Neurological Dysfunction in Coeliac Disease and Non-coeliac Gluten Sensitivity

Marios Hadjivassiliou, MD; Dasappaiah G. Rao, MD; Richard A. Grünewald, DPhil; Daniel P. Aeschlimann, PhD; Ptolemaios G. Sarrigiannis, MD; Nigel Hoggard, MD; Pascale Aeschlimann, BSc; Peter D. Mooney, MD; David S. Sanders, MD


Am J Gastroenterol. 2016;111(4):561-567. 

In This Article


This retrospective review of probably the largest cohort of patients presenting with neurological manifestations of GRD suggests that there are no clear distinguishing neurological features between those patients with CD and those with NCGS. Furthermore, the spectrum, severity, and response to GFD of these neurological manifestations were very similar between the two groups with some minor exceptions: gluten encephalopathy was more commonly associated with enteropathy, whereas neuropathy and ganglionopathy were less commonly associated with enteropathy. In terms of severity, patients in Group 1 tended to have a more severe neuropathy than those in Group 2. Irrespective of these differences, the neurological manifestations in both groups were equally responsive to a GFD. We have also previously shown that a subgroup of patients with gluten ataxia and myoclonus were more likely to belong to Group 1 (i.e., had enteropathy) and often had refractory CD.[16] We have previously reported the beneficial effect of GFD in patients with gluten ataxia and gluten neuropathy.[6,13] In those studies, we again showed that the benefit of the diet was independent of the presence of enteropathy.

NCGS belongs to the spectrum of GRD, but the pathogenesis, unlike CD, remains unclear. Involvement of innate immunity has been proposed.[17] It is as yet unclear if the antigenic stimulus relates to gluten peptides or another component of wheat, e.g., amylase trypsin inhibitors.[18]

However, the mucosal cytokine profile after short-term gluten challenge observed in a recent study also implicates the adaptive immune system and this notion is also consistent with the AGA response seen in NCGS.[19] Support for a role for the adaptive immune system also comes from another recent study showing that a significant number of patients with CD (29%) and NCGS (29%) develop other autoimmune disorders when compared with patients with irritable bowel syndrome (4%).[20]

The role of autoimmunity in CD is well established with a recognized target autoantigen in the form of TG2. The same is true for DH where the target antigen is TG3, an epidermal TG.[9] We have previously shown that patients with gluten ataxia appear to have an immunological response against a primarily brain expressed TG, TG6.[12] All three TGs are capable of deamidating disease-relevant gliadin peptides and form thioester complexes with gliadin peptides, and therefore form entities that drive T- and B-cell responses, respectively.[21] The prevalence of TG6 autoantibodies in the two groups was comparable (67% and 60%, respectively, in Groups 1 and 2). This is in contrast to what was observed with TG2 antibodies that were more prevalent in the group with CD compared with NCGS (91% and 29%, respectively). This observation suggests that the immunological trigger in neurology patients is distinct. Unlike CD that is characterized by TG2 overexpression and activity in the intestinal mucosa, which drives the immunological response, such abundance and overwhelming activity is unlikely the case for TG6, or TG3 in DH, and hence the response is much more subdued (at least as reflected by the level of serum antibodies), perhaps also explaining the absence of the full-blown symptoms of enteropathy. It remains to be seen if an enhanced expression and activation of TG6 akin to the TG2 response in gut occurs at the site involved, i.e., within the cerebrospinal fluid in cases of gluten ataxia.

The presence of TG6 antibodies in a group of patients without the HLA-DQ2 or -DQ8 also suggests that production of such antibodies is not always strictly linked to the HLAs conferring risk for CD. Moreover, of interest is the fact that in the group of patients with neurological manifestations and no enteropathy who had either HLA-DQ2 or -DQ8, there was significant over-representation of DQ8 (29%) when compared with Group 1 (4%). This indicates that differences exist in the HLA profile that predisposes to TG6 as opposed to TG2-driven autoimmunity. It remains to be seen if DQ8 and possibly DQ1 prove to be important susceptibility HLAs for the NCGS neurology cohort.

To investigate any influence of the HLA type and the presence or absence of TG2 antibodies within the NCGS group (Group 2), we also analyzed the data by dividing Group 2 into those with and without HLA-DQ2 or -DQ8 (see Table 1) and those with and without positive TG2 antibodies (Figure 3). Neither of these two parameters substantially influenced the type and severity of the neurological manifestations.

The presence of TG6 antibodies in 38% of patients with newly diagnosed CD presenting with the classic gastrointestinal symptoms to a gastroenterologist may suggest that these patients are susceptible to future development of neurological dysfunction if they continue to consume gluten. This is also supported by the fact that patients with CD presenting with neurological problems are likely to be diagnosed with CD significantly later (mean age 52.6±15.3 years) when compared with those presenting with gastrointestinal symptoms (mean age 43.8±15 years). It could be argued that the presence of gastrointestinal symptoms offers a therapeutic advantage to these patients as it increases the likelihood of them being diagnosed and treated early, as opposed to the neurology patients who on average are diagnosed 10 years later.

As yet, it is unknown at what stage of the immunological response against gluten that TG autoantibodies (TG2, TG3, and TG6) are first produced and appear systemically in relation to the development of symptoms. Although inferable from various lines of evidence, it has not been directly demonstrated that the patients with neurological manifestations (particularly those with CNS involvement) have such antibodies in their cerebrospinal fluid, and whether these antibodies are produced locally or derived from the circulation. However, immunoglobulin deposits against TG6 can be found in the cerebellum of patients with GA and deposits against TG2 can be found in the brain vessel wall in patients with GA.[12,22]

Further evidence in support of a role for TG antibodies in disease pathogenesis comes from mouse models. TG antibodies (TG2 and TG6) cause ataxia-like deficits following intraventricular injection.[23] Antibodies forming the characteristic deposits in the papillary dermis in DH are derived from the circulation, indicating that extraintestinal manifestations of GRD are antibody mediated.[24] Furthermore, HLA-DQ8 transgenic mice develop some features of gluten sensitivity analogous to NCGS that are gluten dependent.

An important finding in this study is that patients with NCGS can present with neurological dysfunction in an identical manner to those patients with CD, suggesting similar immunological processes being responsible at least for the neural damage. This is also supported by the similar prevalence of TG6 antibodies in the two groups.

All the neurology patients described in this report were selected on the basis of positive antigliadin antibodies. Unfortunately, this serological test is no longer in general use as immunology laboratories are preferentially using newer assays (e.g., deamidated gliadin, endomysium, and TG2 antibody assays). These newer assays are far superior for diagnosing CD as they are based on specific molecular events occurring in CD pathogenesis, but unfortunately such assays are of limited use in the diagnosis of patients without enteropathy (Group 2) where molecular preferences show a bias that is distinct. Hence, in cases without enteropathy, the less selective marker AGA can provide an indication that further investigation is warranted, although not diagnostic by itself. In our experience, patients with NCGS are equally likely to respond to a strict GFD as are those patients with CD and neurological manifestations. Although TG6 antibody testing appears to be more specific for the neurological manifestations even in the absence of enteropathy, it is not as yet readily available. Currently, the best approach would be to include all serological testing (TG2, TG6, anti-endomysium antibodies, AGA) for patients suspected of having GRD.

Increasing recognition of the whole spectrum of GRD is the only way of improving diagnosis and thus avoiding the common problem of patients with neurological manifestations remaining untreated if duodenal biopsy does not reveal an enteropathy.