Gluten ataxia: when grain attacks brain
|Like its better known relatives coeliac disease and dermatitis herpetiformis, gluten ataxia is triggered by gluten in the diet – and it is only in more recent years that we have begun to get a clearer picture of this potentially highly disabling condition. Alex Gazzola reports.|
Even though it is sometimes unfairly depicted as a universal dietary evil, gluten can without doubt cause severe damage to health.
Coeliac disease (CD) – the most well understood of the gluten-related disorders – is an autoimmune (‘self attacking’) disorder where gluten triggers a chain of events leading to the erosion of the lining of the gut wall, with potential consequences of diarrhoea, abdominal pain and malnutrition, weight loss, anaemia and extreme tiredness.
Meanwhile, dermatitis herpetiformis (DH) – sometimes viewed as the skin manifestation of CD, but considered by others as a fellow gluten-related autoimmune condition in its own right – is characterised by severe pruritus (itchiness), stinging, and red raised patches of skin, often with blisters – quite often on the elbows and knees (symmetrically, on both sides), but also on the buttocks and scalp.
Until relatively recently, far less understood have been the neurological, or nerve-centred, symptoms which can also be triggered by gluten. Although we have known for many years that such effects have been a part of the spectrum of CD symptoms, what is only now being realised is that they can also manifest in the absence of ‘traditional’ CD.
Much of our new understanding is down to the work of Marios Hadjivassiliou, Professor of Neurology at Sheffield Teaching Hospitals NHS Foundation Trust and the University of Sheffield, and his colleagues. Hadjivassiliou first suspected a direct link between gluten and neurological disorders in 1990 – a view which was initially met with scepticism among some in the medical community, who had assumed such symptoms were mere consequences of malnutrition due to malabsorption in the damaged coeliac gut.
In 1996, he established the Sheffield Ataxia Centre – a weekly clinic and specialist centre for the diagnosis, care and management of patients with all forms of progressive ataxias, in particular gluten ataxia, immune-mediated ataxias and so-called idiopathic ataxias, which have no known cause.
Hadjivassiliou describes gluten ataxia (GA) as a third autoimmune condition triggered by gluten. In common with the other ataxias, symptoms include problems with walking, limb co-ordination, manual and digital manipulation, as well as balance difficulties, speech problems, helpless twitching, difficulty swallowing, and poor control over eye movements.
Underlying GA is damage to the part of the brain called the cerebellum, which is responsible for controlling fundamental bodily functions of co-ordination and movement, and which is in some ways analogous to the damage in the gut of classic CD.
The SAC’s research has found that GA accounts for one in six of all ataxias, and 40% of ataxias for which no other cause can be found.
Neuropathies – and other neurological symptoms
Neuropathy is damage to the body’s nerves.
Peripheral neuropathy is nerve damage in the parts of the nervous system outside the spinal cord and brain. This is typically experienced as tingling and numbness in the hands and feet, a common symptom in gluten-related neuropathy. This is called sensory neuropathy.
Motor neuropathy is difficulty in using the arms, hands, feet and legs.
Gluten neuropathy accounts for 26% of all neuropathies, and 34% of all neuropathies for which no other cause can be found.
Although ataxia and neuropathy are the most common manifestations of gluten-related neurological disorders, others have been identified. These include:
* encephalopathy (stubborn headaches and migraines, with white matter abnormalities in the brain;
The National Institute for Health and Clinical Excellence’s (NICE) relevant guidelines – Coeliac Disease: recognition, assessment and management – updated in 2015, recommend that doctors should “consider serological testing for coeliac disease in people with … unexplained neurological symptoms (particularly peripheral neuropathy or ataxia)”.
Although awareness among GPs of this connection is growing, there is still the problem that gluten-related disorders have traditionally been viewed as gut-related, and in the absence of any gastrointestinal symptoms, many doctors may not consider gluten as a potential culprit when patients present with neurological issues – at least not in the early stages of the diagnostic process.
There is a further problem. Even if suspicions lead an enlightened GP to order gluten antibody blood testing, traditional tests may not necessarily be positive in a patient with GA – as they may not have co-existing CD.
The tissue transglutaminase test looks for IgA antibodies to that enzyme, produced when the gut tries to repair gluten damage. The test is specific, in that it gives few false positive results – but is gut-centred. The same applies to the anti-endomysial antibody test, which looks for antibodies against tissue called endomysium, which joins cells together, and is sometimes used as an adjunct to the tissue transglutaminase test.
