CNS Whipple Disease

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Background

Whipple disease constitutes a rare, relapsing, slowly progressive, infectious, systemic illness characterized by fever of unknown origin, polyarthralgias, and chronic diarrhea.[1]

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).

Fewer 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 Whipple disease, focuses on both the neurologic manifestations and specifics of diagnosis and treatment of Whipple disease with symptomatic CNS involvement (CNS-WD).[2]

Despite the slowly progressive course of most cases of Whipple disease, CNS-WD may have a fulminant course, and manifest isolated CNS-WD cases have been reported in the literature.[3] 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.[4] 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 Whipple disease.[5]

1952: Paulley was first to report a case of a patient with histologically proven Whipple disease whose symptoms responded to chloramphenicol.[6] 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 Whipple disease by finding bacillary bodies within membrane-bound vesicles in the cytoplasm of macrophages. Whipple disease bacillus has a characteristic trilamellar appearance on EM.

1985: A survey by Keinath et al[7] of 88 patients with Whipple disease 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[8] 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 Whipple disease.

1992: Relman et al[9] 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.

1997: Ramzan et al[10] used PCR to confirm Whipple disease 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 Whipple disease 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 Whipple disease is suspected.

2000: Raoult et al[11] 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 Whipple disease. 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 Whipple disease 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.

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.[14]

Host abnormalities

A variety of host abnormalities has been reported in patients with Whipple disease. 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.

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[16] 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 Whipple disease 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[17] ) 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 Whipple disease in an animal model infected with Whipple disease 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 Whipple disease can include the following 3 stages:

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 Whipple disease 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.

Epidemiology

Frequency

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

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

Whipple disease left untreated is uniformly fatal.

Demographics

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

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

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

Prognosis

WD left untreated is uniformly fatal.

WD may represent a diagnostic dilemma in some cases.

For the astute clinician with a high index of suspicion, treating patients with WD could end up being a very rewarding experience. Timely diagnosis and rapid institution of efficacious treatments are paramount in obtaining a potential cure. A long course of antibiotics (over 1 y) which have good BBB penetrance and treatment decisions based on PCR studies of both significant organs (accountable for the symptoms encountered) and CSF are key for successful treatment of WD.

In patients treated for less than 1 year, with antibiotics with low BBB penetrance, or without PCR studies to guide treatment decisions, the likelihood of relapse and potentially irreversible neurological deficits is very high (approaching 40%).

Patient Education

WD may represent a diagnostic challenge, but treatment is readily available and potentially curative.

Patient adherence to a long course of antibiotics is paramount in obtaining a cure; the importance of this should be emphasized repeatedly to the patient.

The alternative to poor antibiotic treatment compliance, as a rule, is worsening or early relapse with new or worse and potentially irreversible CNS symptoms. Resistance to previously, clinically proven, sensitive antibiotics also has been reported at relapse.

For excellent patient education resources, see eMedicineHealth's patient education article Stroke-Related Dementia.

History

Whipple disease 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.

Physical

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

Causes

Whether the clinical manifestations of Whipple disease 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.

Complications

Potentially irreversible CNS symptoms have been reported at relapse together with an increased likelihood of onset of resistance to previously efficacious antibiotics.

Aggressive CSF PCR monitoring of response to treatment at relapse is of utmost importance.

Laboratory Studies

Routine laboratory values are often abnormal. Initial laboratory studies routinely obtained include the following:

Other baseline labs should target some of the differential diagnosis variants and include rapid plasma reagent and HIV testing, erythrocyte sedimentation rate, complement C3 and C5, antinuclear antibody, and angiotensin-converting enzyme levels. Also obtain baseline liver function tests, thyroid function tests, and random cortisol level. Extend endocrinologic workup (free testosterone, luteinizing hormone, follicle-stimulating hormone) on an individual basis to rule out pituitary gland or, more commonly, hypothalamic involvement.

