, pericardium, endocardium, lymph nodes, synovia, lung, brain, meninges) obtained from patients in whom WD was suspected.
• The presence of PAS-positive granules containing macrophages is not pathognomonic. Intestinal lamina propria of AIDS patients with concomitant Mycobacterium avium-intracellulare complex (MAC) infection may be packed with PAS-positive granules containing macrophages, but the intracellular bacilli are acid fast. Concomitant WD and MAC have been reported.

1952: Paulley was first to report a case of a patient with histologically proven WD whose symptoms responded to chloramphenicol. Other reports followed of successful attempts to treat patients with prolonged courses of antibiotics (12 mo or longer), particularly a combination of penicillin and streptomycin followed by trimethoprim-sulfamethoxazole (TMP-SMX).

1961: Electron microscopy (EM) studies by Yardley et al provided more evidence for an infectious cause of WD by finding bacillary bodies within membrane-bound vesicles in the cytoplasm of macrophages. WD bacillus has a characteristic trilamellar appearance on EM.

1985: A survey by Keinath et al of 88 patients with WD whose symptoms responded to antibiotics revealed a high rate of relapse (40%, 31/88); many of the relapses were in the CNS, thus indicating the need to use antibiotics with adequate blood-brain barrier (BBB) penetrance.

1991-1992: Wilson et al reported Whipple bacillus as a gram-positive bacterium rich in guanine and cytosine and likely an actinomycete. They used a gene that encodes for 16S ribosomal RNA (rRNA) in bacteria to characterize the nucleotide sequence of the bacillus from a patient with WD.

1992: Relman et al confirmed the findings of Wilson et al and proposed a classification of the organism. Tropheryma whippelii, a previously uncharacterized organism, was, on the basis of phylogenetic analysis of a specific 16S rRNA gene sequence, a novel actinomycete.

• Relman used polymerase chain reaction (PCR) to amplify this unique bacterial 1321-base sequence of the 16S rRNA gene obtained from tissues from 5 patients with WD. It could not be obtained from 10 control patients with other conditions.
• Further PCR studies have been used successfully to confirm the systemic involvement of other tissues (eg, heart, vitreous fluid, peripheral blood cells, pleural effusion cells).

1997: Ramzan et al used PCR to confirm WD in patients whose histologic studies of small intestine samples obtained by peroral biopsy were nonconfirmatory. PCR studies with 16S rDNA primers of T whippelii proved to be highly sensitive, specific, and useful for monitoring response to therapy and likelihood of relapse. Prior studies had shown no correlation between posttreatment histologic findings, clinical outcome, and likelihood of recurrence.

1997: A study by Herbay et al suggested that most, if not all, patients with WD have CNS involvement and only some develop clinical and radiologic evidence of CNS-WD; PCR analysis of cerebrospinal fluid (CSF) was proposed as routine in the diagnostic evaluation of patients in whom WD is suspected.

2000: Raoult et al successfully cultivated T whippelii using a human fibroblast cell line (HEL). They completed 7 passages of an isolate obtained from the aortic valve of a patient with endocarditis caused by WD. The following findings confirmed that the isolates passaged were T whippelii: the amplified sequences of the 16S rRNA gene of the isolate were identical to those of T whippelii; transmission EM of the isolate revealed the distinctive trilamellar appearance of WD bacillus; PAS-positive bacilli (not acid fast but gram positive) were identified in an intracellular location in the cell-culture monolayer; and mice-produced polyclonal antibodies could detect the bacterium in the patient's excised heart valve.

• Raoult et al developed an immunofluorescence serologic test with which they examined serum from a limited number of patients with WD (9 patients with WD and 40 control subjects). Both immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies against the bacillus were tested with cut-off values of 1:100 and 1:50, respectively. The sensitivity of the IgG antibody testing was high (9 of 9), but the specificity was quite low, as almost 75% of control subjects tested positive. The IgM antibody testing revealed slightly lower sensitivity (7 of 9) but proved to be more specific (only 3 of 40 control subjects tested positive). A caveat is warranted in the interpretation of these results: both IgG and IgM antibody testing results may be distorted by a sampling effect, in that a small number of samples from patients with WD and the relatively small number of control subjects with a limited variety of other infectious diseases may underrate the IgM cross-reactivity.
• The high frequency of IgG antibodies against WD isolate in samples from control subjects suggests that this pathogen is ubiquitous, causing illness only occasionally. This may be due to differences in host factors or virulence amongst strains or a result of the patient's exposure to other cross-reacting microorganisms.

