Neurologic complications of celiac disease

Caroline Miranda MD (

Dr. Miranda of Weill Medical College of Cornell University has no relevant financial relationships to disclose.

)
Russell L Chin MD (Dr. Chin of Weil Medical College of Cornell University has no relevant financial relationships to disclose.)
Francesc Graus MD PhD, editor. (Dr. Graus of the University of Barcelona has no relevant financial relationships to disclose.)
Originally released March 26, 2018; expires March 26, 2021

This article includes discussion of neurologic complications of celiac disease, gluten sensitivity, or gluten intolerance, non-celiac gluten sensitivity, gluten enteropathy; complications include cerebellar ataxia, peripheral neuropathy, headache, migraine, progressive myoclonic ataxic syndrome, epilepsy, seizures, myopathy, myelopathy, stiff person syndrome, and psychiatric disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Celiac disease is an autoimmune condition triggered by exposure and reaction to gluten with evidence of enteropathy on small intestinal biopsy. It can lead to an array of clinical symptoms, with up to 22% of patients exhibiting neurologic or psychiatric symptoms, most commonly ataxia and peripheral neuropathy. Rarer complications include epilepsy and myopathy, among others. In gluten sensitivity, patients react negatively to gluten consumption but do not necessarily have the hallmark pathology seen in the small intestine. In gluten sensitivity, patients may also exhibit neurologic symptoms.

In this article, the authors explore reported neurologic complications of gluten-related disorder (celiac disease or gluten sensitivity), including cerebellar ataxia, peripheral neuropathy, seizure disorders, schizophrenia, depression, migraine, anxiety, attention deficit hyperactivity disorder, autism, myasthenia gravis, and myopathy (Jackson et al 2012).

Key points

 

• Up to 22% of patients with celiac disease have neuropsychiatric manifestations, with ataxia and peripheral neuropathy being the most common.

 

• Gluten sensitivity is clinically similar to but does not meet the diagnostic criteria for celiac disease; it is 6 times more prevalent and may also have neurologic manifestations.

 

• Celiac disease is a genetic autoimmune disease; gluten sensitivity is less well understood.

 

• Vitamin deficiencies, often comorbid with gluten-related disease, rarely play a role in the pathophysiology of the disease.

 

• 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

Celiac disease is triggered by exposure and reaction to two components of gluten (gliadin and glutenin), and its symptoms frequently abate if the affected patient adopts a gluten-free diet by abstaining from wheat, rye, and barley food products (Sapone et al 2012). The estimated prevalence of celiac disease is about 0.7% to 1% (Fasano and Catassi 2012; Kim et al 2016), and affected patients classically present with myriad gastrointestinal complaints (diarrhea, abdominal pain, bloating, and weight loss). Small intestinal biopsy demonstrates hallmark signs of the disease, such as villous atrophy, crypt hyperplasia, increased intraepithelial lymphocytes, or increased expression of interleukin 17A (Catassi and Fasano 2010; Sapone et al 2012).

Up to 22% of patients with celiac disease develop neurologic or psychiatric dysfunction. Some initially present with these symptoms or other extraintestinal manifestations of the disease and may lack small intestine pathology (Briani et al 2008). However, there are several serological screening markers that aid in celiac disease diagnosis, including anti-transglutaminase (tTG), anti-endomysial (EMA), and anti-gliadin antibodies (AGA). Human leukocyte antigen (HLA) typing also shows HLA-DQ2 or HLA-DQ8 in the vast majority of patients with celiac disease (Dieli-Crimi et al 2015). An additional HLA, DQ9, was associated with celiac disease (Bodd et al 2012). Discovery of these clinical, histological, serological, and genetic features supports a celiac disease diagnosis.

Beyond celiac disease, additional immune-mediated disorders relating to gluten have been observed. Gluten allergy is an IgE-mediated immune reaction characterized by asthma and various dermatological symptoms. In cases of gluten sensitivity, as in cases of celiac disease, patients react negatively to gluten consumption and benefit from a gluten-free diet. Gluten sensitivity is 6 times more prevalent than celiac disease and is likely mediated by innate immune mechanisms rather than adaptive ones (Hadjivassiliou et al 2002b; Sapone et al 2011). Small intestine biopsy is normal, and serologies are often negative, although up to 40% of patients have positive AGA titers (Kaukinen et al 2000; Hadjivassiliou et al 2004; Sapone et al 2012). Further, about 50% of patients have HLA DQ2 or DQ8 present, which is significantly higher than the general population (Bizzaro et al 2012).

Patients with gluten sensitivity, like those with celiac disease, often present with extraintestinal symptoms, which is integral in our understanding of the pathophysiology of neurologic complications seen in gluten-related immune disease. Specifically, several studies demonstrate direct immune activity in muscle, peripheral nerves, dorsal root ganglia, spinal cord, brainstem, cerebellum, and brain (Hadjivassiliou et al 2006a; Hadjivassiliou et al 2010a; Leeds et al 2011; Hadjivassiliou et al 2014). This suggests that neurologic complications in gluten-related disorders result from immune-mediated mechanisms rather than being sequelae of enteropathy, such as vitamin and nutrient malabsorption. In fact, the majority of patients with gluten-related disease who present with neurologic complications lack gastrointestinal symptoms (Hadjivassiliou et al 2014).

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