Demyelinating inflammatory neuropathies have been the focus of most research on peripheral neuropathies; yet axonal neuropathies are by far the most common type of neuropathies encountered in everyday neurological practice.12,13
This large prospective study has attempted to identify a prevalence figure (among patients with sporadic axonal neuropathy) and clinically characterise gluten sensitivity‐related neuropathy. Data on the prevalence of other causes of axonal neuropathies are also presented in this study, but are unlikely to represent the true prevalence of each aetiology in the general population because of referral bias. For example, in this study, diabetes accounted for 11% of all the neuropathies but was found to be the cause of neuropathy in >50% of patients in another study.12
In the UK, patients with established and poorly controlled diabetes who have a neuropathy are less likely to be referred to neurology clinics, given that the aetiology and treatment of their neuropathy is apparent. In this study for most patients with non‐insulin‐dependent diabetes, the diagnosis of diabetes was made on the basis of the aetiology of the neuropathy. The figures of prevalence for the different aetiologies of neuropathy found in this study reflect more closely what is seen in a long‐established general neurology clinic where patients with chronic axonal neuropathies are followed up long term.
The principal aim of this study was to investigate the prevalence of gluten sensitivity among patients with chronic idiopathic axonal neuropathy as defined by the presence of antigliadin antibodies. To avoid referral bias (in view of our interest in the neurological manifestations of gluten sensitivity), we deliberately excluded any patients referred to the gluten sensitivity/neurology clinic with an established diagnosis of gluten neuropathy. The prevalence of antigliadin antibody positivity was 34% in patients with otherwise idiopathic axonal neuropathy compared with 9% in patients with established cause of neuropathy and 12% in controls from the same region.10
The prevalence of coeliac disease among these patients was found to be at least 9% and compares with 1% in the controls from the same region.10
It is also possible that in those seven patients with neuropathy of known aetiology (two patients with type 1 diabetes and five patients with low vitamin B12
) who also had antigliadin antibodies, the aetiology of the neuropathy could be linked to gluten sensitivity rather than to diabetes or low vitamin B12
. We, however, found no correlation between vitamin B12
deficiency and the presence of enteropathy.
A previous controlled study has shown that as many as 23% of patients with established coeliac disease on a gluten‐free diet showed axonal neuropathy on neurophysiological testing.8
Given that at least 1% of the healthy population in European countries and the US has coeliac disease and up to 12% has serological evidence suggestive of gluten sensitivity, such sensitivity may well prove to be a common aetiological link to chronic idiopathic axonal neuropathy.
Some clinicians choose to distinguish between those patients with gluten sensitivity who have an enteropathy (coeliac disease) and those without an enteropathy but with positive serological markers for gluten sensitivity. The rationale for this is not clear, as gluten sensitivity represents a spectrum ranging from antibody‐positive but normal small‐bowel mucosa (often referred to as potential coeliac disease or Marsh stage 01
) to the presence of the classic small lesions on a biopsy sample, which define coeliac disease. The range of changes seen on examination of the small‐bowel mucosa, which may relate to gluten load, has been documented in detail and is now known as the Marsh classification.14
Thus, in the case of our patients with peripheral neuropathy associated with gluten sensitivity, there is nothing on clinical, genetic or immunological grounds to distinguish between patients with or without enteropathy. Extraintestinal manifestations can be the presenting feature of this disease (eg, dermatitis herpetiformis, gluten ataxia), and such manifestations can be successfully treated with a gluten‐free diet even in the absence of enteropathy.15
We therefore propose the term “gluten neuropathy” to describe this entity. Such a term encompasses patients with positive antigliadin antibodies with or without the bowel being affected (coeliac disease) and in the absence of an alternative aetiology for the neuropathy. The HLA type may offer additional diagnostic value, given that 80% of these patients have HLA‐DQ2 or HLA‐DQ8. Tissue transglutaminase and antiendomysium antibodies are good markers for the presence of an enteropathy (coeliac disease) but lack sensitivity when the bowel mucosa is normal and the disease presents with extraintestinal manifestations. Some patients reported in this study probably had a neuropathy that was coincidentally rather than aetiologically linked with the presence of circulating antigliadin antibodies. This is inevitable given that as yet there are no specific serological markers for the neurological spectrum of gluten sensitivity. Antigliadin antibodies currently remain the most sensitive markers of the whole spectrum of gluten sensitivity. The prospect of an additional marker seems imminent after the recent discovery that in vivo IgA deposits against tissue transglutaminase type 2 in the small‐bowel biopsy specimens of patients with diverse manifestations within the spectrum of gluten sensitivity are detected even in the absence of enteropathy. Such deposits have also been found in extraintestinal tissue, such as vessels in the cerebellum in patients with gluten ataxia. This marker seems to be highly specific for the whole spectrum of gluten sensitivity, as it was not found to be present in healthy and disease control subjects.16
The pathophysiology of gluten neuropathy remains unclear. Nutrient and vitamin deficiencies are unlikely to play a part, given that most of these patients have a normal nutritional status and no enteropathy. The mechanism is more likely to be immunological along the same lines as gluten ataxia.17
The pathology is that of an inflammatory process as outlined in this study and reported previously.7
This process can clearly affect peripheral nerves as well as the central nervous system.18,19,20
More often than not, however, the biopsy findings are those of axonal degeneration without evidence of inflammation. Patients with gluten sensitivity may rarely present with a rapidly progressive neuropathy, often associated with involvement of the central nervous system, as described for case 3 in Neuropathological findings. Such cases have previously been described by Cooke and Thomas‐Smith.20
On the basis of this study and the review of published case reports, the most common neuropathy encountered in the context of gluten sensitivity is that of a chronic slowly progressive symmetrical sensorimotor axonal distally predominant peripheral neuropathy. Further evidence in support of gluten neuropathy being immune mediated comes from a report on the presence of antiganglioside antibodies in patients with coeliac disease and neuropathy.21
Why the same disease (gluten sensitivity) results in both symmetrical and at times asymmetrical neuropathy (mononeuropathy multiplex), or even pure motor or sensory neuropathy remains unclear. This diverse pattern of peripheral nerve involvement is also seen in other diseases such as diabetes mellitus or neuropathy associated with connective tissue diseases. In one of our patients with gluten sensitivity, we observed progression of the motor neuropathy to involvement of sensory fibres with continuous exposure to gluten.22
It is yet unclear whether the aetiology of the mononeuropathy multiplex seen in some of these patients with gluten sensitivity is mediated through a low‐grade vasculitic process.
We conclude that serological evidence of gluten sensitivity is commonly found in chronic idiopathic axonal neuropathies and may well be aetiologically linked. The effect of a gluten‐free diet on the neuropathy should confirm whether or not this is another manifestation of gluten sensitivity similar to gluten ataxia, dermatitis herpediformis and gluten‐sensitive enteropathy.