Nonspecific results supportive of steatorrhea include decreased serum cholesterol and carotene levels, decreased iron levels, elevated prothrombin time, and low serum albumin as a result of a combination of the protein-losing enteropathy, decreased absorption of amino acids, and decreased hepatic synthesis.

Multifactorial normocytic hypochromic anemia is present in 90% of patients and is caused by chronic infection and malabsorption with decreased iron, vitamin B-12, and folate.

Not infrequently, thrombocytosis is present with counts of greater than 1 million/mL. This may be the basis for a hyperviscosity syndrome (with exacerbation of cardiac disease and stroke). Both anemia and thrombocytosis reverse with specific antibiotic treatment for Whipple disease.

Imaging Studies

Radiology

Of patients with Whipple disease with GI upset, 85% have abnormal results on upper GI series. More than 50% of these patients present with bowel dilation with or without prominent mucosal folds of the duodenum and jejunum. In 60% of these patients, flocculation and segmentation of barium also is reported.

Other findings include dilatation of the proximal ileum, stomach with thickened nodular folds, and possibly edema of the colon on barium enema. All of these findings are nonspecific; they also may be found in other diseases such as celiac sprue and lymphoma.

Various imaging studies reveal enlarged retroperitoneal and mediastinal lymph nodes in 10% of patients with Whipple disease.

Neuroimaging

Neuroimaging is largely nonspecific. CT scan and MRI with and without contrast may reveal nondiagnostic abnormalities including atrophy, hydrocephalus, mass lesions with contrast enhancement, ring-enhancing lesions, and other focal changes, including white matter changes with no mass effect, suggesting demyelination.

Other Tests

Specific tests for malabsorption and biliary salts metabolism

Specific tests indicative of steatorrhea (90% of patients with Whipple disease have malabsorption) include qualitative or 72-hour quantitative stool analysis and absorption of D-xylose (with decreased fractional absorption detected by low serum and urinary levels).[16]

Bile salt metabolism testing reveals an increase in the deoxycholic acid-to-cholic acid ratio after intravenous challenge with taurocholate (ie, the inverse of the normal response).

Electrodiagnostic testing

No diagnostic/specific EEG pattern has been described for CNS-WD. EEG may be normal, show focal or generalized slow wave activity, or identify irritative foci with spike activity.

Electromyography (EMG) of the muscles involved in OFSM has revealed 400-millisecond bursts of bilateral rhythmic activity. The activity originates from the level of CN VII and spreads rostrally to involve the muscles of mastication and caudally to involve muscles of the neck, arms, and legs.

Cerebrospinal fluid studies

CSF is frequently abnormal (high protein, > 5 WBC, intrathecal synthesis of IgA). In patients who carry a diagnosis of Whipple disease, nonspecific inflammatory markers in CSF have been reported as useful surrogates to monitor response and durability of remission. More specific testing of the CSF is required for a positive diagnosis, such as PAS staining, EM, and PCR.

CSF PCR should be considered in all patients with Whipple disease; as it gains acceptance as a useful tool for assessing CNS involvement, it represents the most sensitive tool in evaluating response to antibiotic treatment and early detection of relapse.[21] Termination of a long course antibiotic treatment in a patient with Whipple disease who experienced a good clinical response should be based ultimately on CSF PCR analysis alone.

Procedures

The diagnosis of Whipple disease is made by demonstrating characteristic lesions in tissue obtained from biopsy of significant organs (defined as organs usually known to be involved in Whipple disease and responsible for some of the complaints and/or signs noted on examination).

The medical practitioner should plan significant organ biopsy with PAS staining, EM analysis, and PCR of the tissue sample.

For patients with GI complaints, peroral GI biopsy should be the initial diagnostic method of choice. It reveals foamy macrophages containing PAS-positive, gram-positive bacilli in the lamina propria of the mucosa of the small intestine.

Studies reviewing patients with Whipple disease and GI complaints revealed only a 50% sensitivity of multiple (2-3) peroral GI biopsies. The review of patients with CNS-WD revealed a higher sensitivity of 70%, which is due in part to a sampling effect, since these patients are less likely to be diagnosed with CNS-WD without a positive peroral GI biopsy.

