Tumor Necrosis Factor Inhibitors Exacerbate Whipple's Disease by Reprogramming Macrophage and Inducing Apoptosis.

Tropheryma whipplei is the agent of Whipple's disease, a rare systemic disease characterized by macrophage infiltration of the intestinal mucosa. The disease first manifests as arthralgia and/or arthropathy that usually precede the diagnosis by years, and which may push clinicians to prescribe Tumor necrosis factor inhibitors (TNFI) to treat unexplained arthralgia. However, such therapies have been associated with exacerbation of subclinical undiagnosed Whipple's disease. The objective of this study was to delineate the biological basis of disease exacerbation. We found that etanercept, adalimumab or certolizumab treatment of monocyte-derived macrophages from healthy subjects significantly increased bacterial replication in vitro without affecting uptake. Interestingly, this effect was associated with macrophage repolarization and increased rate of apoptosis. Further analysis revealed that in patients for whom Whipple's disease diagnosis was made while under TNFI therapy, apoptosis was increased in duodenal tissue specimens as compared with control Whipple's disease patients who never received TNFI prior diagnosis. In addition, IFN-γ expression was increased in duodenal biopsy specimen and circulating levels of IFN-γ were higher in patients for whom Whipple's disease diagnosis was made while under TNFI therapy. Taken together, our findings establish that TNFI aggravate/exacerbate latent or subclinical undiagnosed Whipple's disease by promoting a strong inflammatory response and apoptosis and confirm that patients may be screened for T. whipplei prior to introduction of TNFI therapy.

Primary Whipple disease of the Central Nervous System presenting with rhombencephalitis.

Primary Whipple disease of the Central Nervous System is a rare entity whose outcome might be fatal if not promptly diagnosed and treated. Few cases are reported in the literature with heterogeneous clinical and radiological presentations which often make the diagnosis extremely challenging. We report a case of primary Whipple disease of the Central Nervous System presenting with rhombencephalitis in a female patient in immunosuppressive treatment for rheumatoid arthritis. We describe the management of our patient and discuss the features of this rare clinical entity.

Peripheral-blood b-cell subset disturbances in inflammatory joint diseases induced by Tropheryma whipplei.

OBJECTIVE: To look for abnormalities in circulating B-cell subsets in patients with rheumatic symptoms of Whipple's disease (WD). METHOD: Consecutive patients seen between 2010 and 2016 for suspected inflammatory joint disease were identified retrospectively. Results of standardized immunological and serological tests and of peripheral-blood B-cell and T-cell subset analysis by flow cytometry were collected. Patients with criteria suggesting WD underwent PCR testing for Tropheryma whipplei, and those with diagnosis of WD (cases) were compared to those without diagnosis (controls). We used ROC curve analysis to evaluate the diagnostic value of flow cytometry findings for WD. RESULTS: Among 2917 patients seen for suspected inflammatory joint disease, 121 had suspected WD, including 9 (9/121, 7.4%) confirmed WD. Proportions of T cells and NK cells were similar between suspected and confirmed WD, whereas cases had a lower proportion of circulating memory B cells (IgD-CD38low, 18.0%±9.7% vs. 26.0%±14.2%, P = 0.041) and higher ratio of activated B cells over memory B cells (4.4±2.0 vs. 2.9±2.2, P = 0.023). Among peripheral-blood B-cells, the proportion of IgD+CD27- naive B cells was higher (66.2%±18.2% vs. 54.6%±18.4%, P = 0.047) and that of IgD-CD27+ switched memory B cells lower (13.3%±5.7% vs. 21.4%±11.9%, P = 0.023), in cases vs. controls. The criterion with the best diagnostic performance was a proportion of IgD+CD27- naive B cells above 70.5%, which had 73% sensitivity and 80% specificity. CONCLUSION: Our study provides data on peripheral-blood B-cell disturbances that may have implications for the diagnosis and pathogenetic understanding of WD.

Tropheryma whipplei Increases Expression of Human Leukocyte Antigen-G on Monocytes to Reduce Tumor Necrosis Factor and Promote Bacterial Replication.

