Diagnosis of gluten-sensitive neuropathies without a clear cause is on the rise. These idiopathic neuropathies were first identified by screening for anti-gliadin IgG (AGA).[1] The criteria has been critiqued because of the large misdiagnosis rate of coeliac disease (CD), and because AGA exists in the normal population at >12%, far more abundant than cases of neuropathy.[2] The problem in diagnosis arises because there are precursor states prior to coeliac disease. These are called subclinical coeliac disease and early gluten-sensitive enteropathy and are defined as Marsh grade 1 and 2 coeliac disease.[3] Coeliac disease was diagnosed by duodenal biopsy, frequently misinterpreted as negative as high as grade 3 on the Marsh scale. Anti-gliadin antibodies may precede or lag the appearance of coeliac disease. Studies in Scandinavia found an increase of pathologies as much as 10 years in advance of coeliac disease. These included gastrointestinal symptoms, anemia or other autoimmune disease. In addition IgG and IgA responses sometimes accompany allergic responses to proteins. Gliadin is exceptional in that it has several proteins which remain peptides of considerable length after digestion, and migrate into systemic circulation.
There is a controversial subset of people with idiopathic neuropathies and anti-gliadin antibodies that fail to fit all enteropathic criteria except anti-gliadin antibodies. About 1/3 have no DQ2 or DQ8 and an apparent abundance of HLA-DQ1. One percent of coeliacs in Europe have no DQ2 and DQ8 but have DQ1. The DQ1 serotype is very common in the normal population, over 65% of Americans have one copy, therefore the linkage is speculative.
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Gluten involvement in idiopathic neuropathies was first defined as neurological dysfunction of an unknown cause associated with increased anti-gliadin antibodies.[1] Early studies primarily focused on "gluten ataxia" and peripheral neuropathies.[4] In the period preceding these early studies saw the recognition of gluten's role in coeliac disease, the development of methods of biopsy, and improved serological analysis. However, the test for gliadin antibodies included substantial false positives. Many people, 5 to 20%, have anti-gliadin antibodies. During the period prior to extensive serological testing, children were much more frequently diagnosed than adults. Many patients suffering from associated autoimmune diseases were not routinely tested for celiac disease. During the subsequent period better testing for subclinical coeliac disease evolved, better antibody tests for coeliac disease became common, and a growing proportion of adults relative to children have been diagnosed with coeliac disease. Therefore the primary concern with idiopathic gluten sensitivity or gluten sensitive idiopathic disease is how carefully the enteropathic cohort of gluten-sensitivity has been removed.[5] In coeliac disease a number of neurological pathologies are associated, these can be generally linked to systemic stress (vitamin or mineral deficiencies) or secondary inflammatory conditions.[6] Anti-neuronal antibodies, epilepsy and white matter lesions are all increased in celiac disease, and studies of subclinical disease finds some extra-intestinal inflammatory conditions can precede coeliac disease.[7][8]
In addition to an increase in anti-gliadin antibodies a HLA-DQ association has been suggested. Since there is a component of latent or subclinical coeliac disease within the idiopathic population it is not surprising an association with DQ2 was found. Also suggested was a link to DQ1.