Consider all patients with CNS-WD for a peroral GI biopsy as part of their initial diagnostic workup.

PAS-positive macrophages in the lamina propria of the colon and rectum are nondiagnostic, since they have been reported in healthy people and in patients with histiocytosis, melanosis coli, or pneumatosis intestinales.

PAS-positive macrophages in lymph node biopsy alone, not corroborated by other significant tissue biopsy results, is not diagnostic, since this can be a common finding in tuberculosis, sarcoidosis, Gaucher disease, and berylliosis.

Lumbar puncture: CNS involvement can be demonstrated quite well with CSF analysis; PAS staining of cellular material may be adequate, or the diagnosis may be confirmed with PCR when PAS staining is inconclusive.

Brain biopsy[22] is a last resort in a patient with a nonspecific focal lesion amenable to biopsy in whom the diagnosis cannot be made by testing other sites (eg, GI biopsy) or by CSF analysis.

Histologic Findings

Macrophages containing PAS-positive, gram-positive bacilli have been found in various body tissues of patients with Whipple disease, including heart and heart valves, CNS and CSF, lung, spleen, Kupffer cells (ie, cells with functional role of macrophages in the liver), pancreas, muscle, bone marrow, kidney, lymph nodes, and synovial membranes.

Medical Care

Treatment of Whipple disease is less challenging than its diagnosis. Antibiotics are the mainstay of therapy. A good outcome relies on a timely diagnosis and initiation and completion of a long-term antibiotic course. The literature comprises a consensus about the need for completion of a lengthy antibiotic course of 1–2 years. Treatments of shorter duration have been associated with a high rate of relapse. The use of specific diagnostic techniques (eg, PCR) is important in establishing a diagnosis[23] and in evaluating response and adjusting the antibiotic therapy.

The following guidelines have been proposed for diagnostic screening, biopsy, and treatment of CNS-WD:

A combination of antibiotics is preferable, particularly at the initiation of treatment. Antibiotics usually provide rapid resolution of extraneuraxial symptoms. Arthralgias and fever usually resolve within a few days. Diarrhea and malabsorption disappear within 2-4 weeks.

Relapse is quite common in Whipple disease; the disease relapses in approximately one third of patients in whom cessation of treatment was made based on negative serial duodenal biopsies alone.

Monitor clinical response to treatment and complement it with other data obtained with biopsy and imaging studies.

Surgical Care

Neurosurgical care is relevant for both obtaining diagnostic biopsy specimens in selected patients and placement of ventriculoperitoneal shunt (VPS) in patients with hydrocephalus.

Both communicating and noncommunicating hydrocephalus has been reported in patients with CNS-WD. The role of shunting has to be assessed thoroughly.

WD bacillus has a predilection for the periaqueductal gray matter, making noncommunicating hydrocephalus (secondary to aqueductal stenosis) more likely in patients with advanced CNS-WD. Patients with aqueductal stenosis represent a neurosurgical emergency and VPS should be placed urgently.

In progressive CNS-WD with progressive, communicating hydrocephalus, some of the cognitive and motor deficits noted in these patients potentially could be limited rapidly and sometimes reversed by shunting. This is especially important as the reported reversal of other CNS symptoms and signs remains limited and requires several weeks to months despite otherwise efficient antibiotic treatment.

Rapid initiation of efficacious antibiotic treatment prior to, or at the time of, shunting is most important as placement of VPS without concomitant antibiotic treatment potentially could initiate dissemination of disease in the peritoneal cavity. No such cases have been reported in the literature.

Placement of a VPS (with Ommaya reservoir) raises an interesting question about a great therapeutic opportunity, intrathecal/intraventricular antibiotic therapy concomitant with systemic treatment. No reports of attempted intraventricular antibiotic treatment have been published. This is especially important as some reports emphasized the meningoependymitis (ventriculitis) pattern seen in patients with CNS-WD.

