CNS Whipple Disease

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CNS Whipple Disease

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Whipple disease 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).

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). [1]

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. [2] 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.

1907: Whipple proposed the name of “intestinal lipodystrophy” for a new, distinctive clinical syndrome. [3] 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. [4]

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 Whipple disease 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 Whipple disease and MAC have been reported.

1952: Paulley was first to report a case of a patient with histologically proven Whipple disease whose symptoms responded to chloramphenicol. [5] 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 [6] 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 [7] 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 [8] 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 Whipple disease. 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 [9] 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 [10] 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.

Raoult et al [11, 12] developed an immunofluorescence serologic test with which they examined serum from a limited number of patients with Whipple disease (9 patients with Whipple disease 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 Whipple disease 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 Whipple disease 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. [13]

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.

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 Whipple disease 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 Whipple disease has been supported by the decreased in vitro phagocytic ability of monocytes collected from patients with Whipple disease.

The reduced in vitro phagocytic ability of macrophages from patients with Whipple disease 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 Whipple disease. This is supported further by a case report of a patient with Whipple disease who had developed resistance to antibiotics on recurrence and subsequently had been treated successfully with gamma interferon.

Patients with Whipple disease 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. [14]

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 Whipple disease.

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 [15] 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 [16] ) 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.

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.

The clinical course of untreated Whipple disease 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 Whipple disease 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 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.

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.

Whipple disease 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 Whipple disease than in the general population.

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.

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

George C Bobustuc, MD is a member of the following medical societies: American Academy of Neurology, Texas Medical Association, Society for Neuro-Oncology, American Medical Association

Disclosure: Nothing to disclose.

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, Multiple Sclerosis Center and Hereditary Neuropathy Centers, 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

Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi

Disclosure: Nothing to disclose.

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

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Headache Society

Disclosure: Nothing to disclose.

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

Norman C Reynolds, Jr, MD is a member of the following medical societies: American Academy of Neurology, Association of Military Surgeons of the US, International Parkinson and Movement Disorder Society, Sigma Xi, Society for Neuroscience

Disclosure: Nothing to disclose.

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.

CNS Whipple Disease

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