In gluten ataxia, early studies of disease identified a number patients with idiopathic cerebellar ataxia that had coeliac disease or signs of enteropathy.[4][9][10][11] The ataxia, which involved gait and often limbs, was often associated with higher anti-gliadin antibodies. Gluten sensitivity was also suggested as a rare but possible cause of cerebral ataxia in small children[12] Each of these studies uncovered a higher than expected number of coeliacs relative to the general population, but a subset of ataxia remained with elevated anti-gliadin antibodies.[13] This idiopathic gluten ataxia may have anti-purkinje antibodies that are not adsorbed by gliadin.[14] A gluten-free diet may improve gluten ataxia in the idiopathic subset, however a percentage did not respond to the diet.[15] Other studies find no association between anti-gliadin antibodies and idiopathic cerebral ataxia. Still other studies suggest that a gluten-free diet has no impact on the course of disease.[4][16] Both the proponents and critics of gluten ataxia have produced studies that lacked the proper sample size or controls to be considered objective.[4]
The link of peripheral neuropathies with gluten-sensitive enteropathy is considerably stronger than with gluten ataxia. Coeliacs complain of burning, tingling or numbness in the hands or feet with some sensory loss.[4][17] In addition axonopathy, nultifocal axonal polynephropathy, small-fiber neuropathy, motor neuropathy and anti-ganglioside antibody are found in coeliac disease. A few studies report idiopathic neuropathies which were not defined as enteropathic and fewer studies report the presence of anti-gliadin antibodies.[18][19] Other studies found a normal occurrence of AGA in idiopathic peripheral neuropathies.[20] Even among those that advocate gluten-sensitive neuropathies, the effective treatment rate on gluten-free diet is low.[21] In instances where vitamin or mineral deficiencies are involved the recovery rate is substantially higher, however within the coeliac subset of neuropathies and within the idiopathic gluten-sensitive subset the response rate to gluten abstinence is low.[4] One possibility is that enteropathy or gluten sensitivity is causing an autoimmune condition that once triggered becomes irreversible,[7] the other possibility is that transient malnutrition causes damage that is irreversible, and a final possibility is that atypical anti-gliadin antibodies are damaging the nervous system; however such damage should quickly abate on a gluten-free diet.
As early as the 1960s it had been noticed that individuals with coeliac disease have neurological problems sometimes resembling epilepsy[22] Subsequently epilepsy, particularly temporal lobe epilepsy, was found in coeliac disease patients.[23] In the mid 1980s, studies conducted in Southern Europe noticed an association between epilepsy, occipital calcifications, and folic acid deficiency.[24] Such calcifications are also seen in dementia.[25][26] There is a growing body of evidence suggesting that subclinical cases in older adults will typically progress toward dementia,[27] a large number of studies in Italy and Spain have documented earlier onset cases. Though the autoimmune condition is not known, folic acid malabsorption may be the cause.
A number of studies have shown a link between gluten and brain calcifications that are either linked to epileptic disease such as Sturge-Weber syndrome, to a risk of epilepsy, or to visual or auditory problems caused by rare forms of epilepsy. Some of the studies have found celiac disease, while others have found increased anti-gliadin IgA, and still others have found remission or more easily treated disease with the removal of gluten. In the case of epileptic diseases the role of avitaminosis appears to be the key to restoring gastrointestinal function and folic acid and vitamin B12 metabolism. However, there is a gap in the literature as to the extent to which neuropathology is either caused by enteropathy or is the result of anti-gliadin IgA. The involvement of gluten in epilepsy is minor: Aside from the normal risk, the increase of coeliac disease incidence in epilepsy is small, and the idiopathic gluten-sensitive component is smaller still. The increased risk of epilepsy in coeliac disease is also small, but there appear to be substantive differences in the types of epilepsy coeliacs have, and this may extend to people who have idiopathic gluten-sensitivity.
In the early 1990s it was hypothesized that autism can be caused or aggravated by opioid peptides that are metabolic products of gluten.[28] Several treatments based on this hypothesis are widely promoted.[29] Popular diets eliminate foods containing gluten, often in combination with casein; studies supporting these diets have had significant flaws, so the data are inadequate to guide autism treatment recommendations.[30] A recent review of the benefit of gluten-elimination diets indicates studies lack large scale, good quality randomised controlled trials.[31]
Reductions and remissions of schizophrenic symptoms on a gluten-free diet have been noted in a subset of schizophrenic patients.[32][33][34] Many of these definitions were developed when the ability to define Marsh 1 and 2 grades CD was poor; and given the "brain calcification" association with GSE, it is likely that some cases of schizophrenia can be explained by GSE. The associations that remain, in terms of treatment results, appear to be weak.
