Chapter 41 - Gluten-related neurologic dysfunction

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Abstract

The term gluten-related disorders (GRD) encompasses a spectrum of systemic autoimmune diseases with diverse manifestations. GRD are characterized by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Celiac disease (CD) or gluten-sensitive enteropathy is only one of a number of GRD. Extraintestinal manifestations include dermatitis herpetiformis (DH) and neurologic dysfunction. Furthermore it is only recently that the concept of extraintestinal manifestations without enteropathy has become accepted. In this chapter we review the spectrum of neurologic manifestations in GRD, discuss recent advances in their diagnosis, and look at their possible pathophysiologic mechanisms.

Section snippets

Historical perspective

Celiac disease (CD) was first described by the Greek doctor Aretaeus the Cappadocian, in ad 100, only to be forgotten and then rediscovered by Samuel Gee in 1888 (Gee, 1888). In a lecture on “the coeliac affection,” Gee described the classic pediatric presentation of the disease. Whilst clinicians began to recognize this disease entity, the etiologic agent remained obscure until the observations of Willem Dicke, a Dutch pediatrician, in 1953 of “the presence in wheat, of a factor having a

Epidemiology of neurologic manifestations

The prevalence of CD in the healthy population has been shown to be at least 1% in both European and North American studies (Sanders et al., 2003). There are no accurate figures of the prevalence of the neurologic manifestations of gluten sensitivity in the general population. Figures of between 10% and 22.5% have been reported amongst patients with established CD attending gastrointestinal clinics (Holmes, 1997, Briani et al., 2008). These are unlikely to be accurate because such figures are

The diagnosis of gluten-related diseases

CD is characterized by the presence of an enteropathy, a reliable gold standard. It is now accepted, however, that an enteropathy is not a prerequisite for the diagnosis of GRD with predominantly neurologic or other extraintestinal manifestations. Furthermore, the small bowel mucosal changes in the context of GRD represent a spectrum, from histologically normal mucosa to full-blown enteropathy to a pre-lymphomatous state also referred to as the Marsh classification (Marsh, 1992). Most pathology

Gluten ataxia

Gluten ataxia (GA) was originally defined as otherwise idiopathic sporadic ataxia with positive AGA (Hadjivassiliou et al., 2003a). This original definition was based on the serologic tests available at the time. In a series of 853 patients with progressive ataxia evaluated over a period of 15 years in Sheffield, UK, there were 152 patients out of 681 with sporadic ataxia who had serologic evidence of GRD. Therefore gluten ataxia had a prevalence of 22% amongst sporadic ataxias but as high as

Pathogenesis

Current evidence suggests that neurologic manifestations are immune mediated. Postmortem examination from patients with gluten ataxia demonstrate patchy loss of Purkinje cells throughout the cerebellar cortex, a nonspecific finding in many cerebellar disorders. However, additional findings supporting an immune-mediated pathogenesis include diffuse infiltration mainly of T lymphocytes within the cerebellar white matter as well as marked perivascular cuffing with inflammatory cells (

Conclusions

GRD include immune-mediated diseases triggered by ingestion of gluten proteins. While celiac disease has been the most comprehensively studied of all GRD, dermatitis herpetiformis and neurologic manifestations are the commonest extraintestinal manifestations. To fully understand the immunologic insults resulting from gluten ingestion, the emphasis should perhaps shift toward the study of extraintestinal manifestations. In addition there is a need for the early identification of those patients

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