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  • Updated 11.17.2021
  • Released 03.26.2018
  • Expires For CME 11.17.2024

Neurologic manifestations of celiac disease and gluten sensitivity

Introduction

Overview

The term “gluten-related disorders” refers to a group of autoimmune diseases triggered by the ingestion of gluten in genetically susceptible individuals. The best characterized gluten-related disorder is celiac disease, also known as gluten-sensitive enteropathy. The presence of enteropathy is not a prerequisite for the diagnosis of gluten-related disorders, and most extraintestinal manifestations can present without gastrointestinal symptoms and without enteropathy. Ataxia is the most common neurologic manifestation, followed by peripheral neuropathy. “Gluten encephalopathy” describes the combination of headache, cognitive slowing, and often abnormal MR brain imaging in the context of gluten sensitivity. There are other less common neurologic manifestations, such as myoclonic ataxia, epilepsy with occipital calcifications, and myopathies. This article focuses on the common neurologic manifestations of gluten-related disorders and discusses what is known about the pathophysiology.

Key points

• Up to 67% of patients with celiac disease have neurologic symptoms and signs. Gait instability, headache, and sensory symptoms are the most common.


• Gluten sensitivity without enteropathy is clinically similar. It is much more prevalent and may present with identical neurologic manifestations.


• Celiac disease is an autoimmune disease with a genetic predisposition. “Gluten sensitivity” is an umbrella term that includes celiac disease, dermatitis herpetiformis, and gluten-related neurologic dysfunction.


• These diverse manifestations are a result of autoimmunity against different transglutaminases (transglutaminase 2 in celiac disease, transglutaminase 3 in dermatitis herpetiformis, and transglutaminase 6 in neurologic manifestations).


• Adherence to a gluten-free diet is the main therapeutic intervention for both celiac disease and gluten sensitivity.


• Although the evidence is limited, various immunomodulatory agents can also be used in the treatment of gluten-related disorders.

Historical note and terminology

Gluten-related disorders represent a spectrum of diverse clinical manifestations that share a common trigger—the ingestion of gluten. Most readers will be familiar with celiac disease, also known as gluten-sensitive enteropathy (an enteropathy histologically characterized by the triad of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes). Classic celiac disease is characterized by gastrointestinal symptoms, such as diarrhea, abdominal bloating and pain, weight loss, and malabsorption (54). The evolution of the concept of extraintestinal manifestations first developed with the realization that the skin condition, dermatitis herpetiformis, was treatable with a gluten-free diet. Neurologic manifestations had been described, but the etiology was assumed to be related to malabsorption and vitamin deficiencies. In 1996, Hadjivassiliou and colleagues published a study demonstrating the high prevalence of gluten sensitivity with and without enteropathy amongst patients with neurologic dysfunction of unknown cause (30). The majority of serologically positive patients had idiopathic ataxia or idiopathic peripheral neuropathy. Because all patients improved on a strict gluten-free diet, it was obvious that the presence of enteropathy was irrelevant to the neurologic manifestations of gluten sensitivity. Apart from ataxia and neuropathy, additional manifestations include gluten encephalopathy and other less common neurologic deficits (41). Such neurologic manifestations are increasingly seen in clinical practice in the absence of gastrointestinal symptoms and enteropathy.

Serological evidence of gluten sensitivity defined by the presence of anti-gliadin antibodies, but in the absence of enteropathy, has previously been largely ignored by gastroenterologists. However, there has been an improved understanding of this entity in the last few years, primarily based on the observation that such patients also benefit symptomatically from a gluten-free diet. Terms like “non-celiac gluten sensitivity” or “non-celiac wheat sensitivity” were introduced to describe patients with primarily gastrointestinal symptoms triggered by the ingestion of gluten and who do not have enteropathy but symptomatically benefit from a gluten-free diet (67). Such patients, usually under the care of gastroenterologists, are not necessarily routinely tested for all gluten sensitivity–related antibodies. By contrast, when it comes to neurologic manifestations, the definition of gluten sensitivity is based on positive serology in the form of native anti-gliadin IgG or IgA, or transglutaminase 6 IgG or IgA, antibodies with or without positivity for transglutaminase 2 or endomysial antibodies (41). Some, but not all, of these patients will also have enteropathy. Those with enteropathy are usually positive for transglutaminase 2 and endomysial antibodies.

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