Neurological complications of celiac disease and autoimmune mechanisms: A prospective study

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Abstract

Humoral immune mechanisms may have a role in the neurological complications of celiac disease (CD). We assessed 71 CD patients for neurologic manifestations and presence of serum antibodies to neural antigens. Sixteen patients (22.5%) were found to have neurological deficits including headache, depression, entrapment syndromes, peripheral neuropathy, and epilepsy. Antibody reactivity to neural antigens was detected in 30/71 (42.2%) patients. There was no clear correlation between anti-neural reactivity and neurologic dysfunction. Follow-up of 62 patients did not reveal change in electrophysiology or antibodies, regardless of diet. However, in 2 patients with neuropathy, symptoms improved or worsened depending on the diet.

Introduction

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten proteins in genetically susceptible individuals, with more than 95% of patients carrying the major histocompatibility complex class II human leukocyte antigen (HLA) DQ2 or DQ8 haplotype (Farrell and Kelly, 2002). The enzyme tissue transglutaminase (tTG, TG2) is involved in the generation of T cell stimulatory gluten peptides through deamidation of glutamine residues. It is also the main autoantigen in CD, making anti-tTG antibodies a highly specific marker of the disease (Alaedini and Green, 2008). Intestinal biopsy showing varying degrees of villous atrophy of the small intestinal mucosa that improve after gluten-free diet allows for a definitive diagnosis of the disease. Approximately 50% of adult celiac patients present with extraintestinal manifestations, including iron deficiency anemia, osteoporosis, infertility, and neurological alterations. Peripheral neuropathy and cerebellar ataxia are the most common neurologic deficits in CD (Cooke and Smith, 1966, Chin and Latov, 2005, Hadjivassiliou et al., 2002a). The pathogenesis of neurological damage is poorly understood and the response to gluten-free diet is still controversial (Green et al., 2005). Humoral immune mechanisms have been proposed in the pathogenesis of both ataxia and peripheral neuropathy. Antibodies to gliadin that cross react with Purkinje cells have been inconsistently reported in sera of celiac patients with ataxia, (Hadjivassiliou et al., 2002b, Wiendl et al., 2003, Wurster, 2003) and IgG antibodies to gangliosides have been found in adult CD patients with neuropathy and other neurological manifestations (Chin and Latov, 2005, Alaedini et al., 2002, Volta et al., 2006). A recent study from our group in a cohort of celiac children did not find a correlation between antibodies to gangliosides and neurological manifestations or gluten-free diet (Briani et al., 2004). Different biological and immunological characteristics in childhood and adulthood, however, make it difficult to compare our findings in CD children to those reported in adults. We therefore undertook a prospective study in an adult CD population in order to evaluate the incidence of neurological symptoms or signs, the presence of antibodies to neural antigens, and the correlation of neurological symptoms and anti-neural antibodies with gluten-free diet.

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Patients and methods

Seventy-one unselected consecutive patients (16 men, 55 women, mean age 36.7 ± 12.1 years) with histologically proven CD, were enrolled and prospectively investigated. Of the 71 patients, 69 were referred to our centre from the Department of Surgical and Gastroenterological Science of University of Padova, whereas 2 sought treatment at our clinic for neuropathic symptoms, 1 without a previous diagnosis of CD.

Forty-two patients were on gluten-free diet at recruitment (median duration of diet

Results

At recruitment, neurological manifestations were present in 16 patients (22.5%): 4 had headache, 4 had depression, 4 had entrapment syndromes (carpal tunnel syndrome, 1 also with cubital tunnel syndrome), 3 had sensorimotor peripheral neuropathy, 1 had facial hemispasm. One patient with neuropathy was also affected by epilepsy.

On neurological examination, all the 3 patients with neuropathy (Table 1), had reduced deep tendon reflexes, and two (#2 and #3) had symptoms of neuropathy (cramps at

Discussion

The results of our study demonstrated the presence of neurological complications in 22.5% of patients. However, the relatively common occurrence in the general population of headache, depression, and entrapment neuropathies makes it difficult to define a likely association with CD.

On the other hand, peripheral neuropathy, in clinical and subclinical forms, was present in 3 of 71 CD patients, a frequency which is lower than what is reported in the literature (Luostarinen et al., 2003). Several

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