BACKGROUND & AIMS: Infection with Tropheryma whipplei has a range of effects-some patients can be chronic carriers without developing any symptoms, whereas others can develop systemic Whipple disease, characterized by a lack a protective inflammatory immune response. Alterations in HLA-G function have been associated with several diseases. We investigated the role of HLA-G during T whipplei infection. METHODS: Sera, total RNA, and genomic DNA were collected from peripheral blood from 22 patients with classic Whipple's disease, 19 patients with localized T whipplei infections, and 21 asymptomatic carriers. Levels of soluble HLA-G in sera were measured by enzyme-linked immuosorbent assay, and expressions of HLA-G and its isoforms were monitored by real-time polymerase chain reaction. HLA-G alleles were identified and compared with a population of voluntary bone marrow donors. Additionally, monocytes from healthy subjects were stimulated with T whipplei, and HLA-G expression was monitored by real-time polymerase chain reaction and flow cytometry. Bacterial replication was assessed by polymerase chain reaction in the presence of HLA-G or inhibitor of tumor necrosis factor (TNF) (etanercept). RESULTS: HLA-G mRNAs and levels of soluble HLA-G were significantly increased in sera from patients with chronic T whipplei infection compared with sera from asymptomatic carriers and control individuals. No specific HLA-G haplotypes were associated with disease or T whipplei infection. However, T whipplei infection of monocytes induced expression of HLA-G, which was associated with reduced secretion of TNF compared with noninfected monocytes. A neutralizing antibody against HLA-G increased TNF secretion by monocytes in response to T whipplei, and a TNF inhibitor promoted bacteria replication. CONCLUSIONS: Levels of HLA-G are increased in sera from patients with T whipplei tissue infections, associated with reduced production of TNF by monocytes. This might promote bacteria colonization in patients.

Gamma delta T cell expansion in Whipple's disease with muscular granulomatous vasculitis.

Whipple's disease usually presents as chronic joint pain followed by digestive manifestations. However, many different presentations have been described in the literature. We report here the first proven case of muscular vasculitis related to Whipple's disease, associated with an expansion of circulating activated γδ T lymphocytes.

Impaired intracellular pathogen clearance and inflammatory joint disease: Is Whipple's disease a guiding light?

Whipple's disease can mimic spondyloarthritis (SpA) or rheumatoid arthritis (RA) for many years and, in a few cases, induces the development of antibodies to cyclic citrullinated peptides. The causative agent Tropheryma whipplei can smolder within cells, including macrophages, by suppressing the xenophagic process, a type of selective autophagy that targets pathogens. Other inflammatory joint diseases may also stem from impaired xenophagy with persistence of bacteria or viruses that can eventually migrate from the mucous membranes to the joints and entheses, where they may exert adverse effects on immune responses, even if they fail to replicate. Xenophagy interferes with the loading of peptides (including self-peptides) onto major histocompatibility complex proteins. Another effect of xenophagy is the induction of citrullination, which accelerates pathogen clearance but can also contribute to loss of self-tolerance. Pathogens react to citrullination by becoming dormant. These facts suggest a role in SpA and RA for impaired xenophagy with migration of pathogens to joints and entheses, where they may remain dormant. Studies of fibroblast-like synoviocytes showed alterations in autophagy that correlated with citrullination of vimentin, alpha-enolase, and filaggrin, which are targets of RA-specific autoantibodies. Compared to autoimmune responses (T-cell or B-cell clones, autoantibodies) alone, metastatic spread of pathogens initially located in the mucous membranes as the event inducing inflammatory joint disease would constitute a better explanation to the heterogeneous distribution of the joint involvement, palindromic onset in some cases (as seen in Whipple's disease), occurrence of flares, and possible development of escape phenomenon to immunomodulating drugs in a manner reminiscent of delayed antibiotic resistance.

Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease.

Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward Tropheryma whipplei in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from T. whipplei was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-γ) were determined in T cells by flow cytometry. Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of T. whipplei, the proportions of activated effector CD4+ T cells, determined as CD40L+ IFN-γ+, were significantly lower in patients with CWD than in healthy controls; CD8+ T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and T. whipplei-specific degranulation, although CD69+ IFN-γ+ CD8+ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei-derived proteins. Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against T. whipplei to control bacterial spreading. The lack of specific T-cell responses against these T. whipplei-derived proteins may contribute to the pathogenesis of CWD.

