Personal ViewGluten sensitivity: from gut to brain
Introduction
Coeliac disease was first described in 100 AD by the Greek doctor Aretaeus,1 who used the term abdominal diathesis. When his extant works were first published in Latin in 1552, the Greek word for abdominal, koiliaki, was transcribed to coeliac. The study of coeliac disease was renewed by Gee2 in 1888. His lecture on the coeliac affection described the disease according to his observations while treating children with the disease. Although clinicians began to recognise and diagnose coeliac disease, its aetiology remained obscure until 1953 when Dicke and colleagues3 reported “the presence in wheat, of a factor having a deleterious effect in cases of celiac disease”. Because gastrointestinal symptoms were dominant in patients with coeliac disease, and enteropathy was seen after enteroscopy and small bowel biopsy, it is not surprising that coeliac disease was thought to be exclusively a disease of the gut. In 1963–65, Shuster, Marks, and Watson4 observed that dermatitis herpetiformis was a form of gluten-sensitive dermatopathy that shared the same small bowel pathology, but not the gastrointestinal symptoms seen in patients with coeliac disease. This was the first reported evidence that coeliac disease might present with extraintestinal manifestations.
Few case reports of patients with malabsorption or steatorrhoea (also referred to as sprue) and neurological manifestations5, 6, 7 were published before the discovery of the aetiology of coeliac disease and the introduction of jejunal biospy, which identified the typical histological features that define coeliac disease.8 Such reports need to be treated with caution as a definite diagnosis of coeliac disease had not been made in patients. When the first comprehensive report of neurological manifestations in the context of histologically confirmed coeliac disease was published in 1966,9 the assumption was that such manifestations were caused by vitamin deficiencies secondary to malabsorption as a result of the enteropathy. The patients were undernourished, with severe weight loss, low albumin, and often multiple vitamin deficiencies. Detailed post-mortem data from the same report, however, showed an inflammatory process that primarily, but not exclusively, affected the cerebellum, and also involved other parts of the CNS and peripheral nervous system. This finding favoured an immune-mediated pathogenesis.
Single and multiple case reports of patients with established coeliac disease who then developed neurological dysfunction continued to be published.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 The key findings from these reports were that ataxia (with and without myoclonus) and neuropathy were the most common manifestations; neurological manifestations were usually reported in the context of established coeliac disease and were almost always attributed to malabsorption of vitamins; and the effects of dietary restriction were inconsistent. A gluten-free diet did not always alleviate neurological dysfunction, although assessment of the effect of the gluten-free diet was not the main aim of these reports. None of the reports documented any attempts to monitor adherence to the diet with repeat serological testing.
In 1996, 30 years after publication of the first comprehensive case series on neurological manifestations of coeliac disease, we investigated the prevalence of gluten sensitivity in patients who presented with neurological dysfunction of unknown aetiology; most patients had ataxia either with or without neuropathy.30 Presence of antigliadin antibodies (AGA) in these patients was common compared with controls. AGA were the only readily available serological markers of coeliac disease when the study was done (with the exception of R1-type antireticulin antibodies; endomysium antibodies were gradually introduced into clinical practice in the mid-1990s). On the basis of duodenal biopsy samples, results from this study indicated that the prevalence of coeliac disease in these patients was 16 times higher than the prevalence of coeliac disease in the healthy population. These data rekindled the interest of neurologists in a possible link between gluten sensitivity and certain neurological presentations.
Section snippets
Epidemiology
The prevalence of coeliac disease in the healthy population is at least 1%.31, 32 There are no accurate estimates of the prevalence of the neurological manifestations of gluten sensitivity in the general population. A range of 10% to 22·5% for the prevalence of neurological dysfunction among patients with established coeliac disease has been reported,33, 34 but is unlikely to be accurate because such numbers are usually derived retrospectively from gastrointestinal clinics and thus focus
Diagnosis of gluten sensitivity presenting with neurological manifestations
Most patients who present with neurological manifestations of gluten sensitivity have no gastrointestinal symptoms. Patients with coeliac disease might not have gastrointestinal symptoms either. Therefore, gluten sensitivity cannot be diagnosed on a clinical basis alone. Several diagnostic tests are now available that can help to decide whether patients might have coeliac disease or gluten sensitivity with extraintestinal manifestations with or without enteropathy. Figure 1 is a diagnostic flow
Limitations of conventional approach for diagnosis
Coeliac disease is characterised by the presence of an enteropathy, a practicable and mostly reliable gold standard of diagnosis. However, an enteropathy is not necessarily a prerequisite for the diagnosis of gluten sensitivity with predominantly neurological manifestations. Gluten sensitivity causes a range of changes in the small bowel mucosa—from histologically normal mucosa to full-blown enteropathy to a pre-lymphomatous state. This range is categorised by the Marsh classification, which is
Genetics
Gluten sensitivity is strongly heritable, with about 40% of the genetic load coming from MHC class II association.43 In white populations, more than 90% of patients with coeliac disease carry the HLA DQ2.5 variant (DQA1*05-DQB1*02) and most other patients carry HLA-DQ8 (DQA1*03-DQB1*0302). A few patients with coeliac disease do not belong in either of these groups but carry just one chain of the DQ2 heterodimer, either DQA1*05 (DQ7) or DQB1*02 (DQ2.2), but not both.44 Of the two heterodimers,
Neurological manifestations of gluten sensitivity
The range of neurological manifestations of gluten sensitivity encountered in our specialist clinic over the past 15 years are listed in table 2.
Neurological deficits are immune mediated
Current evidence suggests that neurological manifestations are immune mediated. Vitamin and trace element deficiencies rarely play a part, particularly as most patients with neurological manifestations have no enteropathy and are thus not prone to malabsorption and vitamin deficiencies. Post-mortem examination from patients with gluten ataxia showed patchy loss of Purkinje cells throughout the cerebellar cortex, a common finding in many end-stage diseases of the cerebellum (figure 3D).9, 111
Conclusions and future directions
Gluten sensitivity is a common disease that can manifest in diverse ways. As screening for gluten sensitivity has become a reality in clinical practice, and as more details of the individual genetic background that leads to aberrant immune responses are being revealed,43 emphasis is likely to shift towards the early identification of patients who are specifically at risk of severe, and sometimes permanent, complications (eg, T-cell lymphoma, liver failure, neurological deficits). New diagnostic
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