2003: The genome sequencing of 2 different T whippelii strains (Twist and TW08/27) is achieved. It revealed interesting particularities, which could explain some of the clinical traits already observed. T whippelii genome encodes for around 800 protein coding genes. It lacks key biosynthetic pathways and has a reduced capacity for energy metabolism. It has a family of large surface proteins, some associated with large amounts of noncoding repetitive DNA, which appears to trigger frequent genome rearrangements, potentially resulting in the expression of different subsets of cell surface proteins. This could be the basis of a mechanism to evade host defenses.

Host abnormalities

A variety of host abnormalities has been reported in patients with WD. They point to an anomalous cytokine-driven regulation of both phagocytosis and humoral and cellular immunity and specifically suggest a defect in the axis of interleukin-12 (IL-12) and gamma interferon.

• IL-12 is a proinflammatory cytokine, rapidly produced by phagocytic cells, professional antigen-presenting cells such as dendritic cells and skin Langerhans cells, and B cells.
• IL-12 production is triggered by intracellular pathogens, bacteria, fungi, viruses or their phagocytosis-induced breakdown products.
• It is secreted in both a T-cell–dependent and –independent manner.
• IL-12 elicits gamma interferon production by activating both T and natural killer cells and resting peripheral monocytes and thus enhances completion of phagocytosis.
• IL-12 also functions as a growth factor for the activated cluster of differentiation (CD) 4 and CD8 lymphocytes and inhibits immunoglobulin E (IgE) production.
• Patients with WD have shown a decreasing number of immunoglobulin A (IgA)–containing plasmacytes in the lamina propria of the bowel during the infection as the clinical symptoms worsened; this number returns to normal with treatment and inversely correlates with the number of foamy macrophages. The foamy macrophages represent transformed monocytes already engaged in the engulfing and phagocytosis of T whippelii bacilli. The number of foamy macrophages declines with treatment.
• Accumulation of foamy macrophages in the advanced stages of WD has been supported by the decreased in vitro phagocytic ability of monocytes collected from patients with WD.
• The reduced in vitro phagocytic ability of macrophages from patients with WD has been explained on the basis of anomalous cytokine-related regulation of this function. A decrease in the IL-12 secretory ability of the monocytes and subsequently gamma interferon by T cells has been identified in vitro in patients with WD. This is supported further by a case report of a patient with WD who had developed resistance to antibiotics on recurrence and subsequently had been treated successfully with gamma interferon.
• Patients with WD have shown an increased number of lymphocytes in the lamina propria of the small intestine with a decrease in the CD4-to-CD8 ratio and a decrease in the CD11b (complement receptor 3alpha chain)–expressing subpopulation. This represents another immunological abnormality encountered in this disease, which could be explained by a defect in the axis of IL-12 and gamma interferon.
• Specific molecular defects involving the axis of IL-12 and gamma interferon have been recognized as the basis for a variety of host anomalies responsible for the increased susceptibility to chronic inflammatory conditions caused by intracellular pathogens, including nontuberculous mycobacteria, vaccine associated bacille Calmette-Guérin (BCG) infections, Salmonella species, and some virus-induced infections.
• The mutations described in these cases involved gamma interferon receptor, IL-12 receptor beta1, and IL-12 p40 genes.
• No reports have yet attempted to identify and clarify any specific genetic defect involving the proven IL-12–gamma-interferon axis functional deficit in patients with WD.

Humans remain the only known host for the disease. No evidence exists of person-to-person transmission, and no reported outbreaks have occurred. In Germany, an environmental source was suggested by findings of specific T whippelii DNA in sewage water and the saliva and jejunal juice of some healthy controls.

The initial gastrointestinal (GI) involvement argues for this site as the entry portal of T whippelii and probable dissemination through the body by the lymphatics and bloodstream either directly or via a carrier (eg, monocytes). The brain ultimately represents a favored site, but the mechanism by which the BBB is breached is unclear and insidious, supporting the theory of carrier-mediated dissemination.

Whether the clinical manifestations of WD result from direct bacterial invasion or from the ensuing inflammatory response is not clear.