The anti-gliadin tests (IgA and IgG) look for antibodies to gliadin, which is the toxic fraction of gluten that causes coeliacs problems. The test is not highly specific, in that it often records false positives, but it may be more useful in flagging potential gluten ataxia or neuropathy. If levels are high, and all other potential causes have been ruled out, a gluten-free diet (GFD) may be recommended.
A ‘New’ Antibody
One of the most important pieces of research that Hadjivassiliou and his colleagues have been involved in in recent years concerns finding new blood markers for gluten neuropathy and ataxia.
He has discovered that patients may not produce the ‘usual’ gluten-related tissue transglutaminase antibodies found in patients with CD – which are called tissue transglutaminase-2 (tTG2) – nor those found in DH – which are tissue transglutaminase-3 (tTG3) – but instead they appear to produce a different variety called tissue transglutaminase-6 (tTG6), which the standard test does not recognise.
Antibodies against tTG6, he has found, are a more reliable, sensitive and specific marker for gluten-related neuropathy and ataxia than anti-gliadin antibodies, work which was published in the journal Neurology in 2013. The team found that 73% of those with positive anti-gliadin antibodies and ataxia were positive for tTG6, while 32% of those with idiopathic ataxia, negative for all CD serology, were positive for tTG6 antibodies, and responded to a GFD.
Although tests for this ‘new’ form are not yet widely available, this discovery could pave the way for the eventual development of a routine blood test.
Hadjivassiliou’s team’s research has found that for every 7 patients diagnosed with CD presenting to a gastroenterology clinic, 2 patients are diagnosed with CD presenting to a neurology clinic.
How common is neurological dysfunction in patients with newly diagnosed CD? Hadjivassiliou’s team undertook a three-year prospective study, completed in 2014. Data taken from 100 consecutive patients revealed 61% had neurological symptoms, 45% intractable headaches, 26% balance problems and 14% sensory symptoms. Of the 100, 42% had evidence of neurological dysfunction on clinical examination, and 38% of dysfunction of the cerebellum.
In terms of differences between patients presenting with neurological versus gastrointestinal symptoms, it is worth noting the former tend to be older – an average of 61 versus 47 – and tend to be more severely affected neurologically at the time of presentation (both in terms of symptoms and clinical testing).
Gluten neuropathy improves within a year of a strict GFD.
Similar results have been found thanks to earlier research on gluten encephalopathy, where 9 out of 10 patients with intractable headaches, and high prevalence of white matter abnormalities detected on MR imaging, experienced total symptomatic relief by following the GFD.
GA does partly improve within a year of a very strict GFD, even in those patients who do not have the ‘traditional’ enteropathy in the gut associated with classical CD. However, a degree of permanent disability may result. It seems that the longer the cause of the disease remains undetected, the less likely the patient is to experience noticeable improvement or stabilisation once settled into a GFD.
In GA, it is cells in the brain’s cerebellum called Purkinje cells which are damaged, and these control the balance function. They do not regenerate, and so prolonged exposure to gluten cannot be reversed, leading to permanent detrimental effects. This is unlike coeliac disease, where the gut lining almost always repairs itself fully over time. It is thought that avoiding cross-contamination of trace gluten at lower levels may be even more important in GA than in CD – as the cells lining the gut may be more ‘forgiving’ or ‘tolerant’ towards minute gluten exposure than Purkinje cells.
There remain key questions that remains as far as this fascinating subject is concerned – and some may be revealed by further work on the genetics of gluten-related disorders.
First, what determines the target of the autoimmune response – be it tTG2, tTG3 or tTG6 – and the primary clinical manifestation in gluten-related disorders?
And second, how can we predict extra-intestinal manifestations using the detected presence of these three antibodies? This can only be understood by researching the effects on patients diagnosed with an auto-immune gluten-related disorder who are unwilling to switch to a GFD, which is obviously unusual and difficult. From the few cases he has personally overseen, Hadjivassiliou suspects that non-adherence to a GFD may lead to additional gluten-related auto-immune disorders developing further down the road.
Sheffield Hospital’s Gluten Ataxia Patient Information Leaflet (PDF download).