Coeliac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten in genetically susceptible individuals. Classical CD typically presents to gastroenterologists with a combination of abdominal pain, diarrhea, bloating, anemia and other gastrointestinal symptoms [1
]. Over the past decades, a shift in presentation has been observed from these classic symptoms to extraintestinal symptoms in children as well as adults [2
]. A wide range of extraintestinal manifestations has been attributed to CD, changing the classic perception of a disease limited to the intestine, to a multisystem disorder. CD can therefore manifest with dental problems, consequences of malabsorption, skin and neurological disorders [4
]. Some patients can develop refractory CD. This is characterized by persistent villous atrophy despite strict adherence to gluten-free diet. Symptoms are often severe with diarrhea, weight loss and severe malabsorption [5
Cerebellar ataxia and peripheral neuropathy are the most common neurological manifestations [5
]. These can also occur in the absence of enteropathy and are sometimes referred to as non-coeliac gluten sensitivity, or simply gluten sensitivity [7
]. Not much is known about the pathogenesis of such neurological manifestations. However, both humoral and cell-mediated immune mechanisms have been proposed. The aim of this systematic review is to analyze the published neuropathology of confirmed cases of gluten-related neurological dysfunction in an attempt to aid our understanding of the pathogenesis.
This systematic review examined the neuropathological findings in gluten-related neurological disorders. Neuropathological findings in the context of gluten ataxia showed loss of Purkinje cells, cerebellar atrophy and gliosis, especially in the granular layer with also atrophy of the dentate nucleus. However, findings were not limited to the cerebellum, but involved other parts of the central nervous system that are closely linked to the cerebellum such as the pons, inferior olives and thalamus.
While vitamin B1, B3, B6, B12, E deficiencies are well known causes of neuropathy and other neurological disorders and can be a consequence of malabsorption due to untreated CD, they are unlikely to be responsible for the pathology described in this review. Furthermore, in almost all cases discussed in this review other possible causes for the neurological deficit, like genetic causes had been ruled out. This review suggests that the pathophysiology of neurological damage in the context of gluten sensitivity has an immune mediated basis.
Whilst there is a female predominance in CD (2.4 F:1.M) and other auto-immune diseases [44
], the majority of gluten-related neurological disorders affected men (57%). In the ataxia group this percentage was even higher (76%). The median age at onset of neurological complaints was 50.3 years (excluding the two epilepsy cases with onset at age 6 months and 5 years). The median age at time of CD diagnosis was 44.9 years. There is an increased risk of autoimmunity in individuals diagnosed with CD later on in life [45
]. Whether this increased risk can be attributed merely to age and years of gluten exposure is still debated [46
More importantly, in most studies, adherence to a strict gluten-free diet was not monitored. It is therefore unknown whether patients were still exposed to gluten at the time of the development of their neurological dysfunction. [48
A consistent finding in three of the ataxia studies was the presence of diffuse infiltrates and perivascular cuffing with lymphocytes in the cerebellar tissue [9
]. Lymphocytic infiltration was also demonstrated in several nerve biopsies of patients with neuropathy [17
], muscle biopsies of myopathy patients [26
] and in brain tissue of patients with encephalopathy [33
] and epilepsy [42
]. Characterization of these cell infiltrates was only performed by Mittelbronn et al. [15
] who described a cytotoxic T-cell population (CD8+ and granzyme B+), and by Souayah (CD68+/CD45ro+ cell populations) [22
]. The origin and target epitope of these lymphocytes remain unclear. However, these findings strongly support the notion that the pathology is immune mediated and not related to vitamin or trace elements deficiencies.