At this time, the inability to grow T whippelii in cell-free, medium-only culture prevents researchers from developing better testing procedures (eg, selection of more specific antigens for development of more specific serologic tests) and treatments (antimicrobial susceptibility testing) and from answering important questions about this pathogen (eg, what is T whippelii, a commensal intestinal organism or a saprobe [ie, an organism that lives in and derives its nourishment from organic matter in stagnant or foul water]? What are the differences in pathogenicity among various strains? Is the infection acquired primarily through the GI tract?). Furthermore, the 2 remaining Koch postulates are still to be fulfilled—the development of WD in an animal model infected with WD isolate and subsequent isolation of T whippelii from the animal.

Morphology of T whippelii

T whippelii has a specific morphology. The thick wall of this 1- to 2-mm rod gives it the appearance of encapsulation, and the inner layer is PAS positive.

Stages of Whipple disease

The clinical course of untreated WD can include the following 3 stages:

• Nonspecific: This stage includes vague complaints of migratory polyarthralgias, abdominal fullness, low-grade fever, anorexia, and cough. This stage may last more than 5 years.
• Abdominal: This stage involves weight loss, weakness, chronic diarrhea, and abdominal pain. This stage may last 10-20 years.
• Generalized: This stage is characterized by steatorrhea; cachexia; lymphadenopathy; hyperpigmentation; and cardiovascular, pulmonary, neurological, and ocular dysfunction. This stage may last as long as 5 years until death if WD is not diagnosed and remains untreated.

This proposed staging had at its base a limited review of 15 patients. This review also showed that 50% of patients had symptoms for more than 5 years before presentation. Patients with WD who were left untreated had a 5-year survival rate of 80% after onset of arthralgias, but only 20% of patients survived 5 years after onset of diarrhea or abdominal pain.

Frequency

United States

Whipple disease is a rare condition. No incidence and prevalence studies have been reported.

• Several difficulties are encountered when these studies are contemplated, such as lack of a target population, low index of suspicion in the medical community, unavailability of diagnostic methods, and variations in diagnostic standards.
• No reported cluster of cases indicates a target population. No specific natural habitat of the organism is known, and the specific mechanisms by which the infection takes place are not known.

International

Several comprehensive reviews of the literature have been conducted over the years, and the number of approximate reported cases evolved as follows: 300 cases in 1983; 800 cases in 1996; and 1000 cases in 1998. This may represent an increase in the index of suspicion, availability of new diagnostic techniques, and population increase. These numbers still are believed to represent an underestimate of the disease frequency.

Mortality/Morbidity

WD left untreated is uniformly fatal.

• Fewer than 5% of patients have signs and symptoms suggesting CNS involvement at the clinical onset of the disease, but the brain reportedly represents the final target organ in most patients.
• The incidence of relapse may be quite high (approaching 40%) in patients in whom antibiotic treatment was terminated after 1 year but is not correlated with significant tissue findings on PCR studies (ie, tissue deriving from an organ accountable for clinical symptoms). Patients with negative PCR results in significant tissue at the time of completion of their antibiotic course had a very low relapse rate.
• Human leukocyte antigen (HLA) B27 was reported in some studies as being more frequent in patients with WD than in the general population.

Race

Most of the cases reported originated from Europe and North America, and some prior reports mentioned a preponderance of WD in white, middle-aged men. Still, the number of reported cases is too low to reveal any significant racial susceptibility.

Sex

The male-to-female ratio is 6-8:1.

Age

Onset is usually in middle age (30-40 y). Age range at diagnosis reported in the literature is 3 months to 81 years.

Clinical

History

WD commonly starts with GI complaints, but because of the multisystemic involvement, presentation can be quite variable. At any time in the course of the disease a constellation of symptoms relating to different organ systems may be present. The GI symptomatology is initially mild, and affected persons may go years before seeking medical attention, often for symptoms other than GI-related ones.