No attempts at concomitant systemic antibiotic treatment together with intrathecal antibiotic treatment through lumbar puncture have been reported.

Medication Summary

Various antibiotics have been used with different efficacies. The most commonly used antibiotics, as reported in the literature, are tetracycline, penicillin, TMP-SMX, and chloramphenicol. Others used include demeclocycline, doxycycline, oxytetracycline, minocycline, gentamicin, streptomycin, amoxicillin, ampicillin, pefloxacin, erythromycin, profloxacin, vancomycin, ceftriaxone, cephalexin, and rifampin.[24]

A consensus is found in the literature about using a combination of parenteral antibiotics at the initiation of therapy ("induction period") for 2–4 weeks, followed by long-term treatment (1–2 y) with an oral antibiotic. Options reported as efficacious for the induction period are a combination of parenteral antibiotics (penicillin and streptomycin) or third-generation cephalosporins such as ceftriaxone for at least 2–4 weeks.

Ceftriaxone (Rocephin)

Clinical Context:  Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

For treatment of WD, induction period of 2-4 wk should be pursued, followed by long-term oral antibiotics; role of induction period has not been studied extensively; it may not be necessary, as long as good combination antibiotic regimen (ie, one with high BBB penetrance) is initiated for long-term use.

Sulfamethoxazole and trimethoprim (Bactrim, Septra, Cotrim)

Clinical Context:  TMP-SMX inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Both sulfamethoxazole and trimethoprim diffuse into CSF.

For treatment of WD, long-term treatment (1-2 y) should be pursued

Cefixime (Suprax)

Clinical Context:  Semisynthetic third-generation cephalosporin for oral administration; can be administered in tab or susp form; chemically is (6R,7R)-7-[2-(2-Amino-4-thiazolyl) glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72(Z)-[O-(carboxymethyl)oxime]-trihydrate.

Molecular weight is 507.50 as trihydrate.

Most commonly used in treatment of bronchitis, gonorrhea, urinary tract infections, otitis media, pharyngitis, and tonsillitis. Has been reported as successful long-term treatment alternative to TMP-SMX in patients with WD.

Arguably, any antibiotic with good BBB penetrance, benign toxicity profile, and activity against gram-positive bacteria can be used in long-term treatment of CNS-WD.

Approximately 40-50% absorbed from gut whether administered with or without food. Time to maximal absorption is increased approximately 0.8 h when administered with food. Single 200-mg tab produces average peak serum concentration of approximately 2 mcg/mL (range 1-4 mcg/mL); single 400-mg tab produces average peak concentration of approximately 3.7 mcg/mL (range 1.3-7.7 mcg/mL).

PO susp produces average peak concentrations approximately 25-50% higher than tab. Area under time versus concentration curve is greater by approximately 10-25% with PO susp than with tab after doses of 100-400 mg when tested in healthy adult volunteers. Consider this increased absorption if PO susp is to be substituted for tab.

Because of lack of bioequivalence, do not substitute tab for PO susp in treatment of otitis media.

Peak serum concentrations occur 2-6 h following administration of both tab and susp. Approximately 50% of absorbed dose excreted unchanged in urine in 24 h. Also believed to be excreted in bile in excess of 10% of administered dose.

Serum protein binding is concentration independent with bound fraction of approximately 65%.

In multiple dose regimen, little accumulation in serum or urine after dosing for >14 d. Serum half-life in healthy subjects is independent of dosage form and averages 3-4 h but may range to as long as 9 h.

Average AC at steady state in elderly patients is approximately 40% higher than average AC in other healthy adults.

In subjects with moderate impairment of renal function (CrCl 20-40 mL/min), average serum half-life prolonged to 6.4 h. In severe renal impairment (CrCl 5-20 mL/min), half-life increased to average of 11.5 h. Not cleared significantly from blood by hemodialysis or peritoneal dialysis. Patients undergoing hemodialysis have similar blood profiles as subjects with CrCl of 21-60 mL/min.