Architectural and functional alterations of the small intestinal mucosa in classical Whipple's disease.

Classical Whipple's disease (CWD) affects the gastrointestinal tract and rather elicits regulatory than inflammatory immune reactions. Mechanisms of malabsorption, diarrhea, and systemic immune activation are unknown. We here analyzed mucosal architecture, barrier function, and immune activation as potential diarrheal trigger in specimens from 52 CWD patients. Our data demonstrate villus atrophy and crypt hyperplasia associated with epithelial apoptosis and reduced alkaline phosphatase expression in the duodenum of CWD patients. Electrophysiological and flux experiments revealed increased duodenal permeability to small solutes and macromolecules. Duodenal architecture and permeability ameliorated upon antibiotic treatment. Structural correlates for these alterations were concordant changes of membranous claudin-1, claudin-2, claudin-3, and tricellulin expression. Tumor necrosis factor-α and interleukin-13 were identified as probable mediators of epithelial apoptosis, and altered tight junction expression. Increased serum markers of microbial translocation and their decline following treatment corroborated the biological significance of the mucosal barrier defect. Hence, mucosal immune responses in CWD elicit barrier dysfunction. Diarrhea is caused by loss of absorptive capacity and leak flux of ions and water. Downregulation of tricellulin causes increased permeability to macromolecules and subsequent microbial translocation contributes to systemic inflammation. Thus, therapeutic strategies to reconstitute the mucosal barrier and control inflammation could assist symptomatic control of CWD.

-295 T-to-C promoter region IL-16 gene polymorphism is associated with Whipple's disease.

Whipple's disease (WD) is a rare systemic condition caused, in genetically predisposed subjects, by Tropheryma whipplei, a common bacterium widespread in the environment. The relevance of genetic predisposition in WD is shown by the association with HLA alleles DRB1*13 and DQB1*06 and by the demonstration that, in patients with WD, the cytokine genetic profile is skewed toward a Th2 and Treg response. Since IL-16 is involved in hampering the development of a protective macrophagic response against Tropheryma whipplei, we investigated whether the genetic background of IL-16 is different between patients with WD and controls. The -295 T-to-C polymorphism of the promoter region of the IL-16 gene was studied in 90 patients with WD and 152 healthy controls. Levels of serum IL-16 protein were also tested. The frequency of the wild type T allele was significantly higher in patients with WD compared to the controls (155/180 vs. 235/304; p = 0.02 for the Chi(2) test), odds ratio 1.82 [95 % confidence interval (CI) 1.07-3.10]. The TT genotype was found in 65/90 patients with WD and 88/152 controls (p = 0.026). No relationship was found between serum levels of IL-16 and genotypes. Although the functional consequences of this genetic background on levels of IL-16 and on the course of the disease are still unknown, we found, for the first time, that the wild type T allele and the TT genotype of the -295 polymorphism are associated with WD.

Tropheryma whipplei , Immunosuppression and Whipple's Disease: From a Low-Pathogenic, Environmental Infectious Organism to a Rare, Multifaceted Inflammatory Complex.

BACKGROUND: The actinobacterium Tropheryma whipplei was detected 20 years ago by molecular techniques, and following its culture has been characterized as the cause of a systemic infection known as Whipple's disease (WD). T. whipplei occurs in the environment, is prevalent only in humans, is believed to be transmitted via oral routes and to be host dependent. KEY MESSAGES: The classical form of T. whipplei infection, i.e. classical WD (CWD), is rare. It is well defined as slowly progressing chronic infection with arthralgia, diarrhea and weight loss, mostly in middle-aged men. However, current research revealed a much broader spectrum of clinical features associated with T. whipplei infection. Thus, T. whipplei may cause acute and transient infections (observed primarily in children) and the bacterium, which is found in soil and water, occurs in asymptomatic carriers as well as in CWD patients in clinical remission. In addition, T. whipplei affects isolated and localized body compartments such as heart valves or the central nervous system. Subtle immune defects and HLA associations have been described. New findings indicate that the progression of asymptomatic T. whipplei infection to clinical WD may be associated with medical immunosuppression and with immunomodulatory conditions. This explains that there is a discrepancy between the widespread occurrence of T. whipplei and the rareness of WD, and that T. whipplei infection triggered by immunosuppression presents with protean clinical manifestations. CONCLUSIONS: This review highlights recent findings and the clinical spectrum of infection with T. whipplei and WD, focusing specifically on the role of host immunity and immunosuppression. Current concepts of the pathogenesis, diagnosis and therapy are discussed.

