By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Gluten neuropathy should be suspected in any patient who presents with a neuropathy and has a history of gastrointestinal disease. The diagnosis is made using blood serology plus intestinal mucosal biopsy.
SOURCE: Zis P, Sarrigiannis P, Artemiadis A, et al. Gluten neuropathy: Electrophysiological progression and HLA associations. J Neurol 2021;268:199-205.
Sensitivity to dietary gluten and related proteins in genetically predisposed persons carrying human leukocyte antigen (HLA) DR3-DQ2 and/or DR4-DQ8, results in an immune-mediated small bowel inflammatory disease, known as celiac disease or gluten-sensitive enteropathy, classically manifesting with gastrointestinal symptoms, including diarrhea, flatulence, and weight loss, but also with neuropsychiatric symptoms including peripheral neuropathy, headache, ataxia, epilepsy, depression, and anxiety. Describing the progression of gluten neuropathy (GN) over time, and the role of genetic susceptibility in its development, were the aims of this study.
Conducted at the Sheffield Institute of Gluten Related Diseases, Sheffield, UK, this cohort study involved 45 GN patients, over a mean follow-up period of 8 ± 5 years. Inclusion criteria required patients age 18 years or older who were able to provide written consent, with serologic evidence of gluten sensitivity (antigliadin immunoglobulin G [IgG] and/or immunoglobulin A [IgA], endomysial, or transglutaminase antibodies), electrodiagnostically proven peripheral neuropathy, and absence of other potential causes of neuropathy. Normalization of circulating antigliadin IgG and/or IgA, endomysial, and/or transglutaminase antibodies was considered evidence of adherence to a strict gluten-free diet.
All patients underwent an electrodiagnostic study at enrollment and another at least one year later. Using sequence-specific primers, HLA-DQ typing was performed using the polymerase chain reaction. Statistical analysis included Fisher’s exact test, the Mann-Whitney U test, the Chi-square test, and Yates correction as appropriate.
Among 45 consecutive patients with GN, 73.3% were male, the mean age of onset was 56 ± 12 years, and the mean age of diagnosis was 60 ± 12 years. Numbness (36%), tingling (18%), and pain (13%) were the most common initial symptoms, with 9% presenting with weakness and/or fasciculations. Length-dependent neuropathy was seen in 75.6%, and sensory ganglionopathy in the remainder, with the former more likely to carry the DQB1*06 allele and the DQA1*01/DQB1*06 haplotype, and the latter more likely to be DQA1*02-positive rather than negative (P = 0.009).
Nerve conduction studies showed a linear deterioration over time in the amplitudes of the radial and sural sensory nerves and tibial motor nerves, independent of age or gender. Gluten neuropathy is a late manifestation of gluten intolerance, it usually is a length-dependent neuropathy that deteriorates in a linear fashion over time, and HLA genotyping can help identify patients at risk for developing this complication.
Although the pathogenesis of celiac disease remains unclear, the gastrointestinal microbiome composition may play a central role. Ingestion of gluten is needed to initiate the disease, and recent evidence suggests that earlier age of disease onset may be related to the amount of gluten ingested in infancy. Abnormal permeability of the intestinal lining, perhaps a consequence of intestinal viral infection, allows entry of incompletely degraded gliadin peptides, and this is thought to be the initial event in disease pathogenesis.
Gliadin appears to have a direct toxic effect on the mucosa, resulting in immediate modification, within an hour, of the mucosal microenvironment, followed by involvement of T cells and full-blown mucosal changes characteristic of the disease. Although serologic markers are highly specific for the diagnosis, confirmation in adults still requires duodenal biopsies, although for the pediatric population, a “biopsy avoidance strategy” is afoot.
Therapeutic trials currently in progress offer promising nondietary treatment for celiac patients, including latiglutenase, an orally administered mixture of two enzymes that degrade gluten proteins.