No evidence of metabolism in vivo. Penetrates BBB but adequate detailed data of correlative CSF levels not available.

Class Summary

TMP-SMX taken PO 2-3 times per day for long-term treatment (1-2 y) is the agent mostly reported as effective. An alternative reported as efficacious for long-term treatment is cefixime. Some treatment failures and acquired resistance at relapse have been reported with TMP-SMX.

Valproic acid (Depacon, Depakene, Depakote)

Clinical Context:  Indicated for seizures and myoclonus; chemically unrelated to other drugs that treat seizure disorders; although mechanism of action not established, activity may be related to increased brain levels of GABA or enhanced GABA action; also may potentiate postsynaptic GABA responses, affect potassium channel, or have direct membrane-stabilizing effect.

For conversion to monotherapy, concomitant AED dosage ordinarily can be reduced by approximately 25% every 2 wk; this reduction may start at initiation of therapy or be delayed by 1-2 wk if concern that seizures may occur with reduction; monitor patients closely during this period for increased seizure frequency.

As adjunctive therapy, divalproex sodium may be added to regimen at 10-15 mg/kg/d; may increase by 5-10 mg/kg/wk to achieve optimal clinical response; ordinarily, optimal clinical response achieved at daily doses < 60 mg/kg/d.

Has been used with some notable success for control of OMM and/or OSFM (reports exist of complete suppression of OMM and/or OSFM) once therapeutic levels were attained (75-100 mcg/mL).

Subtherapeutic levels or attempts to wean in most patients resulted in return of abnormal movements, in some patients even after completion of long-term antibiotic treatment.

Class Summary

Various antiepileptic drugs (AEDs) and benzodiazepines reportedly have been tried to control movement abnormalities encountered in some patients with CNS-WD. Carbamazepine, phenobarbital, and lorazepam demonstrated no notable success in control of OMM and/or OSFM. Valproic acid has been reported as effective in controlling OMM and/or OSFM in some patients.

Further Outpatient Care

Regular visits in various specialty clinics targeting monitoring clinical response to treatment of significant symptoms and laboratory tests should be pursued.

Significant symptom inventory should be reviewed with the patient at each clinic visit.

Treatment adherence should be emphasized continuously.

Guidelines for response assessment should be reviewed consistently with other specialty teams involved in the care of the patient.

CSF PCR analysis should be used as the ultimate tool in monitoring response and treatment decision making.

Further Inpatient Care

Diagnosis and treatment of patients with Whipple disease should be based on a multiteam approach, targeting early involvement of gastroenterology, neurology, ophthalmology, cardiology, and rheumatology specialists.

No patients in whom multiple target-organ routine inventory status has been pursued, unless indicated by symptomatology or clinical examination (except for CNS), have been reported.

Some have speculated that by the time the CNS involvement becomes clinically relevant in patients with Whipple disease, they also might have disseminated pulmonary, cardiovascular, hepatic, and/or ocular disease. Furthermore, the choice and duration of antibiotic treatment might be influenced by the presence of disease in these organs.

The role of routine echocardiogram and chest and abdomen imaging (CT scan or MRI) remains to be established; these should be pursued on an individual case basis and on the clinician's need to know for significant management decisions and prognostic evaluation.

Inpatient and Outpatient Medications

A long course of antibiotics (more than 1 y) that has good BBB penetrance represents the key in successful treatment of patients with Whipple disease.

Deterrence/Prevention

Limited information suggests that the WD bacillus is a saprobe.

A limited number of cases have been reported of patients diagnosed with WD several months after spending vacation time in lake regions.

In patients who might have a specific IL-12–gamma-interferon axis defect, swimming in lakes may be hazardous, especially in those where accidental drainage of sewage water took place.

Author

George C Bobustuc, MD, Consulting Staff, Department of Neuro-oncology, MD Anderson Cancer Center of Orlando

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Florian P Thomas, MD, PhD, MA, MS, Chair, Neuroscience Institute and Department of Neurology, Director, National MS Society Multiple Sclerosis Center and Hereditary Neuropathy Foundation Center of Excellence, Hackensack University Medical Center; Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Professor Emeritus, Department of Neurology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine

Disclosure: Nothing to disclose.