Sewage workers with low antibody responses may be colonized successively by several Tropheryma whipplei strains.

OBJECTIVES: Asymptomatic faecal carriage of Tropheryma whipplei, the agent of Whipple's disease, is reported among sewage workers. However, the potential development of such carriage is unknown. A 7-year follow-up of T. whipplei-carrying sewage workers is reported. METHODS: Nineteen sewage workers previously detected as faecal carriers of T. whipplei were followed to ascertain the chronicity of their carriage. Faeces were tested by molecular assays using quantitative real-time PCR specifically targeting T. whipplei. Serological anti-T. whipplei Western blotting was also performed. RESULTS: Seventy-nine percent (15/19) of workers exhibited a strong immune response against T. whipplei. Among these, five were followed for more than 1 year. Four maintained a strong response, with three carrying the same strain and one becoming negative. The fifth exhibited a decreased immune response, a negative faeces result, and subsequent carriage of another strain. Three individuals with low immune responses were also followed. Two never developed a response, with one carrying the same strain and one becoming negative and then positive with another strain; the third developed a strong response and became negative. CONCLUSIONS: Chronic T. whipplei carriers appear to be protected against reinfection, but those with low or decreasing antibody levels may be re-colonized by another strain.

Systematic review: Whipple's disease (Tropheryma whipplei infection) and its unmasking by tumour necrosis factor inhibitors.

BACKGROUND: The classical form of Whipple's disease (WD), clinically characterised by arthropathy, diarrhoea and weight loss, is rare. Recently, other more frequent forms of Tropheryma whipplei infection have been recognised. The clinical spectrum includes an acute, self-limiting disease in children, localised forms affecting cardiac valves or the central nervous system without intestinal symptoms, and asymptomatic carriage of T. whipplei which is found in around 4% of Europeans. Genomic analysis has shown that T. whipplei represents a host-dependent or opportunistic bacterium. It has been reported that the clinical course of T. whipplei infection may be influenced by medical immunosuppression. AIM: To identify associations between immunomodulatory treatment and the clinical course of T. whipplei infection. METHODS: A PubMed literature search was performed and 19 studies reporting on immunosuppression, particularly therapy with tumour necrosis factor inhibitors (TNFI) prior to the diagnosis in 41 patients with Whipple?s disease, were evaluated. RESULTS: As arthritis may precede the diagnosis of WD by many years, a relevant percentage (up to 50% in some reports) of patients are treated with immunomodulatory drugs or with TNFI. Many publications report on a complicated Whipple?s disease course or T. whipplei endocarditis following medical immunosuppression, particularly after TNFI. Standard diagnostic tests such as periodic acid-Schiff stain used to diagnose Whipple?s disease often fail in patients who are pre-treated by TNFI. CONCLUSIONS: In cases of doubt, Whipple?s disease should be excluded before therapy with TNFI. The fact that immunosuppressive therapy contributes to the progression of T. whipplei infection expands our pathogenetic view of this clinical entity.

Chronic infections of the small intestine.

PURPOSE OF REVIEW: Chronic infections of the small intestine cause significant morbidity and mortality globally. This review focuses on the recent advances in the field of our understanding of selected intestinal infections. RECENT FINDINGS: Primary and secondary immunodeficiency increase the susceptibility to many chronic intestinal infections. Endoscopy and intestinal biopsies are central to establishing a diagnosis of these conditions. Tuberculosis (TB) remains a major global health challenge. Emerging therapeutic agents to counteract multidrug-resistant strains have shown clinical efficacy, but concerns regarding mortality remain. PCR-based diagnostic TB tests have the potential to reduce diagnostic delays, but remain to be validated for intestinal infections. Adjunctive diagnostic imaging modalities can differentiate infections from Crohn's disease with increasing accuracy. Whipple's disease remains rare, but there have been substantial advances in our understanding of the causative organism Tropheryma whipplei. Extended treatment with broad-spectrum antibiotics is effective in most cases. The narrow therapeutic window and limited armamentarium for treating invasive filamentous fungal infections contribute to their significant morbidity and high rates of mortality. SUMMARY: The speed and accuracy of diagnosing chronic intestinal infections have improved with recent imaging and laboratory methodologies. Significant research opportunities remain for clinicians and scientists to improve the diagnostic accuracy and clinical outcomes of chronic intestinal infections.