It is as yet unknown if and how such cells travel from the intestine to the brain. Crossing of the blood-brain barrier may occur after a compromise due to local inflammation [54
]. Nanri et al. [16
] hypothesized a humoral response in which anti-gliadin antibodies also recognize epitopes on Purkinje cells. Indeed Hadjivassiliou et al. have demonstrated that anti-gliadin antibodies cross-react with Purkinje cells in vitro. Previously published work has also shown that sera of gluten ataxia patients strongly stain Purkinje cells in cerebellar rat tissue, even after adsorption with crude gliadin [55
]. In another study the sera of twenty CD patients and twenty healthy controls were applied on rat brain sections. Sixteen CD patient sera showed immune-reactivity for IgA or IgG on Purkinje cells, deep cerebellar nuclei and brainstem neurons whereas only four sera from healthy controls showed immune-reactivity on the rat brain sections. An additional adsorption experiment with recombinant Transglutaminase (TG2) indicated that anti-TG2 antibodies substantially contribute to neuronal epitope recognition. Of interest is that injection of these antibodies into the lateral ventricle of mice resulted in motor dysfunction. The IgA component from the CD patient sera also cross-reacted with Transglutaminase 3 and 6 [56
Transglutaminase 6 (TG6), a member of the Transglutaminase family of protein-crosslinking enzymes and is closely linked to TG2 (the autoantigen in CD) and Transglutaminase 3 (TG3, the autoantigen in dermatitis herpetiformis). Transglutaminase 6 has been proposed as the autoantigen in gluten-related neurological disorders [57
]. IgA deposits against TG6 have been observed in vessels from cerebellar tissue of a patient with gluten ataxia [49
]. Moreover, antibodies against TG6 have been detected in the sera of patients with gluten ataxia (73%) and gluten neuropathy (50%), regardless of enteropathy [59
]. These studies indicate that TG6 antibodies might be helpful in the diagnostic workup of GRND.
The current gold standard for CD diagnosis is based on Transglutaminase 2 (TG2) antibodies (with or without additional testing for endomysium antibodies) followed by histological examination of duodenal biopsies (presence of villous atrophy, crypt hyperplasia and increased intraepithelial lymphocytes). However, even if clinicians consider GRND in a patient with idiopathic neurological complaints, the diagnostic yield using these antibodies is low. This is because the majority of patients with GRND are seronegative for TG2 because they do not have enteropathy [48
]. Therefore a TG2 antibody test is not sufficient to diagnose GRND [50
]. Recent data suggest that a coeliac “lymphogram”, defined as an increase in CD3+ T-cell receptor gamma delta+ (TCRγδ+) intraepithelial lymphocytes (IEL) plus a concomitant decrease in CD3− cells in a mucosal duodenal biopsy, was associated with a sensitivity of 87% (CI, 73.7–95%) and specificity of 96.7% (82.7–99.9%) for CD [52
]. Therefore it might be worthwhile to assess the intraepithelial lymphogram of duodenal biopsies in (suspected) GRND patients that test negative for TG2 but are positive for TG6 and gliadin antibodies.
Addolorato and colleagues observed a state of hypo-perfusion in multiple cerebral brain regions in untreated CD patients compared to gender and age-matched CD patients on a gluten-free diet and healthy control subjects [61
]. In another study, significantly more perfusion abnormalities in the frontal cortex were found in CD patients, regardless of dietary regimen, compared to gender- and age-matched controls [62
]. It is unclear if these findings have a bearing on the cognitive deficits observed in patients with gluten encephalopathy.
Three patients, described by Keller, Dimberg (gluten encephalopathy) and Souayah (small-fiber neuropathy), suffering from RCD [22
] had evidence of aberrant intraepithelial lymphocytes that disseminated into mesenteric lymph nodes, blood, bone marrow and other epithelial tissue like skin or lung [63
]. It is possible that these aberrant T-cells can also enter the central nervous system. This may explain the observation that ataxia with cortical myoclonus can be a phenotype of RCD that is often extremely difficult to treat both from the gut and the brain perspective. Whatever seems to be driving the gut inflammation seems to also be driving the brain inflammation generating the disabling cortical myoclonus and the ataxia.
Future studies should focus on the characterization of lymphocytes found in brain tissue or CSF and clonality studies may be able to clarify if they originated from the gut. In addition investigating the role of TG6 as a target autoantigen in neurological manifestations may shed light to the pathophysiology of GRND.