Chief Editor

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM, Adjunct Associate Professor of Neurology, University of Missouri-Columbia School of Medicine; Medical Director of St Mary's Stroke Program, SSM Neurosciences Institute, SSM Health

Disclosure: Nothing to disclose.

Additional Contributors

Norman C Reynolds, Jr, MD, Neurologist, Veterans Affairs Medical Center of Milwaukee; Clinical Professor, Medical College of Wisconsin

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Mark Gilbert, MD to the development and writing of this article.

References

  1. El-Abassi R, Soliman MY, Williams F, England JD. Whipple's disease. J Neurol Sci. 2017 Jun 15. 377:197-206. [View Abstract]
  2. Compain C, Sacre K, Puéchal X, Klein I, Vital-Durand D, Houeto JL, et al. Central nervous system involvement in Whipple disease: clinical study of 18 patients and long-term follow-up. Medicine (Baltimore). 2013 Nov. 92(6):324-30. [View Abstract]
  3. Balasa M, Gelpi E, Rey MJ, Vila J, Ramió-Torrentà L, Quiles Granado AM, et al. Clinical and neuropathological variability in clinically isolated central nervous system Whipple's disease. Brain Pathol. 2014 Apr. 24(3):230-8. [View Abstract]
  4. Whipple GH. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Johns Hopkins Hosp Bull. 1907. 18:382-391.
  5. Black-Schaffer B. The tinctorial demonstration of a glycoprotein in Whipple's disease. Proc Soc Exp Biol Med. 1949. 72:225.
  6. Paulley JW. A case of Whipple's disease (intestinal lipodystrophy). Gastroenterology. 1952. 22:128-33.
  7. Keinath RD, Merrell DE, Vlietstra R, Dobbins WO 3rd. Antibiotic treatment and relapse in Whipple's disease. Long-term follow-up of 88 patients. Gastroenterology. 1985 Jun. 88(6):1867-73. [View Abstract]
  8. Wilson KH, Blitchington R, Frothingham R, Wilson JA. Phylogeny of the Whipple's-disease-associated bacterium. Lancet. 1991 Aug 24. 338(8765):474-5. [View Abstract]
  9. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple's disease. N Engl J Med. 1992 Jul 30. 327(5):293-301. [View Abstract]
  10. Ramzan NN, Loftus E, Burgart LJ, et al. Diagnosis and monitoring of Whipple disease by polymerase chain reaction. Ann Intern Med. 1997 Apr 1. 126(7):520-7. [View Abstract]
  11. Raoult D, Birg ML, La Scola B, Fournier PE, Enea M, Lepidi H, et al. Cultivation of the bacillus of Whipple's disease. N Engl J Med. 2000 Mar 2. 342(9):620-5. [View Abstract]
  12. Raoult D, Ogata H, Audic S. Tropheryma whipplei Twist: a human pathogenic Actinobacteria with a reduced genome. Genome Res. 2003 Aug. 13(8):1800-9. [View Abstract]
  13. Raoult D, Ogata H, Audic S, et al. Tropheryma whipplei Twist: a human pathogenic Actinobacteria with a reduced genome. Genome Res. 2003 Aug. 13(8):1800-9. [View Abstract]
  14. Bentley SD, Maiwald M, Murphy LD, Pallen MJ, Yeats CA, Dover LG, et al. Sequencing and analysis of the genome of the Whipple's disease bacterium Tropheryma whipplei. Lancet. 2003 Feb 22. 361(9358):637-44. [View Abstract]
  15. Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev. 2000 Dec. 11(4):321-33. [View Abstract]