Role of dendritic cells in the pathogenesis of Whipple's disease.

Accumulation of Tropheryma whipplei-stuffed macrophages in the duodenum, impaired T. whipplei-specific Th1 responses, and weak secretion of interleukin-12 (IL-12) are hallmarks of classical Whipple's disease (CWD). This study addresses dendritic cell (DC) functionality during CWD. We documented composition, distribution, and functionality of DC ex vivo or after in vitro maturation by fluorescence-activated cell sorting (FACS) and by immunohistochemistry in situ. A decrease in peripheral DC of untreated CWD patients compared to healthy donors was due to reduced CD11c(high) myeloid DC (M-DC). Decreased maturation markers CD83, CD86, and CCR7, as well as low IL-12 production in response to stimulation, disclosed an immature M-DC phenotype. In vitro-generated monocyte-derived DC from CWD patients showed normal maturation and T cell-stimulatory capacity under proinflammatory conditions but produced less IL-12 and failed to activate T. whipplei-specific Th1 cells. In duodenal and lymphoid tissues, T. whipplei was found within immature DC-SIGN(+) DC. DC and proliferating lymphocytes were reduced in lymph nodes of CWD patients compared to levels in controls. Our results indicate that dysfunctional IL-12 production by DC provides suboptimal conditions for priming of T. whipplei-specific T cells during CWD and that immature DC carrying T. whipplei contribute to the dissemination of the bacterium.

Whipple's disease concomitant with candida esophagitis and subsequent Giardia lamblia coinfection.

Whipple's disease is a rare systemic condition resulting from a chronic infection by Tropheryma whipplei. Clinical presentation can be widely heterogeneous, often leading to delayed diagnosis and treatment. Furthermore, little is known about the underlying pathogenic mechanisms, although several abnormalities in immune cell function have been observed. We describe the case of a 51-year-old woman presenting with dysphagia, odynophagia, long-lasting low-grade fever, and malabsorption syndrome who underwent an upper gastrointestinal endoscopy showing esophageal candidiasis. On the same occasion, duodenal biopsies were also performed, with evidence of mucosal infiltration of periodic acid-Schiff-positive and CD68+ foamy macrophages at microscopic examination. Such findings were suggestive of Whipple's disease, as also confirmed by molecular analysis by PCR for T. whipplei. No specific risk factors were identified in our patient that could explain the occurrence of an opportunistic infection such as candida esophagitis, thus leading to the hypothesis of a direct correlation with Whipple's disease. Interestingly, a Giardia lamblia coinfection was subsequently identified, which is consistent with an underlying immune deficit although still undefined.

A severe Whipple disease with an immune reconstitution inflammatory syndrome: an additional case of thalidomide efficiency.

We report the case of a 38-year-old man who presented with severe diarrhea, weight loss of 10 kg, ankles paresthesia and severe motor weakness in the left fibular nerve territory after introduction of azathioprine and corticosteroid for proteinuria. Coloscopy and gastroscopy revealed a typical aspect of Whipple disease (WD), associated with both positive PAS staining and specific immunohistochemistry. T. whipplei PCR results were positive in blood, faeces, saliva and duodenal biopsy specimens. Diagnosis of WD with systemic manifestations was retained and doxycycline plus hydroxychloroquine therapy were started. This treatment improved joint pain, and skin and intestinal symptoms. One month later, our patient presented with fever and an important inflammatory syndrome (CRP 150 mg/dL and 16.8 10(9)/L leukocytes), while no infection was found despite a thorough review. We concluded it was an immune reconstitution inflammatory syndrome (IRIS). Manifestations persisted despite increasing corticosteroids and thalidomide (200 mg/day) was introduced with good efficacy on these symptoms. WD may be revealed by non-specific symptoms such as weight loss or arthralgia, but also by many other misleading signs. Our observation illustrates the highly polymorphic clinical presentation of WD, and the diagnostic difficulties that may arise. This is also a new report of thalidomide effectiveness in IRIS in WD.