• Symptoms at presentation (other than CNS related) include the following:
  • Weight loss (80-100% of patients) generally ranges from 20-40 pounds over several months to years.
  • Diarrhea, watery or fatty, occurs in 75% of patients. Occult blood loss was reported with almost all patients, but clinically relevant lower GI bleed (hematochezia or melena) is distinctly unusual.
  • Arthralgia (70% of patients) typically is the most common cause of initial concern for the patient. It is migratory in nature and involves large joints in an asymmetric fashion.
  • Abdominal (nonspecific) pain (50%) is usually more severe after eating.
  • Chest (ie, pleural and/or pericardial) pain with or without nonproductive cough occurs in 50% of patients.
  • Fever occurs in 45% of patients.
  • Leg swelling (25%) typically occurs after 1-2 years of progressive arthralgias and diarrhea.
  • Glossitis occurs in 20% of patients.
  • Abdominal fullness (ie, ascites and/or splenomegaly) occurs in 20% of patients.
• Fewer than 10-15% of patients with WD eventually develop clinically significant CNS involvement. A review of patients with CNS-WD showed that by the time of CNS disease onset they often report previous systemic problems, including the following:
  • Chronic migratory arthralgias or polyarthralgias, sometimes for several years, preceding the onset of neurological symptoms (48% of patients)
  • Unexplained weight loss (46% of patients)
  • GI complaints (45% of patients), including chronic diarrhea in 39%, abdominal pain in 20%, steatorrhea in 13%, and abdominal distension in 8%
  • Fever of unknown origin (40%)
  • Malaise (29%)
  • Night sweats (4%)
  • Blurry vision (2%)
• GI complaints usually precede WD-CNS symptoms by several years. A limited group of patients has manifestations other than GI at onset, and they seem to have a higher likelihood of developing CNS involvement. CNS symptoms are more frequent at the time of relapse (60-70% of relapse patients, most of whom do not have recurrence of intestinal symptoms).
• CNS symptoms: Fewer than 100 cases of patients with confirmed CNS-WD have been reported. Most of these patients presented for a combination of neurological and psychiatric symptoms. Most commonly the symptoms included cognitive changes, movement disorders (eg, myoclonus), hypothalamus-related problems (eg, polydipsia, hyperphagia, decreased libido), and seizures.
• Altered mentation was the most frequent presenting symptom, seen in almost 75% of patients with CNS-WD.
  • Almost 50% of these patients had a concomitant psychiatric illness (eg, depression, hypomania, anxiety, psychosis; mostly with delusional content, or change in personality).
  • Two thirds of patients with altered mentation (almost 50% of all patients with CNS-WD) had dementia.
  • Other mentation problems were limited loss of memory, change in reasoning, and change in attention span.
• Hypothalamus-related problems (eg, polydipsia, hyperphagia, decreased libido, amenorrhea, change in sleep-wake cycle with insomnia, but never with isolated somnolence), though clinically significant and largely disregarded by patients, represented initial manifestations of CNS involvement in 30% of patients.
• Myoclonus, including brief, irregular, jerky movements, represented the presenting symptom in 10-15% of patients.
• Seizures (ie, simple or complex partial seizures, generalized tonic-clonic seizures, either alone or complicating partial seizures) represented the presenting symptom in about 10-15% of patients.
• A specific clinical triad noted in CNS-WD includes dementia, vertical ophthalmoplegia, and myoclonus.

Physical

Exhaustive physical examination should be performed to assess the extent of extraneuraxial involvement; systems and/or organs usually known to be affected in WD (ie, GI, cardiovascular, pulmonary, CNS, liver, skin) should be targeted.