  16. Fenollar F, Laouira S, Lepidi H, Rolain JM, Raoult D. Value of Tropheryma whipplei quantitative polymerase chain reaction assay for the diagnosis of Whipple disease: usefulness of saliva and stool specimens for first-line screening. Clin Infect Dis. 2008 Sep 1. 47(5):659-67. [View Abstract]
  17. Bonhomme CJ, Renesto P, Nandi S, Lynn AM, Raoult D. Serological microarray for a paradoxical diagnostic of Whipple's disease. Eur J Clin Microbiol Infect Dis. 2008 Oct. 27(10):959-68. [View Abstract]
  18. Panegyres PK, Foster JK, Fallon M, Connor C. The amnesic syndrome of primary Whipple disease of the brain. Cogn Behav Neurol. 2010 Mar. 23(1):49-51. [View Abstract]
  19. Schwartz MA, Selhorst JB, Ochs AL, Beck RW, Campbell WW, Harris JK, et al. Oculomasticatory myorhythmia: a unique movement disorder occurring in Whipple's disease. Ann Neurol. 1986 Dec. 20(6):677-83. [View Abstract]
  20. Brandle M, Ammann P, Spinas GA, Dutly F, Galeazzi RL, Schmid C, et al. Relapsing Whipple's disease presenting with hypopituitarism. Clin Endocrinol (Oxf). 1999 Mar. 50(3):399-403. [View Abstract]
  21. von Herbay A, Ditton HJ, Schuhmacher F, Maiwald M. Whipple's disease: staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid. Gastroenterology. 1997 Aug. 113(2):434-41. [View Abstract]
  22. De Coene B, Gilliard C, Indekeu P, Duprez T, Trigaux JP. Whipple's disease confined to the central nervous system. Neuroradiology. 1996 May. 38(4):325-7. [View Abstract]
  23. Le Scanff J, Gaultier JB, Durand DV, Durieu I, Celard M, Benito Y, et al. [Tropheryma whipplei and Whipple disease: false positive PCR detections of Tropheryma whipplei in diagnostic samples are rare]. Rev Med Interne. 2008 Nov. 29(11):861-7. [View Abstract]
  24. Seneca V, Imperato A, Colella G, Cioffi V, Mariniello G, Gangemi M. Recurrent acute obstructive hydrocephalus as clinical onset of cerebral Whipple's disease. Clin Neurol Neurosurg. 2010 Oct. 112(8):717-21. [View Abstract]
  25. Adams M, Rhyner PA, Day J, DeArmond S, Smuckler EA. Whipple's disease confined to the central nervous system. Ann Neurol. 1987 Jan. 21(1):104-8. [View Abstract]
  26. Benito-León J, Sedano LF, Louis ED. Isolated central nervous system Whipple's disease causing reversible frontotemporal-like dementia. Clin Neurol Neurosurg. 2008 Jul. 110(7):747-9. [View Abstract]
  27. Clarke CE, Falope ZF, Abdelhadi HA, Franks AJ. Cervical myelopathy caused by Whipple's disease. Neurology. 1998 May. 50(5):1505-6. [View Abstract]
  28. Comer GM, Brandt LJ, Abissi CJ. Whipple's disease: a review. Am J Gastroenterol. 1983 Feb. 78(2):107-14. [View Abstract]
  29. Cooper GS, Blades EW, Remler BF, Salata RA, Bennert KW, Jacobs GH. Central nervous system Whipple's disease: relapse during therapy with trimethoprim-sulfamethoxazole and remission with cefixime. Gastroenterology. 1994 Mar. 106(3):782-6. [View Abstract]
  30. Dobbins WO 3rd. The diagnosis of Whipple's disease. N Engl J Med. 1995 Feb 9. 332(6):390-2. [View Abstract]
  31. Fenollar F, Birg ML, Gauduchon V. Culture of Tropheryma whipplei from human samples: a 3-year experience (1999 to 2002). J Clin Microbiol. 2003 Aug. 41(8):3816-22. [View Abstract]
  32. Fenollar F, Fournier PE, Robert C. Use of genome selected repeated sequences increases the sensitivity of PCR detection of Tropheryma whipplei. J Clin Microbiol. 2004 Jan. 42(1):401-3. [View Abstract]