Constrictive pleuropericarditis: a dominant clinical manifestation in Whipple's disease.

BACKGROUND: Whipple's disease is a rare, multisystemic, chronic infectious disease which classically presents as a wasting illness characterized by polyarthralgia, diarrhea, fever, and lymphadenopathy. Pleuropericardial involvement is a common pathologic finding in patients with Whipple's disease, but rarely causes clinical symptoms. We report the first case of severe fibrosing pleuropericarditis necessitating pleural decortication in a patient with Whipple's disease. CASE PRESENTATION: Our patient, an elderly gentleman, had a chronic inflammatory illness dominated by constrictive pericarditis and later severe fibrosing pleuritis associated with a mildly elevated serum IgG4 level. A pericardial biopsy showed dense fibrosis without IgG4 plasmacytic infiltration. The patient received immunosuppressive therapy for possible IgG4-related disease. His poor response to this therapy prompted a re-examination of the diagnosis, including a request for the pericardial biopsy tissue to be stained for Tropheryma whipplei. CONCLUSIONS: Despite a high prevalence of pleuropericardial involvement in Whipple's disease, constrictive pleuropericarditis is rare, particularly as the dominant disease manifestation. The diagnosis of Whipple's disease is often delayed in such atypical presentations since the etiologic agent, Tropheryma whipplei, is not routinely sought in histopathology specimens of pleura or pericardium. A diagnosis of Whipple's disease should be considered in middle-aged or elderly men with polyarthralgia and constrictive pericarditis, even in the absence of gastrointestinal symptoms. Although Tropheryma whipplei PCR has limited sensitivity and specificity, especially in the analysis of peripheral blood samples, it may have diagnostic value in inflammatory disorders of uncertain etiology, including cases of polyserositis. The optimal approach to managing constrictive pericarditis in patients with Whipple's disease is uncertain, but limited clinical experience suggests that a combination of pericardiectomy and antibiotic therapy is of benefit.

Immunopathology of immune reconstitution inflammatory syndrome in Whipple's disease.

During antimicrobial treatment of classic Whipple's disease (CWD), the chronic systemic infection with Tropheryma whipplei, immune reconstitution inflammatory syndrome (IRIS), is a serious complication. The aim of our study was to characterize the immunological processes underlying IRIS in CWD. Following the definition of IRIS, we describe histological features of IRIS and immunological parameters of 24 CWD IRIS patients, 189 CWD patients without IRIS, and 89 healthy individuals. T cell reconstitution, Th1 reactivity, and the phenotype of T cells were described in the peripheral blood, and infiltration of CD4(+) T cells and regulatory T cells in the duodenal mucosa was determined. During IRIS, tissues were heavily infiltrated by CD3(+), predominantly CD45RO(+)CD4(+) T cells. In the periphery, initial reduction of CD4(+) cell counts and their reconstitution on treatment was more pronounced in CWD patients with IRIS than in those without IRIS. The ratio of activated and regulatory CD4(+) T cells, nonspecific Th1 reactivity, and the proportion of naive among CD4(+) T cells was high, whereas serum IL-10 was low during IRIS. T. whipplei-specific Th1 reactivity remained suppressed before and after emergence of IRIS. The findings that IRIS in CWD mainly are mediated by nonspecific activation of CD4(+) T cells and that it is not sufficiently counterbalanced by regulatory T cells indicate that flare-up of pathogen-specific immunoreactivity is not instrumental in the pathogenesis of IRIS in CWD.

[Neurological complications of inflammatory bowel diseases]. / Neurologische Komplikationen entzündlicher Darmerkrankungen.

Inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, autoantibody driven celiac disease and infectious Whipple's disease can all be associated with neurological symptoms. The neurological manifestation may occur even before the gastrointestinal symptoms or the enteropathic symptoms can even be absent as in celiac disease. These diseases can be caused by malresorption and lack of vitamins due to enteral inflammation as well as (auto-)immunological mechanisms and drug-associated side effects. Thus, inflammatory bowel diseases have to be considered in the differential diagnosis. In this review the most common neurological manifestations of these diseases will be described as well as the diagnostic approach.