• Signs (other than CNS) seen at presentation are as follows:
  • Hypotension (defined as systolic blood pressure <110 mm Hg and diastolic blood pressure <60 mm Hg): This is usually a very late finding and has been described in more than 70% of patients with long-standing GI complaints (usually for several years). In some patients, hypotension is part of their dysautonomia. Another dysautonomic feature described in the late stages of WD is hypothermia.
  • Peripheral lymphadenopathy (more than 50% of patients)
  • Nonspecific abdominal tenderness (50% of patients)
  • Hyperpigmentation and/or skin photosensitivity (40% of patients; does not represent adrenal failure)
  • Low-grade fever (40% of patients)
  • Cardiac murmurs (more than 30% of patients)
  • Peripheral edema (25% of patients)
  • Splenomegaly (25% of patients)
  • Glossitis (25% of patients)
  • Ill-defined abdominal mass (20% of patients)
  • Pleural and pericardial friction rubs (less than 10% of patients)
  • Ascites (very infrequently chylous): This is rare.
  • Uveitis (2% of patients)
• In patients with a high likelihood of having WD (based on historical data and general examination), the comprehensive neurologic examination should target cognition and (eye) movement abnormalities, especially signs with high pathognomonic value (eg, vertical supranuclear ophthalmoplegia [SNO] with or without oculomasticatory myorhythmia [OMM] and/or oculofacialskeletal myorhythmia [OFSM]).
• Although dementia, ophthalmoplegia, and myoclonus represent a highly specific diagnostic triad, it is encountered in only approximately 10% of patients with CNS-WD.
  • Dementia - Present in more than 50% of patients with CNS-WD
  • Psychiatric illness (ie, depression; hypomania; anxiety; psychosis, mostly with delusional content; change in personality) - Present in almost 50% of patients
  • Ophthalmoplegia - Present in 50% of patients
  • Myoclonus - Present in 20% of patients
• Eye findings in CNS-WD are as follows:
  • Supranuclear ophthalmoplegia
    • Both horizontal and vertical SNO are found in approximately two thirds of patients with SNO.
    • Pure vertical SNO is found in approximately one third of patients with SNO.
    • Pure horizontal SNO is never found in CNS-WD.
  • OMM and OSFM are synchronous movements combining pendular vergence oscillations (PVOs) with myorhythmia.
    • PVOs are characterized by 1-Hz, rhythmic, smooth, continuous, convergent eye movements (unilateral or bilateral), varying from 1-25 degrees of amplitude per eye. Return divergent movements never go beyond the primary position. The oscillations continue during sleep and may be subtle and asymmetric. Convergent and return divergent movements happen at the same speed (this does not represent nystagmus, as both phases are of the same speed) and are not accompanied by miosis or accommodation.
    • Myorhythmia represents regular, repetitive contractions (1-2 Hz) of the facial, masticatory, and pharyngeal muscles with or without limb involvement. It persists through sleep and should be distinguished from oculopalatal myoclonus, which most commonly is caused by brainstem strokes and demyelination with a similar average frequency, although it is slightly irregular.
    • PVOs are synchronous with myorhythmic movements of the masticatory muscles and in some patients may include facial and pharyngeal muscles (in the case of OMM) and more extensive myorhythmic movements involving facial and limb muscles (in the case of OFSM).
    • OMM and OFSM are very infrequent signs (<20 cases have been reported in the literature), and they have been described only in CNS-WD. In all reported cases, OMM and OFSM always have been associated with vertical SNO. Although OMM and OSFM are highly specific for CNS-WD, they have a very low sensitivity of approximately 20%.
    • OMM/OFSM together with vertical SNO are highly pathognomonic for CNS-WD and should prompt timely diagnosis and treatment.
  • Isolated ptosis is found in 23% of patients.
  • Pupillary abnormalities (usually anisocoria or unreactive pupil) are found in only 18% of patients.
• Other neurological signs are as follows:
  • Hypothalamic manifestations (in 30% of patients) included polydipsia, hyperphagia, decreased libido, amenorrhea, changes in sleep-wake cycle, and disruptive insomnia. Somnolence as an isolated symptom has never been encountered. Hypothalamus-driven hypopituitarism as a presenting feature was reported in one patient with WD at relapse, with an MRI-proven rostral infundibular lesion and low levels of cortisol, free testosterone, and free thyroxine without an elevated thyroid-stimulating hormone.
  • Ataxia (cerebellar) is found in 25% of patients.
  • Seizures are found in 25% of patients (ie, simple or complex partial seizures, generalized tonic-clonic seizures, either alone or complicating partial seizures).
  • Segmental myoclonus (which is irregular/nonrhythmic, to be distinguished from myorhythmic movements of OMM and OSFM) is found in 20% of patients.
  • Sensory deficits (usually in a central distribution) are found in 10% of patients.
  • Isolated cranial nerve (CN) palsy (CN III, IV, V, VI, or VII) is very rare ( <3% of patients).

Causes

Whether the clinical manifestations of WD result from direct bacterial invasion or from the ensuing inflammatory response is not yet clear.

• More effective (ie, sensitive) diagnostic techniques (eg, PCR) have continued to provide more and more evidence of direct bacterial invasion at the various symptomatic-target organ sites, suggesting a combined mechanism of bacterial invasion and ensuing inflammatory response.

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