  33. Knox DL, Green WR, Troncoso JC, Yardley JH, Hsu J, Zee DS. Cerebral ocular Whipple's disease: a 62-year odyssey from death to diagnosis. Neurology. 1995 Apr. 45(4):617-25. [View Abstract]
  34. Kowalczewska M, Villard C, Lafitte D, Fenollar F, Raoult D. Global proteomic pattern of Tropheryma whipplei: a Whipple's disease bacterium. Proteomics. 2009 Mar. 9(6):1593-616. [View Abstract]
  35. Louis ED, Lynch T, Kaufmann P, Fahn S, Odel J. Diagnostic guidelines in central nervous system Whipple's disease. Ann Neurol. 1996 Oct. 40(4):561-8. [View Abstract]
  36. Lynch T, Odel J, Fredericks DN, Louis ED, Forman S, Rotterdam H, et al. Polymerase chain reaction-based detection of Tropheryma whippelii in central nervous system Whipple's disease. Ann Neurol. 1997 Jul. 42(1):120-4. [View Abstract]
  37. Marth T, Neurath M, Cuccherini BA, Strober W. Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease. Gastroenterology. 1997 Aug. 113(2):442-8. [View Abstract]
  38. Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE. Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease. Clin Immunol Immunopathol. 1994 Aug. 72(2):217-26. [View Abstract]
  39. Masselot F, Boulos A, Maurin M. Molecular evaluation of antibiotic susceptibility: Tropheryma whipplei paradigm. Antimicrob Agents Chemother. 2003 May. 47(5):1658-64. [View Abstract]
  40. Moos V, Kunkel D, Marth T, Feurle GE, LaScola B, Ignatius R, et al. Reduced peripheral and mucosal Tropheryma whipplei-specific Th1 response in patients with Whipple's disease. J Immunol. 2006 Aug 1. 177(3):2015-22. [View Abstract]
  41. Pollock S, Lewis PD, Kendall B. Whipple's disease confined to the nervous system. J Neurol Neurosurg Psychiatry. 1981 Dec. 44(12):1104-9. [View Abstract]
  42. Richardson DC, Burrows LL, Korithoski B, Salit IE, Butany J, David TE, et al. Tropheryma whippelii as a cause of afebrile culture-negative endocarditis: the evolving spectrum of Whipple's disease. J Infect. 2003 Aug. 47(2):170-3. [View Abstract]
  43. Ryser RJ, Locksley RM, Eng SC, Dobbins WO 3rd, Schoenknecht FD, Rubin CE. Reversal of dementia associated with Whipple's disease by trimethoprim-sulfamethoxazole, drugs that penetrate the blood-brain barrier. Gastroenterology. 1984 Apr. 86(4):745-52. [View Abstract]
  44. Sanavro SM, Voerman HJ. Whipple's disease: easily diagnosed, if considered. Neth J Med. 2009 Mar. 67(3):108. [View Abstract]
  45. Schneider T, Stallmach A, von Herbay A. Treatment of refractory Whipple disease with interferon-gamma. Ann Intern Med. 1998 Dec 1. 129(11):875-7. [View Abstract]
  46. Schnider P, Trattnig S, Kollegger H, et al. MR of cerebral Whipple disease. AJNR Am J Neuroradiol. 1995 Jun-Jul. 16(6):1328-9. [View Abstract]
  47. Sloan LM, Rosenblatt JE, Cockerill FR. Detection of Tropheryma whipplei DNA in clinical specimens by LightCycler real-time PCR. J Clin Microbiol. 2005 Jul. 43(7):3516-8. [View Abstract]
  48. Swartz MN. Whipple's disease--past, present, and future. N Engl J Med. 2000 Mar 2. 342(9):648-50. [View Abstract]
  49. Wilson KH. New vistas for bacteriologists: analysis based on 16S rRNA sequences provides a rapid and reliable approach to the identity of human pathogens. ASM News. 1992. 58:318-21.