Anti-gliadin antibodies are often elevated in Chronic fatigue syndrome; however, the study was conducted at a time when it was difficult to diagnose all grades of enteropathy.[35] Significantly increased levels of IgA and IgG antibodies against gliadin and gluten were found in multiple sclerosis compared with controls. IgA antibodies against casein were significantly increased. Anti-endomycium and anti-transglutaminase antibodies were negative.[36] Recent studies indicate that GSE is not associated with multiple sclerosis.[37][38] And other studies question the association with idiopathic disease.[39] A recent study of children with severe cerebral palsy suggest a high percentage have anti-gliadin antibodies[40] A study of patients with neurological myopathies demonstrated large percent were 'gluten sensitive' and many responded favorably with no other treatment.[41] Single studies with no corroborating studies or approaches are often difficult to use as evidence of association. Coeliac disease can cause a broad spectrum of problems, but associating non-enteropathic sensitivity is considerably less certain.
Unlike coeliac disease, there is no developed pathophysiology for gluten-sensitive idiopathic neuropathies. Many studies rely either on the diagnosis of elevated anti-gliadin antibodies or an improvement with the removal of gluten. In either case the disease pathway is unclear. There is currently no consensus whether antigliadin antibodies can cause disease, with the exception of IgE in which it is known that omega-gliadin can mediate anaphylaxis and urticaria. Recently, Synapsin I has been identified as an autoimmune target of crossreactive anti-gliadin antibodies, and possible links to patients with peripheral neuropathies or cerebral ataxia.[42] Other studies show that antigliadin antibodies can cross react with tissue-transglutaminase. These studies have to be considered in light of idiopathic sensitivity, where gluten in removed and anti-gliadin antibodies remain. The key to enteropathy is in the T-cell responses, not antibody responses. Fifteen percent of people with elevated anti-gliadin antibodies do not have coeliac disease, and also may not have enteropathy. In cases where enteropathy is subclinical or underdiagnosed, avitaminosis may play a role. Paralleling the neuropathological gliadin issue, it has been recently shown that removing wheat as well as other allergens identified by RAST testing in autoimmune arthritis patients results in the reduction of certain indicators or disease. With wheat, unidentified allergenic motifs can potentially elicit crossreactive autoantibodies. Another possibility that has precedence in EIA is the possible action of glutens directly on nerves or a combination of IgE or IgA and gluten on these neuronal tissues. The bottom-line on idiopathic sensitivity is there can be many causes from different pathways, most of which have not been thoroughly investigated.
In these studies, less than 65% of AGA positive patients did not have CD indicating, based on the normal random occurrence of AGA, that less than 50% of the idiopathic neuropathy/AGA+ set were idiopathic with regard to anti-gliadin antibodies.[43] Some of these cases are the result of underdiagnosis of coeliac disease or inability to diagnose Marsh grade 1 and 2 CD (subclinical diseases, gluten sensitive enteropathy). An additional critique pointed out that several cases of latent GSE, where associated with neuropathies that appeared as a result of avitaminosis, and were unlikely due to AGA.,[44] but are secondary consequences of GSE. Therefore ~15% of GSE who were neuropathic could be missed due to AGA-/GSE+ exceptions. The same team that introduced these AGA phenomena has also found patients with Neuropathy that are AGA negative but still had CD. Therefore AGA+ may not be directly involved.
Several diagnostic groups report a significance of finding HLA-DQ1, this finding is virtually absent in the peer-reviewed primary literature. In the USA, Caucasian population DQ1 (DQ5 and DQ6) is quite common. A survey of 1899 European derived Americans revealed 30 DR-DQ1 genetic haplotypes, with a combined allele frequency of 40.07%. Hardy-Weinberg principle suggest the random phenotype frequency is 64.1%; however since balancing selection acts on HLA-DQ the phenotype frequency may be slightly higher. There appears to be an uncontestable and elevated DQ2 involved in a few studies, routine testing of idiopathic neuropathies with high resolution DR or DQ typing has not been done.
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